Conditions: Multiple Myeloma
Keywords: GSK2857916, Pembrolizumab, Multiple Myeloma, RP2D
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This is a phase I/II, single arm, open label, two-part study that will assess safety, tolerability and clinical activity of GSK2857916 given in combination with a programmed cell death-1 (PD-1) inhibitor pembrolizumab in subjects with RRMM. This study will enroll adult subjects with RRMM, who have undergone stem cell transplant or who are considered transplant ineligible. Part 1 is a dose escalation phase to evaluate the safety and tolerability of escalating doses of GSK2857916 in combination with 200 milligrams (mg) pembrolizumab to establish the recommended phase 2 dose (RP2D). The following dose levels of GSK2857916 are planned to be studied: 2.5 milligrams per kilograms (mg/kg) (dose level \[DL\] 1) and 3.4 mg/kg (DL2). Part 2 is a dose expansion cohort. Once the RP2D has been identified, an expansion cohort will open for enrolment to confirm the safety profile and to evaluate the clinical activity of the combination. Up to 40 evaluable subjects will be enrolled in this two-part study (up to 12 in Part 1, and 28 in Part 2).

Detailed description:

Arms:
arm 1: Subjects will receive belantamab mafodotin at escalating doses of 2.5 milligrams per kilograms (mg/kg) and 3.4 mg/kg along with 200 mg pembrolizumab via intravenous (IV) infusion on Day 1 of each 21-day cycle to establish RP2D. There will be maximum of 35 cycles of combination treatment. arm 2: Subjects will receive belantamab mafodotin at RP2D along with 200 mg pembrolizumab via IV infusion on Day 1 of each 21-day cycle. There will be maximum of 35 cycles of combination treatment.

Interventions: intervention 1: belantamab mafodotin intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: belantamab mafodotin will be available as 20 milligrams per millilitre (mg/mL) solution for IV infusion, supplied as frozen liquid. belantamab mafodotin solution will be diluted in normal 0.9% saline to the appropriate concentration for the dose. intervention 2: Pembrolizumab will be available as 100 mg/4 mL solution that should be stored under refrigeration at 2-8 degree Celsius. Pembrolizumab injection (solution) will be diluted prior to IV administration in 0.9% sodium chloride injection or 5% dextrose injection.

Protocol document:
Prot_000.pdf: 
TMF-14344600 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
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Protocol Amendment 04 
 
1 
 
TITLE PAGE 
Division: Worldwide Development 
Information Type: Protocol Amendment 
Title: 
A Phase I/II Single Arm Open-Label Study to Explore Safety 
and Clinical Activity of GSK2857916 Administered in 
Combination with Pembrolizumab in Subjects with 
Relapsed/Refractory Multiple Myeloma (DREAMM 4) 
Protocol Number: 
205207/Amendment 04 
Compound 
Number: 
GSK2857916 
Development 
Phase: 
I/II 
Sponsor Name and 
Legal Registered 
Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline 
Affiliate Company (or designee). If applicable, the details of the alternative Sponsor 
and contact person in the territory will be provided to the relevant regulatory authority 
as part of the clinical trial application. 
Medical Monitor Name and Contact Information: Can be found in Study 
Reference Manual 
Regulatory Agency 
Identifying 
Number(s): 
 
Registry 
ID 
IND number 
119333 
EudraCT number 
2018-002816-29 
Effective Date: 
21-FEB-2022 
 
Copyright 2022 GSK group of companies or its licensor. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


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SPONSOR SIGNATORY 
Title: 
A Phase I/II Single Arm Open-Label Study to Explore Safety 
and Clinical Activity of GSK2857916 Administered in 
Combination with Pembrolizumab in Subjects with 
Relapsed/Refractory Multiple Myeloma (DREAMM 4) 
Protocol Number: 
205207/ Amendment 04 
Compound 
Number: 
GSK2857916 
 
 
 
 
 
 
 
 
 
 
 
 
                            21-FEB-2022 
 
Timothy Crossman, BMBS MRes  
 
 
 
 
 
Date 
Group Sr. Director, Clinical Development Lead 
 
 
 
 
The signed page is a separate document. 
 
 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment No. 4 
21-FEB-2022 
TMF-14344600 
Amendment No. 3 
27-AUG-2021 
TMF-12902367 
Amendment No. 2 
26-FEB-2020 
2016N273410_02 
Amendment No. 1 
26-SEP-2018 
2016N273410_01 
Original Protocol 
11-MAY-2017 
2016N273410_00 
 
Amendment [04] [21-FEB-2022] 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
The protocol has been amended to provide updates including the addition of the end of 
study definition section (Section 5.5.2) and continued access to study intervention after 
the end of the study section (Post Analysis Continued Treatment [PACT]) (Section 6.13). 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1: 
PROTOCOL 
Synopsis for Study 
205207 
Additional content to the overall study has 
been added which includes PACT 
implementation and End of Study 
definition 
To allow continued treatment 
of study participants post 
final analysis   
Section 2.2.5.1: 
Pharmacokinetics and 
Pharmacodynamics 
Revision of pharmacokinetics and 
pharmacodynamics section as per latest 
information available in IB 
Section updated as per latest 
information available in IB 
Section 4.6.1:   
Risk Assessment and 
Mitigation Strategy 
Additional content added to keratopathy, 
nephrotoxicity, and ovarian toxicity 
Updated the data/rationale 
for risk assessment 
Section 5.5.2:  
End of Study 
Definition 
End of Study section added to align with 
PACT implementation and additional 
content added related to PACT 
To allow continued treatment 
of study participants post 
final analysis   
Section 6.13:  
Continued Access to 
Study Intervention 
after the End of the 
Study 
New section added to align to PACT 
implementation and additional content 
added related to PACT 
To allow continued treatment 
of study participants post 
final analysis   


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.3.1.1: 
Time Period and 
Frequency for 
Collecting AE and 
SAE Information  
Additional content added to align to PACT 
implementation 
To allow continued treatment 
of study participants post 
final analysis   
 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
SPONSOR SIGNATORY ................................................................................................ 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS .................................................................................................. 5 
1. 
PROTOCOL SYNOPSIS FOR STUDY 205207 ........................................................ 9 
2. 
INTRODUCTION .................................................................................................... 24 
2.1. 
Study Rationale .......................................................................................... 24 
2.2. 
Belantamab mafodotin ................................................................................ 27 
2.2.1. 
Nonclinical Pharmacology ............................................................ 27 
2.2.2. 
Nonclinical Pharmacokinetics Metabolism of Belantamab 
Mafodotin ..................................................................................... 27 
2.2.3. 
Toxicology of belantamab mafodotin (GSK2857916) ................... 27 
2.2.4. 
Genotoxicity of belantamab mafodotin (GSK2857916)................. 27 
2.2.5. 
Effects in Humans (belantamab mafodotin) ................................. 28 
2.3. 
Pembrolizumab ........................................................................................... 31 
2.3.1. 
Pharmaceutical and Therapeutic Background .............................. 31 
2.3.2. 
Pre-Clinical Pharmacology of Pembrolizumab ............................. 31 
2.3.3. 
Pembrolizumab Background ........................................................ 32 
2.4. 
Assessment of Nonclinical Data for Belantamab Mafodotin when 
Co-Administered with Pembrolizumab ........................................................ 32 
3. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 33 
4. 
STUDY DESIGN .................................................................................................... 37 
4.1. 
Overall Design ............................................................................................ 37 
4.2. 
Study Treatment and Duration .................................................................... 37 
4.2.1. 
Study Treatment .......................................................................... 37 
4.2.2. 
Duration of Treatment .................................................................. 38 
4.2.3. 
Part 1: Dose-Escalation ............................................................... 38 
4.3. 
Type and Number of Subjects ..................................................................... 41 
4.4. 
Design Justification ..................................................................................... 41 
4.5. 
Dose Justification ........................................................................................ 42 
4.5.1. 
Belantamab Mafodotin Starting Dose Justification ....................... 42 
4.5.2. 
Pembrolizumab Dose Justification ............................................... 42 
4.6. 
Benefit: Risk Assessment ........................................................................... 43 
4.6.1. 
Risk Assessment ......................................................................... 44 
4.6.2. 
Benefit Assessment ..................................................................... 51 
4.6.3. 
Overall Benefit: Risk Conclusion .................................................. 51 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ............. 52 
5.1. 
Inclusion Criteria ......................................................................................... 52 
5.2. 
Exclusion Criteria ........................................................................................ 54 
5.3. 
Screening Failures ...................................................................................... 56 


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5.4. 
Withdrawal/Stopping Criteria....................................................................... 57 
5.4.1. 
Safety stopping criteria ................................................................ 58 
5.5. 
Subject and study Completion .................................................................... 62 
5.5.1. 
Subject completion ...................................................................... 62 
5.5.2. 
End of Study Definition ................................................................ 62 
5.5.3. 
Treatment after the End of Study ................................................. 63 
6. 
INVESTIGATIONAL PRODUCT ............................................................................. 63 
6.1. 
Investigational Products .............................................................................. 63 
6.2. 
Medical Devices .......................................................................................... 64 
6.3. 
Treatment Assignment ................................................................................ 64 
6.3.1. 
Study Treatment Administration ................................................... 64 
6.4. 
Planned Dose Adjustments ......................................................................... 65 
6.4.1. 
Adjustments due to body weight .................................................. 65 
6.4.2. 
Intra subject dose escalation........................................................ 66 
6.5. 
Subject Specific Dose Adjustment Criteria .................................................. 66 
6.5.1. 
Dose modifications and management for belantamab 
mafodotin-related toxicity ............................................................. 66 
6.5.2. 
Dose modification and toxicity management for immune-
related AEs associated with pembrolizumab ................................ 71 
6.5.3. 
Dose modification and toxicity management of infusion-
reactions related to pembrolizumab ............................................. 75 
6.6. 
Blinding ....................................................................................................... 78 
6.7. 
Packaging and labelling/Preparation/Handling/Storage ............................... 78 
6.7.1. 
Belantamab Mafodotin ................................................................. 78 
6.7.2. 
Pembrolizumab ............................................................................ 79 
6.8. 
Product Accountability ................................................................................ 80 
6.9. 
Compliance with Study Treatment Administration ....................................... 80 
6.10. 
Treatment of Investigational Product Overdose .......................................... 80 
6.11. 
Lifestyle and/or Dietary Restrictions ............................................................ 82 
6.11.1. 
Contraception .............................................................................. 82 
6.11.2. 
Subjects with Contact Lenses ...................................................... 82 
6.12. 
Concomitant Medications/Vaccinations and Non-Drug Therapies ............... 83 
6.12.1. 
Permitted Medication(s) ............................................................... 83 
6.12.2. 
Tumor Lysis Syndrome (TLS) Prevention and Treatment 
Recommendations ....................................................................... 83 
6.12.3. 
Supportive Care Guidelines for Corneal Events 
(Belantamab Mafodotin) ............................................................... 84 
6.12.4. 
Supportive Care Guidelines for Pembrolizumab........................... 84 
6.12.5. 
Prohibited Medication(s) .............................................................. 85 
6.13. 
Continued Access to Study Intervention after the End of the Study ............ 85 
7. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 87 
7.1. 
Screening and Critical Baseline Assessments ............................................ 98 
7.2. 
Efficacy ....................................................................................................... 98 
7.3. 
Safety ....................................................................................................... 100 
7.3.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) ........ 100 
7.3.2. 
Pregnancy ................................................................................. 107 
7.3.3. 
Medical Device Incidents (including malfunctions) ..................... 107 
7.3.4. 
Physical Exams ......................................................................... 107 
7.3.5. 
Ocular Examinations and Procedures ........................................ 107 


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7.3.6. 
ECOG Performance Status ........................................................ 108 
7.3.7. 
Vital Signs .................................................................................. 108 
7.3.8. 
Electrocardiogram ...................................................................... 109 
7.3.9. 
Echocardiogram......................................................................... 109 
7.3.10. 
Clinical Safety Laboratory Assessments .................................... 109 
7.3.11. 
Suicidal Risk Monitoring ............................................................. 112 
7.3.12. 
Patient-Reported Outcome Version of the Common Term 
Criteria for Adverse Events (PRO-CTCAE) ................................ 112 
7.3.13. 
Visual Function Questionnaires (VFQ) and Ocular Surface 
Disease Index (OSDI). ............................................................... 112 
7.4. 
Pharmacokinetics ..................................................................................... 113 
7.4.1. 
Blood Sample Collection for Pharmacokinetics .......................... 113 
7.4.2. 
Pharmacokinetic Sample Analysis ............................................. 114 
7.5. 
Biomarkers ............................................................................................... 114 
7.5.1. 
sBCMA Analysis ........................................................................ 114 
7.5.2. 
Cytokine and Chemokine Analysis ............................................. 115 
7.5.3. 
Subject Stratification/Predictive Biomarkers ............................... 115 
7.5.4. 
Tumor Biomarker Analysis ......................................................... 116 
7.5.5. 
Circulating Cell Free DNA (cfDNA) Analysis .............................. 116 
7.5.6. 
Immunogenicity Assessments .................................................... 116 
7.6. 
Genetics ................................................................................................... 116 
7.7. 
Value Evidence and Outcome ................................................................... 117 
7.7.1. 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 30-item Core module 
(EORTC QLQ-C30) ................................................................... 117 
7.7.2. 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 20-item Multiple 
Myeloma module (EORTC QLQ-MY20) ..................................... 117 
7.7.3. 
Exit Interview ............................................................................. 118 
8. 
DATA MANAGEMENT ......................................................................................... 118 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................... 118 
9.1. 
Hypothesis(es) .......................................................................................... 119 
9.1.1. 
Part 1: Dose-Escalation Phase .................................................. 119 
9.1.2. 
Part 2: Expansion cohort ............................................................ 119 
9.2. 
Sample Size Considerations ..................................................................... 119 
9.2.1. 
Part 1: Dose-Escalation Phase .................................................. 119 
9.2.2. 
Part 2: Expansion Cohort ........................................................... 119 
9.3. 
Sample Size Sensitivity ............................................................................. 119 
9.3.1. 
Sample Size Re-estimation or Adjustment ................................. 119 
9.4. 
Data Analysis Considerations ................................................................... 120 
9.4.1. 
Analysis Populations .................................................................. 120 
9.5. 
Interim Analysis ........................................................................................ 120 
9.5.1. 
Part 1: Dose Escalation ............................................................. 120 
9.5.2. 
Part 2: Expansion ...................................................................... 120 
9.6. 
Primary Analysis ....................................................................................... 122 
9.7. 
Final Analysis ........................................................................................... 122 
9.8. 
Key Elements of Analysis Plan ................................................................. 122 
9.8.1. 
Clinical Activity Analyses ........................................................... 122 
9.8.2. 
Safety Analyses ......................................................................... 124 


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9.8.3. 
Pharmacokinetic Analyses ......................................................... 125 
9.8.4. 
Pharmacokinetic/Pharmacodynamic Analyses ........................... 126 
9.8.5. 
Translational Research Analyses ............................................... 126 
9.8.6. 
Immunogenicity Assessment ..................................................... 127 
10. STUDY GOVERNANCE CONSIDERATIONS ...................................................... 127 
10.1. 
Posting of Information on Clinicaltrials.gov ................................................ 127 
10.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...................................................................................... 127 
10.3. 
Urgent Safety Measures ........................................................................... 128 
10.4. 
Quality Control (Study Monitoring) ............................................................ 128 
10.5. 
Quality Assurance ..................................................................................... 129 
10.6. 
Study and Site Closure ............................................................................. 129 
10.7. 
Records Retention .................................................................................... 129 
10.8. 
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................. 130 
10.9. 
Review Committees .................................................................................. 130 
10.9.1. 
Internal Safety Review Committee ............................................. 130 
11. REFERENCES ..................................................................................................... 131 
12. APPENDIX ........................................................................................................... 137 
12.1. 
Appendix 1: Abbreviations and Trademarks .............................................. 137 
12.2. 
Appendix 2: ECOG Performance Status1 .................................................. 141 
12.3. 
Appendix 3:  Modified Diet in Renal Disease Formula .............................. 142 
12.4. 
Appendix 4: NYHA Functional Classification System ................................ 143 
12.5. 
Appendix 5:  Liver chemistry stopping and monitoring criteria and 
required actions and follow up assessments ............................................. 144 
12.5.1. 
Liver chemistry stopping criteria ................................................. 144 
12.5.2. 
Liver Safety Drug Restart or Rechallenge Guidelines ................ 146 
12.6. 
Appendix 6:  Genetic Research ................................................................ 150 
12.7. 
Appendix 7:  Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events .......................... 153 
12.8. 
Appendix 8:  Contraceptive Guidance and Collection of Pregnancy 
Information Definitions .............................................................................. 160 
12.9. 
Appendix 9: Belantamab Mafodotin associated Corneal Event 
Severity Grading and Mitigation Strategy .................................................. 163 
12.10. Appendix 10: Country Specific Requirements ........................................... 166 
12.11. Appendix 11: Operating Characteristics of Safety Stopping Rule for 
Expansion Cohort ..................................................................................... 167 
12.12. Appendix 12: Sample Size Calculation for the Expansion Cohort ............. 168 
12.13. Appendix 13: Data Management/Monitoring ............................................. 169 
12.14. Appendix 14: Protocol Amendment History ............................................... 170 
 


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1. 
PROTOCOL SYNOPSIS FOR STUDY 205207 
Rationale 
This is a phase I/II, single arm, open label, two-part study that will assess safety, 
tolerability and clinical activity of belantamab mafodotin (previously referred to as 
GSK2857916) given in combination with a programmed cell death-1 (PD-1) inhibitor 
pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM).  
Belantamab mafodotin is a humanized (IgG1) antibody drug conjugate (ADC), which 
binds specifically to B cell maturation antigen (BCMA). The antibody is conjugated to 
the microtubule inhibitor monomethyl auristatin-F (MMAF) to result in an ADC 
molecule. Belantamab mafodotin has been produced in an afucosylated form to generate 
an enhanced antibody dependent cellular cytotoxicity (ADCC). This dual mechanism of 
action is expected to improve clinical activity by targeting dividing (ADC) and non-
dividing tumor cells (ADCC). 
B-cell maturation antigen expression is restricted to B cells at later stages of 
differentiation [Darce, 2007] and according to GSK internal data all patients with MM 
express various levels of BCMA on the surface of the tumor cells. In addition, 
GSK2857916 belantamab mafodotin was shown to induce immunogenic cell death (ICD) 
characterized by expression of ecto-Calreticulin, release of adenosine tri phosphate 
(ATP), and secretion of HMGB1 in BCMA expressing multiple myeloma cell line (GSK 
unpublished data). Treatment of mice harbouring syngeneic tumors derived from the EL4 
lymphoma cell line expressing human BCMA (EL4-hBCMA) with belantamab 
mafodotin delays tumor growth and promotes durable regressions. Mice which responded 
remained immune to re-challenge suggesting an engagement of the host immune system 
and immunologic memory, providing a strong rationale for clinical combinations with 
immuno-modulatory agents (GSK unpublished data). Exposure of dendritic cells to tumor 
cells undergoing ICD evokes an inflammatory phenotype (innate response), where 
mature dendritic cells (DCs) are activated and may induce an antigen-specific T cell 
response. It is hypothesized that the T cell dependent anti-tumor response induced by 
belantamab mafodotin can be further augmented by PD-1 inhibitor, pembrolizumab when 
both drugs are used in combination.  
Objective(s)/Endpoint(s) 
Part 1: Dose Escalation 
Objectives 
Endpoints 
Primary 
• 
To determine safety, tolerability and to 
establish the recommended Phase 2 dose 
(RP2D) of the combination of belantamab 
mafodotin and pembrolizumab in subjects 
with RRMM   
• 
Percent of subjects with adverse events 
(AEs), changes in clinical signs and 
laboratory parameters 
• 
Number of subjects with dose limiting 
toxicities (DLTs) 


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Objectives 
Endpoints 
Secondary 
• 
To evaluate clinical activity of the combination 
of belantamab mafodotin and pembrolizumab 
in subjects with RRMM 
• 
Overall Response Rate (ORR), defined as 
the percentage of subjects with a confirmed 
partial response (PR) or better (i.e., PR, very 
good partial response [VGPR], complete 
response [CR] and stringent complete 
response [sCR]), according to the 
International Myeloma Working Group 
(IMWG) Response Criteria [Kumar, 2016] 
• 
To evaluate the pharmacokinetic profile of 
belantamab mafodotin when administered 
intravenously in combination with 
pembrolizumab1 
• 
Pharmacokinetic (PK) parameters following 
IV administration as data permit. 
• 
To assess anti-drug antibodies (ADAs) 
against belantamab mafodotin1 
• 
Incidence and titers of ADAs against 
belantamab mafodotin 
Exploratory 
• 
To assess Minimal Residual Disease (MRD) 
in subjects who achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity 
rate, defined as: the percentage of subjects 
who are MRD negative in subjects who 
achieve VGPR or CR 
• 
To characterize the relationship between 
clinical response and other biologic 
characteristics  
• 
BCMA expression levels on malignant cells, 
serum sBCMA levels, serum cytokines, and 
immune cell characterization and their 
relationship to clinical response (Protein, 
RNA, DNA analysis) 
• 
To investigate the relationship between 
genetic variants in the host and response to 
belantamab mafodotin in combination with 
pembrolizumab  
• 
Possible relationship between host genetic 
variation and response to belantamab 
mafodotin in combination with pembrolizumab 
• 
To evaluate the tolerability of belantamab 
mafodotin in combination with pembrolizumab 
based on patient self-report of symptomatic 
adverse effects 
• 
Symptomatic adverse effects as measured by 
the Patient-reported outcome version of the 
Common Term Criteria for Adverse Events 
(PRO-CTCAE) 
• 
Impact of ocular adverse effects on quality of 
life as measured by the Visual Function 
questionnaire(s): National Eye Institute 25-
item Visual Function Questionnaire (NEI-
VFQ-25) and Ocular Surface Disease Index 
(OSDI) 
• 
To evaluate disease and treatment related 
symptoms and associated impacts on 
function and health-related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered only in case of unexpected clinical findings.  
 


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Part 2: Expansion 
Objectives 
Endpoints 
Primary 
• 
To assess the clinical activity of the 
combination treatment with 
belantamab mafodotin and 
pembrolizumab in subjects with 
RRMM   
• 
Overall Response Rate (ORR), defined as the 
percentage of subjects with a confirmed PR or better 
(i.e., PR, VGPR, CR and sCR), according to the IMWG 
Response Criteria [Kumar, 2016]. 
Secondary 
• 
To further evaluate safety of 
belantamab mafodotin administered 
in combination with pembrolizumab 
in subjects with RRMM 
• 
Number (percent) of subjects with AEs, changes in 
clinical signs and laboratory parameters 
• 
Ocular findings on ophthalmic exam 
• 
To further characterize the clinical 
activity of the combination 
treatment with belantamab 
mafodotin and pembrolizumab in 
subjects with RRMM 
• 
Clinical benefit rate (CBR), defined as the percentage 
of subjects with a confirmed minimal response (MR) or 
better per IMWG  
• 
Duration of response (DoR), defined as: the time from 
first documented evidence of PR or better to the time 
when disease progression (PD) is documented per 
IMWG, or death due to PD among subjects who 
achieve an overall response, i.e. confirmed PR or 
better. 
• 
Time to response (TTR), defined as: the time between 
the date of first dose and the first documented evidence 
of response (PR or better) among subjects who 
achieved a confirmed response of PR or better. 
• 
Time to best response, defined as the time between the 
date of first dose and the first best documented 
response (PR or better) among subjects who achieve a 
confirmed response of PR or better. 
• 
Progression-free survival (PFS), defined as: the time 
from first dose to the earliest date of PD per IMWG, or 
death due to any cause. 
• 
Time to disease progression (TTP), defined as: the time 
from first dose until the earliest date of PD per IMWG, 
or death due to PD. 
• 
Overall Survival (OS), defined as the time from first 
dose to death due to any cause 
• 
To evaluate the pharmacokinetic 
profile of belantamab mafodotin 
when administered intravenously in 
combination with pembrolizumab1 
• 
Pharmacokinetic (PK) parameters following IV 
administration as data permit. 
• 
To assess anti-drug antibodies 
(ADAs) against belantamab 
mafodotin1 
• 
Incidence and titers of ADA to belantamab mafodotin 


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Objectives 
Endpoints 
Exploratory 
• 
To assess Minimal Residual 
Disease (MRD) in subjects who 
achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity rate, 
defined as: the percentage of subjects who are MRD 
negative in subjects who achieve VGPR or CR 
• 
To characterize the relationship 
between clinical response and 
other biologic characteristics  
• 
BCMA expression levels on malignant cells, serum 
sBCMA levels, serum cytokines, and immune cell 
characterization and their relationship to clinical 
response (Protein, RNA, DNA analysis) 
• 
To investigate the relationship 
between genetic variants in the 
host and response to belantamab 
mafodotin in combination with 
pembrolizumab 
• 
Possible relationship between host genetic variation 
and response to belantamab mafodotin in combination 
with pembrolizumab 
• 
To explore the effect of the 
combination therapy of belantamab 
mafodotin with pembrolizumab on 
symptoms and health-related 
quality of life in subjects with 
RRMM 
• 
Changes from baseline in symptoms and health-related 
quality of life as measured by the European 
Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core Module 
(EORTC-QLQ-C30) and European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire 20-item Multiple Myeloma Module 
(EORTC-QLQ-MY20) 
• 
To evaluate the tolerability of 
belantamab mafodotin in 
combination with pembrolizumab 
based on patient self-report of 
symptomatic adverse effects 
• 
Symptomatic adverse effects as measured by the PRO-
CTCAE 
• 
Impact of ocular adverse effects on quality of life as 
measured by the Visual Function questionnaire(s): NEI-
VFQ-25 and OSDI 
• 
To evaluate disease and treatment 
related symptoms and associated 
impacts on function and health-
related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered if unexpected clinical findings have been identified.  
 
Overall Study Design 
This is a phase I/II, single arm, open label, two-part study to determine the recommended 
Phase 2 dose (RP2D) of belantamab mafodotin in combination with pembrolizumab, and 
to evaluate safety and clinical activity of the combination in subjects with RRMM. 
Type and Number of Subjects 
The study will enroll adult subjects with RRMM, who have undergone stem cell 
transplant or who are considered transplant ineligible. Subjects must have been 
previously treated with at least 3 prior lines that include the following: an 


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immunomodulatory imide drug -IMiD (eg. lenalidomide or pomalidomide), proteasome 
inhibitor -PI (eg. bortezomib, ixazomib or carfilzomib) and an anti-CD38 antibody alone 
or in combination. Line of therapy are defined by consensus panel of the International 
Myeloma Workshop [Rajkumar, 2011].  
Overall, it is estimated that up to 40 evaluable subjects will be enrolled in this two-part 
study (up to 12 in Part 1, and 28 in Part 2).  
End of Treatment and End of Study Definitions: 
A final data cut-off will occur when all participants have either died, progressed, 
withdrawn consent, or have been followed for a minimum of 24 months from the time the 
last participant receives their first dose of study treatment (LSFD). 
 
Following 24 months post LSFD, a Post Analysis Continued Treatment (PACT) will be 
implemented. At this time, the collection of data for all recruited participants who no 
longer receive study treatment will stop entirely and clinical trial database will be closed. 
Those participants still benefiting from belantamab mafodotin in the opinion of their 
treating physician may continue to receive study drug and only SAEs, overdose and 
pregnancy cases, and pre-specified ocular data will be reported directly to GSK. 
Key Inclusion Criteria 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
• Provide signed written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form 
• Male or female, 18 years or older (at the time consent is obtained) 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
• Histologically or cytologically confirmed diagnosis of MM as defined according 
to IMWG, 2014 [Rajkumar, 2014], and  
o Has undergone stem cell transplant or is considered transplant ineligible, and  
o Has been treated with at least 3 prior lines of anti-myeloma treatments, 
including: an IMiD (eg. lenalidomide or pomalidomide), proteasome inhibitor 
(eg., bortezomib, ixazomib or carfilzomib) and an anti-CD38 antibody, alone 
or in combination. Line of therapy are defined by consensus panel of the 
International Myeloma Workshop [Rajkumar, 2011].   
o Has measurable disease defined as one of the following: 
a) Serum M-protein 0.5 g/dL (5 g/L).  
b) Urine M-protein ≥200 mg/24h.  
c) Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an 
abnormal serum free light chain ratio (<0.26 or >1.65)  
• Subjects with a history of autologous stem cell transplant (SCT) are eligible for 
study participation provided the following eligibility criteria are met: 
a) 
Transplant was > 100 days prior to study enrolment. 
b) 
No active infection (s). 
c) 
Subject meets the other eligibility criteria outlined in this protocol. 
• Subject has adequate organ system functions defined in the Table below: 




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Additional requirements for pregnancy testing during and after study 
intervention are located in Appendix 8. 
The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy. 
• Male Subjects: 
• Male subjects are eligible to participate if they agree to the following from the 
time of first dose of study until 6 months after the last dose of study treatment 
to allow for clearance of any altered sperm :  
• Refrain from donating sperm 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent  
OR 
• Must agree to use contraception/barrier as detailed below 
• Agree to use a male condom, even if they have undergone a successful 
vasectomy, and female partner to use an additional highly effective 
contraceptive method with a failure rate of <1% per year as described 
in Appendix 8 when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant. 
• Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in 
clinical studies. 
Key Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
• Systemic anti-myeloma therapy or an investigational drug 14 days or five half-
lives, whichever is shorter, preceding the first dose of study drug 
• Plasmapheresis within 7 days prior to the first dose of study drug 
• Prior treatment with a monoclonal antibody within 30 days of receiving the first 
dose of study drugs 
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., 
CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a 
Grade 3 or higher immune related adverse event (irAE)  
• Current corneal epithelial disease except mild punctate keratopathy 
• Any major surgery within the last four weeks prior to the first dose of study 
therapy 
• Presence of active renal condition (infection, requirement for dialysis or any other 
condition that could affect subject’s safety). Subjects with isolated proteinuria 
resulting from MM are eligible, provided they fulfil criteria for adequate renal 
function defined in the inclusion criteria 


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Protocol Amendment 04 
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• Pregnant or lactating female 
• Known active infection requiring antibiotic, antiviral, or antifungal treatment 
• Known HIV infection 
• Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody 
(HBcAb at screening or within 3 months prior to first dose of study treatment) 
• Positive hepatitis C antibody test result or positive hepatitis C RNA test result at 
screening or within 3 months prior to first dose of study treatment  
NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained 
NOTE: Hepatitis RNA testing is optional and subjects with negative Hepatitis C 
antibody test are not required to also undergo Hepatitis C RNA testing 
• Has received a live-virus vaccination within 30 days of planned start of study 
therapy 
• Active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment   
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days prior the first dose of study 
therapy 
• Has a known psychiatric or substance abuse disorder that would interfere with the 
subject’s ability to cooperate with the requirements of the study. 
• Has had an allogenic tissue/solid organ transplant 
Study Treatment and Duration 
Product name: 
Belantamab mafodotin 
Pembrolizumab 
[Formulation 
description:] 
20 mg/mL, 1.5 mL/vial 
100 mg/4 mL 
Route of Administration  
Delivered as IV infusion. Refer to 
Study Reference Manual (SRM) for 
details. 
Delivered as 30 min IV infusion 
Treatment Duration 
Belantamab mafodotin and pembrolizumab will be administered via intravenous (IV) 
infusion on day 1 of each 21-day cycle (once every 3 week dosing schedule). Subjects 
enrolled in Part 1 and 2 will be treated until disease progression, intolerable toxicity, 
informed consent withdrawal, or for a maximum of 35 cycles (approximately 2 years, See 
Combination Treatment Schematic below). 


TMF-14344600 
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Protocol Amendment 04 
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Subjects who discontinued treatment for reasons other than PD will be followed up every 
3 weeks until confirmed PD, initiation of a new anticancer therapy or death. All subjects 
with confirmed PD will be followed for OS every 3 months until the end of study. End of 
study is defined as when all subjects have been followed for 36 months from first dose of 
study treatment, or died, or withdrew consent, or are lost to follow-up, or the study is 
early terminated, whichever occurs first. The next subsequent therapy will be collected 
for all subjects who have confirmed PD before initiation of new anticancer therapy. 
Treatment Arms 
The study will comprise of two parts: Part 1- dose escalation and Part 2- expansion.  
Part 1: Dose Escalation 
Part 1 dose escalation will characterize the safety and tolerability of escalating doses of 
belantamab mafodotin in combination with 200 mg pembrolizumab to establish the 
RP2D.  The following dose levels of belantamab mafodotin in combination with 200 mg 
pembrolizumab are planned to be studied: 2.5 mg/kg (dose level [DL] 1) and 3.4 mg/kg 
(DL2) (as outlined in Dose Escalation Schematic for Part 1 below). Additionally, other 
dose levels may also be explored. Dose level 1.92 mg/kg may be tested if dose level 2.5 
mg/kg is not cleared. During the dose escalation, at least 3 evaluable subjects will be 
studied per dose level. In Part 1, any subject who received at least one treatment cycle of 
the combination will be evaluated for DLTs.  Subjects who have received only 
belantamab mafodotin or have been withdrawn from the study for reasons other than 
toxicity but prior to completion of DLT observation period will be replaced. 


TMF-14344600 
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Protocol Amendment 04 
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Dose Escalation Schematic for Part 1 
 
Dose Limiting Toxicity Criteria (Part 1 only) 
The DLT observation window will be 21 days (=1 cycle). Any subject in Part 1 who 
received at least one treatment cycle of the combination of belantamab mafodotin and 
pembrolizumab will be evaluated for DLTs using National Cancer Institute (NCI) 
CTCAE Version 4.03 [NCI, 2010]. In addition, for belantamab mafodotin treatment 
related corneal events, the GSK grading scale for corneal events (Appendix 9) should be 
used for evaluation of DLT.   
A DLT is defined as an AE that meets at least one of the criteria defined below and is 
considered by the investigator to be clinically relevant and attributed (definitely, 
probably, or possibly) to the study therapy during the 21 day DLT observation period.  
1. Any Grade 4 non-hematologic toxicity 
2. Any Grade 3 non-hematologic toxicity, with the following exceptions (i.e., the 
following will not be considered a DLT): Grade 3 diarrhea, nausea, or vomiting that 
responds to standard of care within 72 hours; Grade 3 hypertension (controlled 
following addition of 1 antihypertensive medication); and Grade 3 tumor lysis 
syndrome  
3. Any Grade 3 or greater non-hematologic laboratory value if either: 
• The laboratory abnormality persists for >48 hrs despite supportive treatment, or 
• The abnormality leads to hospitalization 
4. Hematologic toxicity:  
• Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 
• Grade 4 thrombocytopenia of any duration 
• Grade 3 thrombocytopenia associated with clinically significant bleeding 
• Grade 3 or greater febrile neutropenia lasting >48 hours despite adequate 
treatment: 


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TMF-14344600 
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Protocol Amendment 04 
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Safety Assessment 
Safety assessments during the study will include, but not limited:   
• AEs, SAEs, AEs leading to discontinuation of study treatment 
• Clinical laboratory safety assessments, including hematology and clinical 
chemistry data 
• Other safety measures, including data for vital signs, the performance status of the 
ECOG scale, ECG, echocardiogram (ECHO), and serum pregnancy test for 
female subjects of childbearing potential 
• Ocular exam 
Corneal Supportive Care Guidelines (belantamab mafodotin) 
Corneal events, which commonly manifest as a superficial microcystic keratopathy, have 
previously been observed with antibody drug conjugates, including those conjugated to 
MMAF.  It is required that sites establish a close collaboration with an ophthalmologist 
(or optometrist, if ophthalmologist is not available) who will be responsible for assessing 
subjects on study and managing subjects who develop a corneal event in close 
communication with the GSK Medical Monitor and possibly a GSK ophthalmologist.  
Subjects will be assessed by ophthalmologists (or optometrist, if ophthalmologist is not 
available) at baseline, and then every three weeks prior to each dose of belantamab 
mafodotin for the first 4 doses. After the 4th dose of belantamab mafodotin, if there are no 
significant ocular symptoms or vision changes, the frequency of ophthalmologic exams 
may be decreased to once every 6 months until end of study treatment.  In case of 
persistent or newly developed ocular symptoms or vision changes, the subject will have 
further ophthalmologic exams, at least every 3 months until resolution (to Grade 1 or 
baseline) or more frequently as clinically indicated by the eye care specialist.   
Further information regarding corneal event associated with belantamab mafodotin, 
including a grading scale and prophylactic measures are in Appendix 9.  
Clinical Activity Assessment 
Standard disease assessments for MM will include laboratory tests (serum and urine M 
protein test, sFLC, and corrected calcium), bone marrow core biopsy and aspirate (in case 
of suspected CR or to demonstrate progression), immunohistochemistry (IHC) of bone 
marrow samples to confirm sCR to confirm stringent CR) or imaging, and minimal 
residual disease by Next Generation Sequencing (NGS; in subjects with achieve 
confirmed VGPR or CR).  Response evaluation will be performed according to the 
International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma 2016 [Kumar, 2016]. Minimal residual disease negative rate will be assessed in 
those subjects who achieve a VGPR or CR.  
 
 


TMF-14344600 
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Protocol Amendment 04 
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Pharmacokinetic assessments 
Blood PK samples will be collected during the trial and analysed for belantamab 
mafodotin (ADC and total antibody) and cys-mcMMAF concentrations. Blood samples 
for pembrolizumab measurements will be collected and stored, but will only be analyzed 
in case of unexpected clinical findings. 
Translational Research 
BCMA expression in plasma cells from bone marrow aspirates will be evaluated at 
baseline, and at additional timepoints if available, by IHC.  IHC markers may include but 
will not be limited to: BCMA, Blimp1, CD138, and CD38.   
Soluble BCMA (sBCMA) concentrations in serum will be evaluated in all subjects.  
Additionally, bone marrow tumor tissue may be evaluated for any DNA/RNA changes 
correlating with clinical response.   
Value Evidence and Outcome 
The impact of potential ocular toxicity will be assessed using the selected items from the 
Questionnaire of NEI-VFQ-25 and OSDI. 
A subset of items selected from the PRO-CTCAE Version 1.0 Item library will be 
applied to evaluate symptomatic toxicity in subjects. 
Subjects enrolled in Part 2 only will self-complete additional questionnaires to assess the 
symptoms related to multiple myeloma and its treatment, and the impact of these 
symptoms on daily functioning. Symptoms will be assessed using two questionnaires: 
EORTC-QLQ-C30 and EORTC-QLQ-MY20.   
To further evaluate disease and treatment related symptoms and associated impacts on 
function and health-related quality of life, subjects enrolled in both Part 1 and 2 will 
participate in an Exit Interview conducted via telephone subsequent to the End of 
Treatment visit. 
Statistical Analysis 
For part 1, no formal statistical hypotheses are being tested.  In Part 1, the dose escalation 
decisions will be guided by the Modified Toxicity Probability Interval (mTPI) approach, 
as well as the totality of the safety data. After the last cohort of subjects in Part 1 
completes the 21-day DLT observation period, a formal interim analysis will be 
performed to support the RP2D decision, except for scenarios where RP2D is clearly 
defined by the toxicity profile.  
The primary goal of Part 2 is to confirm safety and to characterize clinical activity of the 
combination and to detect if meaningful overall response rate (ORR) can be achieved.  


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During part 2 of the study, treatment-rated Grade 4 or higher AEs will be continuously 
monitored starting from when 5 subjects are dosed. If observed toxicity level is 
significantly higher than 12% at 1-sided alpha of 0.025, the study may be terminated 
early based on totality of safety data. The 12% threshold is chosen based on 11% Grade 4 
or higher AE observed in study BMA117159.  
For Part 2, futility analyses for ORR will start when 10 subjects are evaluable. 
Enrollment may stop if the stopping rule is met based on totality of data.  
Primary analysis of the data captured in Part 1 and Part 2 will be performed 
approximately 15 months from the last subject first visit (LSFV) to test the hypothesis 
that a meaningful response rate (ORR) can be achieved of the combination. Participants 
may discontinue the study treatment if meaningful response rate (ORR) cannot be 
achieved. For primary analysis, data may be combined from parts 1 and 2. 
Final analysis of the data captured in Part 1 and Part 2 will be undertaken after all 
subjects meet at least one of the following criteria: have reached the end of study or died. 
End of study is defined as when all subjects have been followed for 36 months from first 
dose of study treatment or died or withdrew consent or are lost to follow-up or the safety 
stopping criteria is met, whichever occurs first.  
References for Protocol Synopsis 
Darce JR, Arendt BK, Wu XS,Jelinek DF. Regulated expression of BAFF-binding 
receptors during human B cell differentiation. J Immunol. 2007;179:7276-86. 
Kumar S, et al. International Myeloma Working Group consensus criteria for response 
and minimal residual disease assessment in multiple myeloma. The Lancet Oncology. 
2016;17: e328-e346. 
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Richardson PG. Targeting 
CD38 with daratumumab monotherapy in multiple myeloma. N Eng J Med. 
2015;373:1207-19.  
NCI (2010) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
In: Health NIo, editor. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf: U.S.Department of Health and Human Services. 
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. 
International Myeloma Working Group updated criteria for the diagnosis of multiple 
myeloma. The Lancet Oncology. 2014;15: e538-e548. 
Rajkumar SV, Harousseau JL, Durie B, Andreson KC, Dimopoulos M, San Miguel J, et 
al. Consensus recommendations for the uniform reporting of clinical trials; report of the 
International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4697-4695.  
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
Multiple myeloma (MM) is an incurable malignancy and accounts for 1% of all cancers 
and for 10% of all hematologic malignancies. Worldwide, approximately 103,000 new 
cases are diagnosed annually, and an estimated 30,330 new cases and 12,650 deaths will 
occur in the U.S. in 2016 [Siegel, 2016].  Despite significant advances with current novel 
therapies and hematopoietic stem cell transplantation (HSCT), novel therapies like 
second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents, and 
recent addition of monoclonal antibodies (mAbs), most MM patients will relapse and 
ultimately develop resistance to existing therapies [Laubach, 2014]. Thus, there is a need 
to develop treatments with novel mode of action (MOA) which could potentially prevent 
the cross resistance to existing therapies.  
Before the introduction of daratumumab, patients with disease refractory to both 
immunomodulatory agents and PIs had a median overall survival (OS) ranging from 9 
months [Kumar, 2012] to 12 months [San Miguel, 2013].  
Daratumumab [DARZALEX, 2017], is a human IgGk monoclonal antibody that was 
granted accelerated approval as monotherapy for the treatment of relapsed/refractory 
multiple myeloma (RRMM) in the US in November 2015 based on the results from a 
Phase II monotherapy study (n=106), which reported 29.2% overall response rate (ORR) 
and median progression free survival (mPFS) of 3.7 months in patients with RRMM 
[Lonial, 2016].  The median number of prior lines of treatment reported in this study was 
5. 
Daratumumab has also been approved in combination with lenalidomide/dexamethasone 
or bortezomib/dexamethasone for patients who were previously treated with at least one 
prior line of therapy, and in combination with pomalidomide and dexamethasone for 
patients previously treated with at least 2 prior lines of therapy based on improvement in 
mPFS and ORR [DARZALEX, 2017; Janssen-Cilag International NV, 2016]. 
While the data with daratumumab indicates that prolongation of PFS can been achieved, 
patients continue to relapse after treatment with daratumumab; additional treatment 
options to control the disease are needed.  Patients with RRMM who relapse after 
daratumumab, IMiD, and PI based therapies, have few treatment options available.   
B cell maturation antigen (BCMA, also referred to as TNFRSF17 or CD269) is a member 
of the tumor necrosis factor (TNF) receptor superfamily and regulates a variety of 
cellular functions. BCMA is expressed in mature B lymphocytes and binds to two TNF 
family ligands BAFF (B-cell-activating factor belonging to the TNF family) and APRIL 
(a proliferation-inducing ligand) which influence B cell survival and proliferation.  Mice 
deficient for BCMA are viable, have normal B cell development, and exhibit normal 
humoral responses [Xu, 2001]. BCMA is widely expressed on malignant plasma cells in 
MM and to a lesser degree in other B cell malignancies [Tai, 2006]. A soluble form of 
BCMA has been identified in serum from MM patients and shown to correlate with 
progressive disease [Sanchez, 2016].  Since all malignant plasma cells express various 


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levels of BCMA, MM has a biologically based rationale as a key indication for anti-
BCMA therapy. 
Belantamab mafodotin (previously referred to as GSK2857916) is a humanized 
immunoglobulin G1 (IgG1) antibody-drug conjugate (ADC) that binds specifically to B 
cell maturation antigen (BCMA).  The parent antibody (GSK2857914) competes with the 
BCMA ligands APRIL and BAFF and is conjugated to the microtubule inhibitor 
monomethyl auristatin-F (MMAF), resulting in an ADC molecule.  The conjugate is 
produced in an afucosylated form to generate enhanced antibody-dependent cellular 
cytotoxicity (ADCC).  In addition, when MM cells expressing BCMA are exposed to 
belantamab mafodotin, immunogenic cell death (ICD) markers are induced. Exposure of 
dendritic cells to tumor cells undergoing ICD may result in antigen-specific T-cell 
response, enabling the patient’s own immune response against the MM tumor. 
Of the four proposed mechanisms of action (MOA) for belantamab mafodotin, the ADC 
and ADCC MOAs have been linked to efficacy in non-clinical models:  in vitro and in 
vivo against multiple myeloma cell lines, and ex vivo against primary patient myeloma 
samples.  Inhibition of BCMA signaling has been demonstrated biochemically; however, 
functional effects on myeloma cells have not been demonstrated. ICD markers on cells 
are induced by belantamab mafodotin both in vivo and in vitro, but effects on efficacy 
have not been established in non-clinical models.  These different mechanisms may 
enable belantamab mafodotin to deliver anti-tumour activities targeting both dividing and 
non-dividing tumour cells and associate the cell kill with an adaptive immune response; 
these MoA characteristics clearly differentiate belantamab mafodotin from existing 
approved treatments [GlaxoSmithKline Document Number 2013N175128_09, 2021] 
Belantamab mafodotin is a very good candidate for combining with immunomodulating 
drugs, including programmed cell death 1 (PD-1) inhibitors, due to auristatin-induced 
immunogenic cell death (ICD) on target MM tumor cells (GSK unpublished data).  ICD 
is characterized by induction of the endoplasmic reticulum (ER) stress response and 
exposure of danger-associated molecular patterns (DAMPs), many of which are Toll-like 
receptor ligands. Exposure of dendritic cells to tumor cells undergoing ICD evokes an 
inflammatory phenotype (innate response) including an increase in co-stimulatory 
markers CD86 and MHC Class II antigens, and activation of NFB, an intermediate of 
inflammatory signalling pathways.  Mature dendritic cells (DCs) play key roles in 
priming robust immune responses in tumor-bearing hosts and ICD can induce an 
effective anti-tumor immune response through activation of DCs and consequent 
activation of specific T cell response, by priming of tumor antigen-specific T cells 
[Kroemer, 2013; Muller, 2014]. The T cell anti-tumor response can be further augmented 
by pembrolizumab.  
Programmed cell death-1 (PD-1) expressed on T cells is a member of the CD28 
superfamily that delivers negative signals upon interaction with its two ligands, 
programmed cell death ligand 1 (PD-L1) or programmed cell death ligand 2 (PD-L2). 
Physiologically PD-1 and its ligands are broadly expressed and exert a wider range of 
immunoregulatory roles in T cell activation and tolerance. Recent studies show that PD-
1/PD-L1 interaction regulates the induction and maintenance of peripheral tolerance and 


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protect tissues from autoimmune attack. PD-1 and its ligands are also involved in 
attenuating tumor immunity, and facilitating tumor progression.  
Many tumors, including MM use various escape mechanisms to evade the immune 
control and to promote tumor growth and clonal tides [McLaughlin, 2016].  One of those 
mechanisms is the expression of PD-1 ligands (PD-L1). Recent advances in cancer 
treatment include successful checkpoint blockade by using antibodies binding to PD-1 or 
PD-L1 (e.g., pembrolizumab, nivolumab). The anti-PD-1 and anti-PD-L1 antibodies have 
a favorable safety profile and have resulted in durable responses in a variety of cancers, 
including melanoma, kidney cancer, lung cancer, and Hodgkin lymphoma. The agents 
continue to be evaluated in various solid tumors and hematological malignancies, alone 
or in combination with other therapies [Dolan, 2014]. There is also growing body of data 
demonstrating broad expression of PD-1 and its ligands in the microenvironment of MM, 
and indicating an important role of the PD-1 pathway [Liu, 2011; Kuranda, 2010; 
Atanackovic, 2014; Benson, 2010]. Although, so far, anti-PD-1 treatment alone has not 
been effective in MM [Lesokhin, 2014; Suen, 2006].  
The KEYNOTE-023 study examined whether an anti-PD-1 treatment (Keytruda 
[pembrolizumab]) in combination with immunomodulatory agents may create synergism, 
in this case lenalidomide and dexamethasone. Lenalidomide doses of 10 mg and 25 mg 
were examined, with the 25 mg dose further explored. Of the subject’s evaluable for 
efficacy (N=40), 88% of subjects had a decrease in M protein. The ORR for this 
population was 50%, including a 38% ORR for subjects who were lenalidomide 
refractory [Mateos, 2016]. Based on these findings, the KEYNOTE-183 and KEYNOTE-
185 studies were initiated, exploring combinations of pembrolizumab with 
immunomodulatory agents.  
Following review of both studies by data monitoring committees, KEYNOTE-183 and 
KEYNOTE-185 were placed on full clinical hold. In both studies, it was determined that 
the benefit-risk was unfavorable for the combination of pembrolizumab with 
immunomodulatory agents. The US FDA also placed Cohort 1 (combination with 
lenalidomide and dexamethasone) of KEYNOTE-023 on full clinical hold as a result of 
the data from KEYNOTE-183 and KEYNOTE-185. Please refer to Section 2.3.3 for 
additional information.   
This study will evaluate the safety and anti-myeloma activity of belantamab mafodotin in 
combination with pembrolizumab. Safety will be closely monitored with dose 
modification guidelines in Section 6.5. GSK will also use an internal Safety Review 
Committee (iSRC) as described in Section 10.9.1. for review of safety. We hypothesize 
that given the immunogenic properties of the cell death induced by belantamab mafodotin 
an augmented anti-tumor activity will be observed in MM subjects, when treated with 
combination of belantamab mafodotin and pembrolizumab. 


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2.2. 
Belantamab mafodotin 
2.2.1. 
Nonclinical Pharmacology 
In vitro, belantamab mafodotin demonstrated both ADC and ADCC cytotoxicity against 
all MM cell lines tested, including those with low BCMA expression.  Further, 
belantamab mafodotin activity was demonstrated under conditions designed to mimic the 
human target cells and microenvironment in the bone marrow, including in the presence 
of physiological concentrations of BCMA ligands, the presence of shed BCMA, a large 
range of BCMA expression levels, and at concentrations of belantamab mafodotin 
hypothesized to be achievable in humans.  The presence of the drug conjugate on the 
antibody had no impact on the Fc receptor engagement, with identical ADCC potency of 
the ADC compared to the unconjugated mAb. Likewise, afucosylation of the mAb 
portion had no impact on the ADC activity compared to the wild type (WT) fucosylated 
molecule. Belantamab mafodotin significantly inhibited tumor growth in xenograft 
models of female mice bearing human MM NCI-H929, OPM2, and MM1Sluc cells. 
Additionally, a single dose male monkey study showed a pharmacodynamic effect on 
BCMA expressing cells in the blood. 
In vivo safety pharmacology studies were not conducted with belantamab mafodotin.  
Evaluations of potential cardiovascular effects were performed in the 3-week toxicology 
studies.  Electrocardiograms (ECG) were monitored in monkeys for up to 24 hours 
following repeat dosing and did not produce any evidence of test-article induced 
electrocardiographic waveform abnormalities, arrhythmias or QTc changes.  Serum 
cardiac troponin I was also measured in the rat and monkey 3-week studies and no 
treatment-related effects were observed. 
2.2.2. 
Nonclinical Pharmacokinetics Metabolism of Belantamab 
Mafodotin 
Detailed information is available in the Investigator’s Brochure [GlaxoSmithKline 
Document Number 2013N175128_09, 2021].   
2.2.3. 
Toxicology of belantamab mafodotin (GSK2857916) 
A range of nonclinical toxicology studies have been conducted to support the intravenous 
administration of belantamab mafodotin to humans.  Detailed information is available in 
the Investigator’s Brochure [GlaxoSmithKline Document Number Number 
2013N175128_09, 2021].   
2.2.4. 
Genotoxicity of belantamab mafodotin (GSK2857916) 
Intact biopharmaceutical therapeutics, such as monoclonal antibodies and antibody drug 
conjugates, do not directly interact with DNA or other chromosomal material.  Therefore, 
genetic toxicology studies with belantamab mafodotin were not performed [ICH S6(R1), 
2011]. The active moiety of belantamab mafodotin is MMAF cytotoxin which is 
expected to be genotoxic in mammalian systems given it is a microtubule disrupting 
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2.2.5. 
Effects in Humans (belantamab mafodotin) 
Data from two belantamab mafodotin single agent studies conducted in heavily pre-
treated RRMM patients (Q3W schedule via IV administration) is summarized below.  
In the FTIH study DREAMM 1 (BMA117159) (NCT02064387), as of 28 August 2018 
primary analysis data cut-off, a total of 73 subjects with RRMM received at least 1 dose 
of belantamab mafodotin frozen drug product ranging from 0.03 mg/kg to 4.6 mg/kg 
once every 3 weeks [GlaxoSmithKline Document Number 2013N175128_09, 2021].  
Subjects were heavily pre-treated: 57% of subjects had 5 or more prior lines of therapy. 
Data from DREAMM 1 demonstrates a manageable safety profile with thrombocytopenia 
and corneal events being the most frequently reported AEs.  All subjects in Part 2 (MM 
patient population) initiated belantamab mafodotin treatment at 3.4 mg/kg and 
experienced at least one AE. The most common events occurring in ≥30% of subjects 
were corneal events, thrombocytopenia (including the preferred term platelet count 
decreased), nausea, fatigue, anemia, and aspartate aminotransferase increased.  In Part 2, 
Grade 3/4 AEs were reported in 29/35 subjects (83%) and SAEs were reported in 17/35 
(49%) subjects.  The most common SAEs were lung-associated infections, pneumonia, 
pyrexia, and IRR. 
Corneal events are the most frequently reported adverse events associated with 
belantamab mafodotin in the clinic, which include keratopathy (microcyst-like superficial 
deposits in the corneal epithelium), blurred vision, dry eyes and photophobia. These 
findings are consistent with those previously reported with other antibody drug-
conjugates utilizing monomethyl auristatin F in terms of manifestation and incidence of 
events [Donaghy, 2016; Eaton, 2015]. In Part 2 of DREAMM 1, corneal events were 
reported in 24/35 (69%) subjects, most commonly blurred vision (18/35; 51%), dry eye 
(13/35; 37%) and photophobia (10/35; 29%). Most subjects experienced Grade 1 or 2 
corneal events (19/35; 54%); 5 (14%) subjects had Grade 3 events. The median duration 
of corneal events for subjects with a resolution date (n = 16) was 35 days (range 5–442). 
Corneal events led to dose reduction in 16 (46%) subjects, and dose interruptions or 
delays in 17 (49%) subjects [Trudel, 2019]. 
Thrombocytopenia/platelet count decreased was reported in a total of 40 subjects (55%) 
in the All Treated Population (N=73), and 22 subjects (63%) in Part 2 (N=35).  
Belantamab mafodotin may cause transient worsening of thrombocytopenia in some 
subjects, but in most cases these events are resolved during between-dosing intervals.  In 
the Part 2 MM population, two serious bleeding events were reported: intracranial 
hemorrhage in a subject with a history of an intracranial bleeding in the setting of disease 
progression, and hematuria in a subject with a large bladder mass in the setting of 
progressive disease. 
As of the efficacy cut-off date of 31 August 2018, a total of 35 subjects were treated at 
the 3.4 mg/kg dose in Part 2 of the ongoing DREAMM 1 study. The ORR was 60% (95% 
CI: 42.1, 76.1): comprised of PR, 6%; VGPR, 40%; CR, 9%; and stringent CR (sCR), 
6%. The median duration of response (DoR) was 14.3 months (95% CI: 10.6, NR). The 
median PFS (mPFS) in this population was 12.0 months (95% CI: 3.1, NR). For subjects 
refractory to both immunomodulatory agents and PIs (n = 32/35), the confirmed ORR 


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was 56% (95% CI: 37.7, 73.6) and mPFS was 7.9 months (95% CI: 2.3, Not Estimable 
[NE]) [Trudel, 2019].  
A Bayesian logistic regression model (BLRM) was used to determine the dose-response 
relationship for both ORR and ≥Grade 2 corneal event rate (as determined by NCI-
CTCAE grading Version 4.0) based on data from all 73 subjects with RRMM in 
DREAMM 1. The model showed that the posterior probability of observing an ORR 
≥30% is 100% in the 3.4 mg/kg dose group and 83% in the 2.5 mg/kg dose group.  
Similarly, the posterior probability of observing ≥Grade 2 corneal event rate is also 
higher in the 3.4 mg/kg dose group. Based on this analysis, these two doses (2.5 and 3.4 
mg/kg) were selected for further evaluation. 
The ongoing Phase II study 205678/DREAMM 2 (NCT03525678) is evaluating these 
two IV single agent doses (2.5 and 3.4 mg/kg) administered Q3W until disease 
progression in subjects who have failed at least 3 prior lines of anti-myeloma therapy, 
including an anti-CD38 antibody, and who are refractory to an immunomodulatory agent 
and a proteasome inhibitor.  A total of 194 subjects received frozen drug product in the 
main cohort and 24 subjects received 3.4 mg/kg lyophilized drug product.  Preliminary 
data from this study indicated no new safety signals, and the profile of adverse events 
was similar to the experience in the DREAMM 1 study for both arms. Both dose levels, 
2.5 and 3.4 mg/kg, were shown to have a positive benefit/risk profile. 
2.2.5.1. 
Pharmacokinetics and Pharmacodynamics 
The pharmacokinetics and pharmacodynamics of belantamab mafodotin (antibody-drug 
conjugate, including complex with soluble BCMA (sBCMA)) and total monoclonal 
antibody (total mAb; including complex), and cys-mcMMAF were investigated in 291 
participants with RRMM following IV administration at doses from 0.03 to 4.6 mg/kg 
Q3W in Study BMA117159 (n=73) and at doses of 2.5 or 3.4 mg/kg Q3W in Study 
205678 (n=218). 
Maximum concentrations (Cmax) of belantamab mafodotin and total monoclonal 
antibody were observed at or shortly after the end of infusion (EOI), while cys-mcMMAF 
Cmax values were generally observed on Day 2. On a molar basis, plasma concentrations 
of cys-mcMMAF were <1% of belantamab mafodotin concentrations. There was limited 
accumulation (less than 2-fold) of belantamab mafodotin or cys-mcMMAF during 
subsequent cycles.  
Belantamab mafodotin pharmacokinetics were well described by a linear, two 
compartment population model, with a time-varying decrease in clearance in a population 
pharmacokinetic analysis. At Cycle 1, belantamab mafodotin had a systemic clearance of 
0.92 L/day, steady-state volume of distribution of 10.8 L, and an elimination half-life of 
12 days in participants with RRMM in Study 205678. Over time, clearance was reduced 
by 28%, resulting into 0.72 L/day, with an elimination half-life of 14 days. The time to 
50% change in clearance was approximately 50 days.  
No clinically significant differences in the pharmacokinetics of belantamab mafodotin or 
cys-mcMMAF were observed based on age (34 to 89 years), sex, race (African 
American/Black and White), body weight (42 to 130 kg), mild or moderate renal 


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impairment (eGFR ≥30 mL/min/1.73m2) or mild hepatic impairment (NCI-ODWG 
classification). Higher serum levels of 2-microglobulin, IgG, and soluble BCMA 
(sBCMA) and lower levels of albumin are associated with more advanced multiple 
myeloma or a higher multiple myeloma disease burden. Higher baseline IgG and sBCMA 
levels, and lower baseline albumin levels were associated with higher belantamab 
mafodotin clearance leading to lower average and trough concentrations (Ctau) of 
belantamab mafodotin. Higher baseline IgG and sBCMA levels were associated with 
higher cys-mcMMAF central volume of distribution leading to lower cys-mcMMAF 
Cmax.   
In nonclinical studies, cys-mcMMAF had limited metabolic clearance. In vitro data 
suggested that belantamab mafodotin and cys-mcMMAF are unlikely to perpetrate a 
drug-drug interaction or to be a victim of a drug-drug interaction with inhibitors or 
inducers of cytochromes (CYP) P450. Cys-mcMMAF was an in vitro substrate of organic 
anion transporting polypeptides (OATP)1B1 and OATP1B3, multidrug resistance 
associated proteins MRP1, MRP2, and MRP3, a borderline substrate of bile salt export 
pump (BSEP), and a possible substrate of P-glycoprotein (P-gp). Following the 
administration of belantamab mafodotin to participants with RRMM, only intact cys 
mcMMAF was detected in pooled human urine, with no evidence of other MMAF related 
urinary metabolites.  
Free sBCMA levels were measured in Study BMA117159 and Study 205678.  All 
participants exhibited reductions in free sBCMA concentration at end of infusion 
compared to baseline at Cycle 1, with a return to near-baseline level by seven days after 
dosing, reflecting binding of belantamab mafodotin to sBCMA. Maximum decreases 
ranged from 2% to 97%, which were qualitatively dose-dependent, with larger reductions 
in free sBCMA at higher doses.  
Exposure-response analyses performed for Study 205678 and/or Study BMA117159 
found that ocular safety endpoints were most strongly associated with belantamab 
mafodotin exposure, while efficacy endpoints had a weaker association with belantamab 
mafodotin exposure. Both safety and efficacy endpoints were associated with patient 
characteristics. Belantamab mafodotin Ctau was associated with probability of corneal 
events and keratopathy, and cys-mcMMAF Cmax was associated with probability of 
thrombocytopenia. Probability of occurrence of dry eye, blurred vision, neutropenia and 
infusion related reaction were not associated with an exposure measure. In addition, the 
results of the analysis of concentration against corrected QT interval (QTc), 
concentration-QTc analysis, demonstrated that belantamab mafodotin or cys-mcMMAF 
did not have a significant effect on cardiac repolarization. 
Additional information related to belantamab clinical PK, PD, and exposure-response 
relationships can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number  2013N175128_09, 2021] 
 
 


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2.3. 
Pembrolizumab 
2.3.1. 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, 2010].  Accumulating evidence shows 
a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies. In particular, the presence of CD8+ T cells 
and the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells (T-regs) correlates with 
improved prognosis and long-term survival in solid malignancies, such as ovarian, 
colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and 
renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and 
reinfused, including durable objective tumor responses in cancers such as melanoma 
[Dudley, 2005; Hunder, 2008].  
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 signalling upon engagement of its ligands (PD-L1 and/or PD-
L2) [Greenwald, 2005; Okazaki, 2001].   
The structure of murine PD-1 has been resolved [Zhang, 2004]. 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 CD3 
zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase 
(ZAP70), which are involved in the CD3 T cell signaling cascade [Okazaki, 2001; 
Chemnitz, 2004; Sheppard, 2004; Riley, 2009].  The mechanism by which PD-1 down-
modulates T cell responses is similar to, but distinct from that of CTLA-4, because both 
molecules regulate an overlapping set of signalling proteins [Parry, 2005; Francisco, 
2010].  As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in RRMM.  
2.3.2. 
Pre-Clinical Pharmacology of Pembrolizumab 
Therapeutic studies in mouse models have shown that administration of antibodies 
blocking PD-1/PD-L1 interactions enhance infiltration of tumor-specific CD8+ T cells 
and ultimately lead to tumor rejection, either as a monotherapy or in combination with 
other treatment modalities [Hirano, 2005; Blank, 2004; Weber, 2010; Strome, 
2003;Spranger, 2014; Curran, 2010; Pilon-Thomas, 2010].  Anti-mouse PD-1 or anti-
mouse PD-L1 antibodies have demonstrated antitumor responses in models of squamous 
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carcinoma [Strome, 2003; Curran, 2010; Pilon-Thomas, 2010; Nomi, 2007; Zhang, 
2004].  In such studies, tumor infiltration by CD8+ T cells and increased IFN-γ, 
granzyme B and perforin expression were observed, indicating that the mechanism 
underlying the antitumor activity of PD-1 checkpoint inhibition involved local infiltration 
and activation of effector T cell function in vivo [Curran, 2010]. Experiments have 
confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as 
in combination with chemotherapy, in syngeneic mouse tumor models (see the 
Investigator’s Brochure [IB], Keytruda IB, 2021). 
2.3.3. 
Pembrolizumab Background  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with PD-L1 and 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. For more details on specific 
indications refer to the Investigator brochure. 
Keynote-183 was a randomized trial which evaluated pomalidomide and low-dose 
dexamethasone with or without pembrolizumab in subjects with relapsed and refractory 
multiple myeloma. The ORR was 34% in the pembrolizumab containing arm versus 40% 
in the control arm without pembrolizumab; however, there was no difference in time-to-
progression between arms. There were 29 deaths in the pembrolizumab arm compared to 
21 in the control arm, reflecting an overall survival hazard ratio of 1.61 (95% CI: 0.91, 
2.85) [Krauss, 2018]. An analysis conducted with the removal of subjects with high-risk 
disease characteristics (high-risk cytogenetics, plasmacytoma and quadruple refractory 
status) resulted in a similar number of deaths (n=13) in both arms [Mateos, 2018].  
Keynote-185 was a randomized trial which evaluated lenalidomide and dexamethasone 
with or without pembrolizumab in subjects with newly diagnosed multiple myeloma. The 
ORR was 64% in the pembrolizumab containing arm versus 62% in the control arm 
without pembrolizumab; however, there was no difference in time-to-progression 
between arms. There were 19 deaths in the pembrolizumab arm compared to 9 in the 
control arm, reflecting an overall survival hazard ratio of 2.06 (95% CI: 0.93, 4.55) 
[Krauss, 2018]. 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475 [KEYTRUDA Product Information, 2018; Keytruda IB, 2021]. 
2.4. 
Assessment of Nonclinical Data for Belantamab Mafodotin 
when Co-Administered with Pembrolizumab 
The current nonclinical and clinical safety information for both belantamab mafodotin 
and pembrolizumab, used as single agents, provide support for their use in combination 
in the target patient population. Based on the mechanism of action of belantamab 
mafodotin (following engagement with both target and the FcRIIIA, leading to ADCC 


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activity and the potential for cytokine release as a result of inflammation secondary to 
non-specific cytotoxicity) and the identified potential for pembrolizumab to cause 
cytokine release in vitro, there may be a potential risk for cytokine release when these 
agents are administered in combination. The risk is considered to be low. To ensure the 
safety of subjects, a careful dose escalation of belantamab mafodotin will be 
implemented where no more than one subject will be dosed per day.  
In addition, the starting dose of belantamab mafodotin in this combination regimen has 
been selected to be 1 dose level below a dose that has been shown to be well tolerated 
during the belantamab mafodotin monotherapy dose escalation and should provide a 
sufficient safety margin when pembrolizumab is added at 200 mg. In addition, close 
clinical monitoring will be implemented.  
3. 
OBJECTIVE(S) AND ENDPOINT(S) 
Part 1: Dose Escalation 
Objectives 
Endpoints 
Primary 
• 
To determine safety, tolerability and to 
establish the RP2D of the combination of 
belantamab mafodotin with pembrolizumab in 
subjects with RRMM   
• 
Percent of subjects with AEs, changes in 
clinical signs and laboratory parameters 
• 
Number of subjects with dose limiting 
toxicities (DLTs) 
Secondary 
• 
To evaluate clinical activity of the combination 
of belantamab mafodotin and pembrolizumab 
in subjects with RRMM 
• 
Overall Response Rate (ORR), defined as 
the percentage of subjects with a confirmed 
partial response (PR) or better (i.e., PR, very 
good partial response [VGPR], complete 
response [CR] and stringent complete 
response [sCR]), according to the 
International Myeloma Working Group 
(IMWG) Response Criteria [Kumar, 2016]. 
• 
To evaluate the pharmacokinetic profile of 
belantamab mafodotin when administered 
intravenously in combination with 
pembrolizumab1 
• 
 Pharmacokinetic parameters following IV 
administration as data permit. 
• 
To assess anti-drug antibodies (ADAs) 
against belantamab mafodotin 1 
• 
Incidence and titers of ADAs against 
belantamab mafodotin 
Exploratory 
• 
To assess Minimal Residual Disease (MRD) 
in subjects who achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity 
rate, defined as: the percentage of subjects 
who are MRD negative in subjects who 
achieve VGPR or CR 


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Objectives 
Endpoints 
• 
To characterize the relationship between 
clinical response and other biologic 
characteristics  
• 
BCMA expression levels on malignant cells, 
serum sBCMA levels, serum cytokines, and 
immune cell characterization and their 
relationship to clinical response (Protein, 
RNA, DNA analysis) 
• 
To investigate the relationship between 
genetic variants in the host and response to 
belantamab mafodotin in combination with 
pembrolizumab 
• 
Possible relationship between host genetic 
variation and response to belantamab 
mafodotin in combination with pembrolizumab  
• 
To evaluate the tolerability of belantamab 
mafodotin in combination with pembrolizumab 
based on patient self-report of symptomatic 
adverse effects 
• 
Symptomatic adverse effects as measured by 
the Patient-reported outcome version of the 
Common Term Criteria for Adverse Events 
(PRO-CTCAE) 
• 
Impact of ocular adverse effects on quality of 
life as measured by the Visual Function 
questionnaire(s): National Eye Institute 25-
item Visual Function Questionnaire (NEI-
VFQ-25) and Ocular Surface Disease Index 
(OSDI) 
• 
To evaluate disease and treatment related 
symptoms and associated impacts on 
function and health-related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered only in case of unexpected clinical findings.  
Part 2: Expansion 
Objectives 
Endpoints 
Primary 
• 
To assess the clinical activity of the 
combination treatment with belantamab 
mafodotin and pembrolizumab in subjects 
with RRMM   
• 
Overall Response Rate (ORR), defined as 
the percentage of subjects with a confirmed 
PR or better (i.e., PR, VGPR, CR and sCR), 
according to the IMWG Response Criteria 
[Kumar, 2016]. 
Secondary 
• 
To further evaluate the safety of belantamab 
mafodotin administered in combination with 
pembrolizumab in subjects with RRMM 
• 
Number (percent) of subjects with AEs, 
changes in clinical signs and laboratory 
parameters 
• 
Ocular finding on ophthalmic exam 
• 
To further assess the clinical activity of the 
combination treatment with belantamab 
mafodotin and pembrolizumab in subjects 
with RRMM   
• 
Clinical benefit rate (CBR), defined as the 
percentage of subjects with a confirmed 
minimal response (MR) or better per IMWG  
• 
Duration of response (DoR), defined as: the 
time from first documented evidence of PR or 
better, to the time when disease progression 
(PD) is documented per IMWG; or death due 


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Objectives 
Endpoints 
to PD occurs among subjects who achieve an 
overall response, i.e. confirmed PR or better 
• 
Time to response (TTR), defined as: the time 
between the date of first dose and the first 
documented evidence of response (PR or 
better) among subjects who achieved a 
confirmed response of PR or better 
• 
Time to best response, defined as the time 
between the date of first dose and the first 
best documented response (PR or better) 
among subjects who achieved a confirmed 
response of PR or better 
• 
Progression-free survival (PFS), defined as: 
the time from first dose until the earliest date 
of PD per IMWG, or death due to any cause 
• 
Time to disease progression (TTP), defined 
as: the time from first dose until the earliest 
date of PD per IMWG, or death due to PD 
• 
Overall Survival (OS), defined as the time 
from first dose until death due to any cause 
• 
To evaluate the pharmacokinetic profile of 
belantamab mafodotin when administered 
intravenously in combination with 
pembrolizumab1 
• 
Pharmacokinetic parameters following IV 
administration as data permit. 
• 
To assess ADAs against belantamab 
mafodotin1 
• 
Incidence and titer of ADA to belantamab 
mafodotin 
Exploratory 
• 
To assess Minimal Residual Disease (MRD) 
in subjects who achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity 
rate, defined as: the percentage of subjects 
who are MRD negative in subjects who 
achieve VGPR or CR 
• 
To characterize the relationship between 
clinical response and other biologic 
characteristics  
• 
BCMA expression levels on malignant cells, 
serum sBCMA levels, serum cytokines, and 
immune cell characterization and their 
relationship to clinical response (Protein, 
RNA, DNA analysis).  
• 
To investigate the relationship between 
genetic variants in the host and response to 
belantamab mafodotin in combination with 
pembrolizumab 
• 
Possible relationship between host genetic 
variation and response to belantamab 
mafodotin administered in combination with 
pembrolizumab 
• 
To explore the effect of belantamab 
mafodotin in combination with pembrolizumab 
on symptoms and health-related quality of life  
in subjects with RRMM 
• 
Changes from baseline in symptoms and 
health-related quality of life as measured by 
the European Organisation for Research and 
Treatment of Cancer Quality of Life 


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Objectives 
Endpoints 
Questionnaire 30-item Core Module (EORTC-
QLQ-C30) and European Organisation for 
Research and Treatment of Cancer Quality of 
Life Questionnaire 20-item Multiple Myeloma 
Module (EORTC-QLQ-MY20) 
• 
To evaluate the tolerability of belantamab 
mafodotin in combination with pembrolizumab 
based on patient self-report of symptomatic 
adverse effects 
• 
Symptomatic adverse effects as measured by 
the PRO-CTCAE 
• 
Impact of ocular adverse effects on quality of 
life as measured by the Visual Function 
questionnaire(s): NEI-VFQ-25 and OSDI 
• 
To evaluate disease and treatment related 
symptoms and associated impacts on 
function and health-related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered if unexpected clinical findings have been identified.  


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4.2.2. 
Duration of Treatment 
Subjects will be treated until disease progression, intolerable toxicity, informed consent 
withdrawal, or for a maximum of 35 cycles (approximately 2 years).   
After the study treatment discontinuation, subjects will undergo end of treatment 
assessments 30 days (7 days) after the last dosing, or prior to the start of new anti-
cancer treatment (whichever occurs first). Subjects who discontinued treatment for 
reasons other than PD, will be followed up every 3 weeks until confirmed PD, initiation 
of a new anticancer therapy or death. All subjects with confirmed PD will be followed for 
OS and subsequent anti-cancer therapy every 3 months until the end of study. End of 
study is defined in Section 5.5.2.  
4.2.3. 
Part 1: Dose-Escalation 
Part 1 dose escalation will characterize the safety and tolerability of escalating doses of 
belantamab mafodotin in combination with 200 mg pembrolizumab to establish the 
RP2D.  In the currently ongoing FTIH study (ClinicalTrials.gov Identifier: 
NCT02064387), no DLTs were observed up to the highest tested dose level of 4.6 mg/kg 
of belantamab mafodotin and 3.4 mg/kg was selected as RP2D dose. The following dose 
levels of belantamab mafodotin in combination with 200 mg pembrolizumab are to be 
tested in this study: 2.5 mg/kg and 3.4 mg/kg (as outlined in Figure 2). Additionally, 
other dose levels may also be tested if emerging data suggests a beneficial risk/benefit 
profile at those dose levels. The RP2D from the monotherapy FTIH study (3.4 mg/kg 
(ClinicalTrials.gov Identifier: NCT02064387)) will not be exceeded in this combination 
study.  During the dose escalation, at least 3 evaluable subjects will be tested per dose 
level, and escalation will be guided by the modified Toxicity Probability Interval (mTPI) 
approach. 
Figure 2 
Dose Escalation Schematic for Part 1 
 
 


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The mTPI design assumes the true underlying toxicity rate for maximum tolerated dose 
(MTD) of belantamab mafodotin falls within the range from 25% to 35% and centered at 
30%.  The monitoring rules for guiding dose escalations are provided in Table 1.  
Columns provide the numbers of subjects treated at the current dose level, and rows 
provide the corresponding numbers of subjects experiencing toxicity.  The entries of the 
table are dose-finding decisions (i.e., E, S, and D) representing escalating the dose, 
staying at the same dose, and de-escalating the dose.  In addition, decision U means that 
the current dose level is unacceptable because of high toxicity; the current dose level and 
any higher dose level should be excluded from the trial.  For example, when one of three 
subject’s experiences toxicity, the decision can be located at row 1 and column 3, which 
is S – to stay at the current dose level. Consequently, the next cohort of subjects will be 
treated at the same dose level currently being used.  If 0 of 3 subjects experiences 
toxicity, the decision is at row 0 and column 3, which is E – to escalate.  Thus, the next 
cohort of subjects will be treated at the next-higher dose level.  If three of three subjects 
experiences toxicity, the decision is DU – to de-escalate to the next-lower dose level, and 
exclude the current dose and any higher dose from the trial, because the high toxicity 
level is unacceptable. In dose escalation (E)/de-escalation (D), no dose skipping is 
allowed. 
Table 1 
Dose-Escalation Monitoring Rules for Part 1 Using the mTPI Method 
Number of DLTs 
Number of Subjects treated at current dose 
1 
2 
3 
4 
5 
6 
0 
E 
E 
E 
E 
E 
E 
1 
D 
S 
S 
S 
S 
E 
2 
 
DU 
D 
S 
S 
S 
3 
DU 
DU 
D 
S 
4 
DU 
DU 
DU 
5 
DU 
DU 
6 
DU 
The table was generated based on a beta/binomial model and precalculated before trial initiation.  
The letters in different colors are computed based on the decision rules under the mTPI method 
and represent different dose-finding actions.  In addition to actions de-escalate the dose (D), stay 
at the same dose (S), and escalate the dose (E), the table includes action unacceptable toxicity 
(DU), which is defined as the execution of the dose-exclusion rule in mTPI.  Excerpted from Ji et 
al . [Ji, 2010] 
The DLT observation period for subjects in Part 1 is 21 days after the first dose of the 
study treatment. The complete safety data from DLT observation period of at least 3 
subjects are needed for dose escalation decisions. Subjects who have only received 
belantamab mafodotin or have been withdrawn from the study for reasons other than 
toxicity but prior to completion of DLT observation period will be replaced.  
In Part 1, dose escalation/de-escalation decisions will take into account all available 
safety and tolerability data. The decisions will be informed by the mTPI approach and 
will occur following review of these data and joint discussion by the GSK Study Team 
and investigators.  
The dosing may be adjusted to expand any cohort to further evaluate safety at a given 
dose level, or to add cohorts to evaluate additional, intermediate dose levels of 


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excluded.


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• Any other toxicity considered to be dose-limiting that occurs beyond 21 days will be 
considered in the selection of the dose to recommend for expansion cohorts 
• Any other event which in the judgment of the investigator and GSK Medical Monitor 
is considered to be a DLT 
A subject who develops a DLT will be allowed to continue on study treatment if the 
toxicity did not meet predefined stopping criteria (Section 5.4) and recovered to  Grade 
1 within 14 days, if the investigator and medical monitor agree that for a given subject 
the potential benefits may outweigh the risks. 
4.2.3.2. 
Completion of Dose Escalation and the Recommended Phase 2 Dose 
(RP2D)  
The dose escalation will complete when RP2D is determined. A dose level at or below 
the pre-specified max dose of 3.4 mg/kg may be selected as RP2D in combination with 
the fixed dose of 200 mg pembrolizumab. All available data from Part 1 will be analyzed. 
The totality of the data including, but not be limited to, safety, available PK profile, and 
observed signs of clinical activity will be considered for the RP2D selection of 
belantamab mafodotin to be administered in combination with pembrolizumab. If 
necessary, alternative doses and schedules can be explored to determine additional 
clinically active regimens. 
Once the RP2D has been identified, an expansion cohort (Part 2) will open for enrollment 
of up to 28 subjects with RRMM in order to confirm the safety profile and to evaluate the 
clinical activity of the combination.  
If necessary, alternative schedules and/or additional dose(s) of belantamab mafodotin can 
be explored after RP2D is identified. 
4.3. 
Type and Number of Subjects 
The study will enroll adult subjects with RRMM, who have undergone stem cell 
transplant, or are considered transplant ineligible, and who have been previously treated 
with at least 3 prior lines that include the following: an immunomodulatory agent (i.e. 
lenalidomide or pomalidomide), proteasome inhibitor (i.e. bortezomib, ixazomib or 
carfilzomib) and an anti-CD38 antibody alone or in combination. Line of therapy are 
defined by consensus panel of the International Myeloma Workshop [Rajkumar, 2011].  
 Overall, it is estimated that up to 40 evaluable subjects will be enrolled in this two-part 
study (up to 12 in Part 1, and 28 in Part 2).   
4.4. 
Design Justification 
This is the first clinical study in which belantamab mafodotin will be administered in 
combination with pembrolizumab. Therefore, a two-part study design is implemented to 
allow for careful safety assessments during dose escalation.  Part 1 will consist of dose 
escalation to establish the RP2D of belantamab mafodotin in combination with 200 mg of 
pembrolizumab. Once RP2D has been established, Part 2 will enroll an additional 28 
subjects with RRMM to further confirm safety and to assess the clinical activity of the 


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combination at the RP2D of belantamab mafodotin. Futility analyses will be conducted 
from when response data is available from 10 subjects. Details of the futility analysis are 
described in Section 9.5.2. 
4.5. 
Dose Justification 
4.5.1. 
Belantamab Mafodotin Starting Dose Justification 
The starting dose for belantamab mafodotin will be 2.5 mg/kg administered intravenously 
Q3W on Day 1 of each 21-day Cycle. Careful dose escalation and monitoring will be 
implemented to protect subjects’ safety throughout the study. 
The 2.5 mg/kg dose is considered to be appropriate starting dose for combination with a 
fixed dose of 200 mg pembrolizumab:  
• 
The starting dose of 2.5 mg/kg is one dose level below the 3.4 mg/kg, which had 
an acceptable safety profile in FTIH trial; 
• 
Per currently available data, it is anticipated that the starting dose of 2.5 mg/kg 
will be well tolerated and is not expected to result in an excessive toxicity;  
• 
Based on the non-specific clearance mechanism with large capacity of both: 
belantamab mafodotin and pembrolizumab, the likelihood for drug-drug 
interactions from combining belantamab mafodotin with pembrolizumab is low. 
 
4.5.2. 
Pembrolizumab Dose Justification 
The dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications. As outlined below, 
this dose is justified by:  
• 
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W 
to 10 mg/kg every 2 weeks (Q2W), representing an approximate 5 to 7 fold 
exposure range (refer to the IB) [Keytruda IB, 2021]. 
• 
Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W. 
• 
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
• 
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different 
treatment settings (monotherapy and in combination with chemotherapy). Five studies 
compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, 
KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg 


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Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, 
flat dose-exposure-response relationships were also observed in other tumor types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor 
type. These findings are consistent with the mechanism of action of pembrolizumab, which 
acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable 
overlap in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg 
Q3W dose. Supported by these PK characteristics, and given that fixed-dose has 
advantages of reduced dosing complexity and reduced potential of dosing errors, the 
200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols. 
 
4.6. 
Benefit: Risk Assessment 
Pembrolizumab 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on pembrolizumab that may impact subject eligibility is 
provided in the pembrolizumab approved labelling. For detailed background information 
on pembrolizumab refer to [Keytruda SmPC, 2017 and KEYTRUDA PI, 2018, Keytruda 
IB, 2021]. 
Belantamab Mafodotin 
Summaries of non-clinical findings and information regarding warnings, precautions, 
contraindications, adverse events, and other pertinent information on belantamab 
mafodotin that may impact subject eligibility is provided in the Investigator’s Brochure 
[GlaxoSmithKline Document Number 2013N175128-09, 2021]  


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4.6.1. 
Risk Assessment 
The risk assessment and risk mitigation plan for belantamab mafodotin and study 
procedures are summarized in Table 2. Refer to Table 5 for pembrolizumab guidance. 
There is a risk of overlapping toxicities with the combination of belantamab mafodotin 
and pembrolizumab. Potential overlapping toxicities and risk mitigation plans are 
provided in Table 2. The frequency and intensity of these assessments will allow 
Investigators and GSK to identify and to react to potential worsening of toxicities.  
 


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Table 2 
Risk Assessment and Mitigation Strategy 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential overlapping toxicities for belantamab mafodotin in combination with pembrolizumab) 
Keratopathy (changes 
to the corneal 
epithelium, potentially 
resulting in vision 
changes) 
Eye disorders 
associated with 
pembrolizumab 
Belantamab mafodotin: Changes in corneal epithelium on ocular 
examination have been frequently observed with belantamab mafodotin. 
This was most commonly associated with: blurred vision, dry eyes, 
photophobia, and changes in visual acuity.  
Participants with a history of dry eye were more prone to develop 
changes in the corneal epithelium. 
Based on available follow-up data, visual acuity returned to, or near 
baseline in most cases and no permanent loss of vision reported. 
 
Pembrolizumab: Eye disorders including dry eye, uveitis, and rarely 
Vogt-Koyanagi-Harada syndrome, have been reported with 
pembrolizumab. 
 
Active monitoring for corneal events according to Table 4.  
 
Timely evaluation and management by an ophthalmologist 
(or an optometrist if an ophthalmologist is not available) 
upon developing corneal related events (see Section 6.5.1 
and Appendix 9).  
 
In the event of new-onset eye-related symptoms (such as 
pain, significant loss of visual acuity, or bothersome foreign 
body sensation), participants are to urgently seek medical 
attention by a qualified eye care specialist (appropriate 
testing includes slit lap examination [includes fluorescein 
staining] and measurement of visual acuity). Appropriate 
management should be initiated immediately as defined in 
Section 6.5.1.  
 
Recommendations for dose delays / reductions are provided 
in Section 6.5.1.   
 
Infusion related 
reaction 
Belantamab mafodotin: IRRs were reported in patients treated with 
belantamab mafodotin. Most IRRs observed to date were Grade 1 to 2 
and manageable with medical treatment. 
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 
Subjects will be closely monitored for signs of IRR. 
Premedication prior to first infusion of belantamab mafodotin 
is not mandatory but may be considered based on 
investigator judgement.  
If an IRR occurs during belantamab mafodotin 
administration, management may follow guidance in Table 4 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
infusion and generally resolve completely within 24 hours of completion 
of infusion. 
or local standard of care. Management of pembrolizumab 
infusion reactions is provided in Table 6. 

Thrombocytopenia
Belantamab mafodotin: Thrombocytopenic events of all grades (1-4) 
are among the most common AEs associated with belantamab 
mafodotin.  
 
Pembrolizumab: Thrombocytopenia has been reported with 
pembrolizumab therapy. 
.  
Hematological panels are assessed frequently. Supportive 
therapy (including transfusions) is provided according to 
standard medical practice, and dose reductions or treatment 
discontinuations are outlined in Section 6.5. 
Neutropenia
Belantamab mafodotin: Neutropenic events, including febrile 
neutropenia have been observed with treatment with belantamab 
mafodotin,  
In a study of belantamab mafodotin in combination with lenalidomide/ 
dexamethasone, two fatal cases of severe infections associated with 
neutropenia have been observed.    
 
Pembrolizumab: Neutropenia has been reported with pembrolizumab 
therapy. 
 
Hematological panels are assessed frequently.  
Consider prophylactic antibiotics, per physician discretion 
and local institutional guidance, in subjects with Grade 3-4 
neutropenia 
 even if afebrile.  
Immediately hospitalize subjects with febrile neutropenia 
and initiation appropriate management, per local institutional 
guidance.  
Consider additional supportive treatment(s) per local 
practice (e.g., growth factors).  
Dose reductions or treatment discontinuations are outlined 
in Section 6.5  
Potential for 
cardiotoxicity related 
to an inflammatory 
Belantamab mafodotin: Nonclinical studies, predominantly in monkey, 
increased activation of macrophages was noted in a number of organs 
at ≥3 mg/kg/week, reflective of a systemic inflammatory response.  
Minimal inflammatory changes (inflammatory cell infiltrate and/or 
Subjects with significant cardiac risk factors will be excluded 
from study participation.  
CCI


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
response with 
belantamab mafodotin 
Cardiac disorders 
associated with 
pembrolizumab 
haemorrhage) were also noted in hearts (atrial epicardium, ventricle 
endocardium) of single monkeys, which were nonadverse and 
reversible. 
Incidence of cardiac events reported to date with belantamab mafodotin 
was relatively low and mostly grade 1-2.  
 
Pembrolizumab: Cardiac disorders including pericarditis, pericardial 
effusion, and myocarditis, have been reported with pembrolizumab 
therapy. 
Close monitoring of vital signs and ECG, troponin, and 
ECHO will be performed. 
Treatment as medically indicated. Monitoring of other 
cardiac parameters as clinically indicated.  
Dose modifications for myocarditis with pembrolizumab are 
provided in Table 5. 
Hepatotoxicity 
Belantamab mafodotin: In nonclinical studies liver is a target organ for 
toxicity, with increased liver weights and/or raised hepatobiliary enzymes 
and transaminases observed I both rat and monkey. These changes in 
the liver were without clinical consequence in the shorter duration 
studies and in the rat 13-week study. In the monkey 13-week study, 
progression of liver toxicity to include minimal multifocal hepatocellular 
necrosis was observed at all doses administered (≥3 mg/kg/week).  
Mild elevations of liver enzymes have been reported in some patients 
treated with belantamab mafodotin. 
 
Pembrolizumab: Hepatitis has been reported with pembrolizumab 
treatment. 
 
Only subjects with well-preserved liver function per the 
inclusion/exclusion criteria will be allowed on study.  
 
Subjects with Hepatitis B (HBV) and C will be excluded.  
 
Liver function tests will be frequently monitored. In case of 
liver abnormalities, management will be implemented 
according to clinical practice. Subjects that meet liver 
stopping criteria (Section 5.4.1.1) will be withdrawn from the 
study. 
Nephrotoxicity 
 
Belantamab mafodotin: Non-clinical safety studies have demonstrated 
dose dependent and reversible primary glomerular injury and tubular 
degeneration (in rat and monkey), accompanied by large molecular 
proteinuria (albuminuria) and enzymuria. Single cell necrosis of the 
kidney and bladder urothelium was also noted in the 13-week monkey 
study. Severe tubular degeneration/regeneration and marked 
glomerulonephritis exacerbated by immune complex disease, likely 
Subjects will be monitored for kidney function by assessing 
creatinine, eGFR, electrolytes, and albumin/creatinine 
rations (spot urine).  
 
Subjects will be educated about the need of maintaining 
adequate urinary output.  
 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
associated with ADA, led to the early euthanasia of one monkey 
following 5 weekly doses of 10 mg/kg.  
Increased albumin/creatinine ratio (albuminuria) not indicative of disease 
progression has been reported in clinical trials and named patient 
programs with belantamab mafodotin. 
 
Pembrolizumab: Renal disorders, including nephritis and acute kidney 
injury, have been reported with pembrolizumab treatment. 
 
Management will be implemented according to clinical 
practice.  
 
Dose reductions and treatment stopping criteria will be 
applied according to Section 6.5. 
 
Dose modifications for nephritis and renal dysfunction with 
pembrolizumab are provided in Table 5. 
Pulmonary toxicity 
(pneumonitis) 
 
Belantamab mafodotin: Nonclinical safety experiments have 
demonstrated the presence of progressive microscopic changes in the 
lungs (prominent alveolar macrophages associated with eosinophilic 
material; mixed perivascular/neutrophilic inflammation) in rats at all 
doses tested.   
Cases of pneumonitis, including fatal events, have been observed with 
belantamab mafodotin although a causal association has not been 
established.  
 
Pembrolizumab: Pneumonitis has been reported with pembrolizumab 
treatment. 
Monitoring for clinical signs and symptoms potentially 
related to pulmonary toxicity. If a participant experiences 
new or worsening pulmonary symptoms, (e.g., cough, 
dyspnea) without obvious etiology, appropriate diagnostic 
evaluation should performed (see protocol section 6.5.1) 
and further treatment with belantamab mafodotin delayed 
(refer to protocol section 6.5.1). 
An overall benefit/risk assessment should be considered for 
the participant prior to continuing belantamab mafodotin 
treatment.   
Dose modifications for pembrolizumab are provided in Table 
5. 
 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential for Other 
Laboratory 
abnormalities  
Belantamab mafodotin: An increased magnitude of AST relative to 
ALT consistent with increased skeletal troponin I was observed in the 
single dose monkey study. Increased skeletal troponin I and/or creatine 
kinase and aldolase was observed in the rat 3-week study.  
 
Cases of elevated aspartate aminotransferase (AST), lactic 
dehydrogenase (LDH) and creatine kinase (CK) alone or concomitant 
with no clear clinical correlate have been observed in clinical studies. 
 
Pembrolizumab: AST and ALT increase have been reported with 
pembrolizumab treatment. 
Laboratory parameters will be monitored as outlined in 
Section 7.  
 
Subjects with significant laboratory elevations (≥x3 ULN) 
should, where possible, have a sample sent to central 
testing of CK and LDH isoenzyme levels.  
 
Dose modifications for pembrolizumab ALT and AST 
elevations are provided in Table 5.   
Embryo-Fetal Toxicity 
Belantamab mafodotin: Nonclinical reproductive studies with 
belantamab mafodotin have not been conducted. Embryo-fetal toxicity is 
expected due to the cytotoxic component, cys-mcMMAF via nonspecific 
uptake and/or BCMA-mediated toxicity (due to reports of BCMA 
expression in human placental cells [Langat, 2008]). 
Use of belantamab mafodotin in pregnant women may cause fetal harm. 
Pembrolizumab: Animal reproduction studies have not been conducted 
with pembrolizumab; however, in murine models of pregnancy blockade 
of PD-L1 signaling has been shown to disrupt tolerance to the foetus 
and to result in an increased fetal loss. These results indicate a potential 
risk, based on its mechanism of action, that administration of 
pembrolizumab during pregnancy could cause fetal harm, including 
increased rates of abortion or stillbirth. 
See Contraception requirements in Section 6.11.1. 
 
Risks Related to Belantamab mafodotin not listed under potential overlapping toxicities 
Immunosuppression 
In non-clinical studies belantamab mafodotin has been associated with 
decrease in immunoglobulins in monkeys at all doses.  An increase in 
Subjects who have active infection will be excluded.  
 




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4.6.2. 
Benefit Assessment 
Currently there is no cure for MM, and after exhausting available treatment options 
patients frequently relapse, become refractory, and ultimately die of their disease.  This 
study will test a novel combination of belantamab mafodotin and pembrolizumab to 
assess safety, tolerability and clinical activity of this treatment. Belantamab mafodotin 
has been shown to induce immunogenic cell death phenomenon of MM cells in vitro, 
which provides a rationale for testing it in combination with pembrolizumab. It is 
reasonable to hypothesise that such combination will benefit MM patients, who are 
refractory to currently available treatments.  
4.6.3. 
Overall Benefit: Risk Conclusion 
Although there is limited human experience with belantamab mafodotin, and no clinical 
experience with the combination of belantamab mafodotin with pembrolizumab, given 
the currently available safety data and the low likelihood of drug-drug interactions 
between belantamab mafodotin and pembrolizumab, combination therapy may have an 
acceptable safety profile. Additionally, the combination may provide anti-tumor effect in 
subjects with MM; but this is unknown. 
Of note, excess deaths were noted with pembrolizumab in combination with lenalidomide 
and dexamethasone (Keynote-185) or in combination with pomalidomide and 
dexamethasone (Keynote-183) leading the FDA to suspend these phase 3 trials, in 
addition to other trials of anti-PD[L] therapies in combination with immunomodulatory 
agents in myeloma or non-Hodgkin’s lymphoma were suspended . Please refer to Section 
2.3.3 for additional information. This statement does not apply to patients taking 
KEYTRUDA (pembrolizumab) for an approved indication.  The safety and efficacy of 
using KEYTRUDA (pembrolizumab) for approved, on-label uses have been proven. 
(www.fda.gov/Drugs/DrugSafety/ucm574305.htm). Considering the measures taken and 
described in Section 7, to minimize risk to subjects, the potential risks associated with 
belantamab mafodotin in combination with pembrolizumab noted in Section 4.6.1 are 
justified by the anticipated benefits that may be afforded to subjects with MM. 
 


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5. 
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on belantamab mafodotin that may impact subject 
eligibility is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2013N175128_09, 2021]. 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on pembrolizumab that may impact subject eligibility is 
provided in the pembrolizumab approved labelling. For detailed background information 
on pembrolizumab refer to [Keytruda SmPC,2017 and KEYTRUDA PI, 2018]. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
5.1. 
Inclusion Criteria 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. 
Provide signed written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form 
2. 
Male or female, 18 years or older (at the time consent is obtained)   
3. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix 2) 
4. 
Subjects must:  
• Has histologically or cytologically confirmed diagnosis of MM, as defined by 
IMWG, 2014 [Rajkumar, 2014], and  
• Has undergone stem cell transplant or is considered transplant ineligible, and  
• Has been treated with at least 3 prior lines of prior anti-myeloma treatments 
including an IMiD (eg. lenalidomide or pomalidomide), a proteasome 
inhibitor (eg. bortezomib, ixazomib or carfilzomib) and an anti-CD38 
antibody alone or in combination. Line of therapy are defined by consensus 
panel of the International Myeloma Workshop [Rajkumar, 2011].  
• Has measurable disease defined as one the following: 
a) Serum M-protein 0.5 g/dL (5 g/L)  
b) Urine M-protein  ≥200 mg/24h  
c) Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an 
abnormal serum free light chain ratio (<0.26 or >1.65)  
5. Subjects with a history of autologous stem cell transplant are eligible for study 
participation provided the following eligibility criteria are met: 
a) 
transplant was > 100 days prior to study enrolment 
b) 
no active infection (s) 
c) 
subject meets the remainder of the eligibility criteria outlined in this 
protocol 
6. Adequate organ system functions as defined in Table 3 




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women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.  
A WOCBP must have a negative highly sensitive serum pregnancy test (as 
required by local regulations) within 72 hours of dosing on C1D1 and agree to use 
effective contraception during the study and for 4 months after the last dose of 
study medication.  
Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 8. 
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
9. 
Male subjects:  
• Male subjects are eligible to participate if they agree to the following from the 
time of first dose of study until 6 months after the last dose of study treatment 
to allow for clearance of any altered sperm: 
• Refrain from donating sperm 
PLUS either:  
• Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom, even if they have undergone a successful 
vasectomy, and female partner to use an additional highly effective 
contraceptive method with a failure rate of <1% per year as described in 
Appendix 8 when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant 
• Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies 
5.2. 
Exclusion Criteria 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential. 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Systemic anti-myeloma therapy or an investigational drug 14 days or five half-lives, 
whichever is shorter, preceding the first dose of study drug   
2. Plasmapheresis within 7 days prior to the first dose of study drug 
3. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose 
of study drugs 
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., 


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CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 
or higher immune related adverse event (irAE) 
5. Current corneal epithelial disease except mild punctate keratopathy 
6. Any major surgery within the last four weeks prior to the first dose of study therapy  
7. Presence of active renal condition (infection, requirement for dialysis or any other 
condition that could affect subject’s safety). Subjects with isolated proteinuria 
resulting from MM are eligible, provided they fulfil criteria given in Table 3 
8. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions (including lab abnormalities) that could interfere with subject’s safety, 
obtaining informed consent or compliance to the study procedures.  
9. Has received prior radiotherapy within 2 weeks of start of study therapy. Subjects 
must have recovered from all radiation-related toxicities, not require corticosteroids, 
and not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
10. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis 
11. Current active liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or 
gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease 
(including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary 
involvement of malignancy is acceptable if subject otherwise meets entry criteria  
12. Malignancies other than disease under study are excluded, except for any other 
malignancy from which the subject has been disease-free for more than 2 years and, 
in the opinion of the principal investigators and GSK Medical Monitor, will not affect 
the evaluation of the effects of this clinical trial treatment on the currently targeted 
malignancy (RRMM). Subjects with curatively treated non-melanoma skin cancer are 
allowed.  
13. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging 
(note that the repeat imaging should be performed during study screening), clinically 
stable and without requirement of steroid treatment for at least 14 days prior to first 
dose of study therapy  
14. Evidence of cardiovascular risk including any of the following: 
a. QTcF interval ≥470 msecs. 
NOTE:  The QT interval should be corrected for heart rate by Fridericia’s 
formula (QTcF).   
b. Evidence of current clinically significant uncontrolled arrhythmias; 
i. including clinically significant ECG abnormalities including 2nd 
degree (Type II) or 3rd degree atrioventricular (AV) block. 
c. History of myocardial infarction, acute coronary syndromes (including 
unstable angina), coronary angioplasty, or stenting or bypass grafting within 
six months of Screening. 
d. Class III or IV heart failure as defined by the New York Heart Association 
functional classification system (Appendix 4) 
e. Uncontrolled hypertension 
f. Presence of cardiac pacemaker (or defibrillator) with a predominantly 
ventricular paced rhythm, limiting ECG/QTcF analysis.  


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5.4. 
Withdrawal/Stopping Criteria 
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity (including but not restricted to meeting stopping criteria for significant toxicity as 
outlined in Section 5.4.1), or completion of pre-assigned treatment by reaching a 
maximum of 35 treatment cycles. In addition, study treatment may be permanently 
discontinued for any of the following reasons: 
• 
recurrent Grade 2 pneumonitis  
• 
subject has met any of the protocol defined safety stopping criteria (Section 
5.4.1) 
• 
deviation(s) from the protocol 
• 
request of the subject or proxy (withdrawal of consent by subject or proxy) 
• 
investigator’s discretion 
• 
concurrent illness that prevents further administration of study treatment(s) 
• 
study treatment must be permanently discontinued in case of pregnancy 
• 
subject is lost to follow-up  
• 
study is closed or terminated 
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF)  
If the subject withdraws the consent and discontinues from treatment due to toxicity, 
‘adverse event (AE)’ will be recorded as the primary reason for permanently 
discontinuation on the eCRF. 
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be re-entered the study.  
After the study treatment discontinuation, subjects will undergo end of treatment 
assessments 30 days (7 days) after the last dosing, or prior to the start of new anti-
cancer treatment (whichever occurs first). Subjects who discontinued treatment for 
reasons other than PD will be followed up every 3 weeks until confirmed PD, until 
initiation of a new anti-cancer therapy or death. All subjects with confirmed PD will be 
followed for OS and next subsequent anti-cancer therapy every 3 months until the end of 
study. End of study is defined in Section 5.5.2. 
The following actions must be taken for subjects who fail to attend the clinic for a 
required study visit: 
• 
The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible.  
• 
The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study.  
• 
In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 


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telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record.  
• 
Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”.  
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.  
5.4.1. 
Safety stopping criteria 
5.4.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology. 
The diagram below illustrates Liver Stopping Event Algorithm (Figure 3). 
Figure 3 
Liver Stopping and Monitoring Even Algorithm 
 
Refer to Appendix 5 for required Liver Safety Actions and Follow up Assessments. 


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5.4.1.2. 
Study Treatment Restart or Rechallenge 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless: 
• 
GSK Medical Governance approval is granted (as described below), 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the subject 
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments. 
5.4.1.3. 
QTc Stopping Criteria 
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.   
• 
QT interval corrected for heart rate by Fridericia’s formula (QTcF = QT / 
CubeRootRR) >530 msec  
OR 
• 
Increase of QTcF by ≥60 msec from baseline 
1Based on average QTc value of triplicate ECGs to include manual over-read.  For 
example, if an ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs 
over a brief period (e.g., within approximately 10 minutes of the abnormal ECG, if 
possible, and approximately 10 minutes apart from each other), and then use the averaged 
QTc values of the 3 ECGs to determine whether the subjects should have study 
treatment(s) withheld. 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.   
5.4.1.4. 
Left Ventricular Ejection Fraction (LVEF) stopping criteria 
Echocardiography (ECHO) must be performed at Screening and as outlined in the Time 
and Events Table (Table 7). Subjects who have an asymptomatic, absolute decrease of 
>15% in LVEF compared with baseline or an absolute decrease of >10% in LVEF 
compared with baseline and the ejection fraction is below 50% should temporarily 
interrupt study treatment and have a repeat evaluation of LVEF within 1 week.  ECHO 
should be repeated every 1 to 2 weeks for 4 weeks or until LVEF recovery to within 15% 
of baseline or to above 50% and within 10% of baseline depending on which stopping 
criteria above were met. 
• 
If the LVEF recovers (defined as absolute decrease 15% compared to baseline or 
50% and absolute decrease 10% compared with baseline) at any time during the 
next 4 weeks, after consultation and approval of the GSK Medical Monitor, the 
subject may be restarted on belantamab mafodotin at a reduced dose.  For such 


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subjects, monitoring of LVEF will be performed 2, 4, and 8 weeks after rechallenge, 
and then per protocol 
• 
If LVEF does not recover within 4 weeks, treatment with the combination of 
belantamab mafodotin and pembrolizumab should be permanently 
discontinued.  Ejection fraction should be monitored every 4 weeks for a total of 16 
weeks or until resolution 
Subjects with Grade 3 or 4 symptomatic left ventricular systolic dysfunction must 
discontinue treatment with the combination of belantamab mafodotin and 
pembrolizumab.  Ejection fraction should be monitored every 4 weeks for a total of 16 
weeks or until resolution. Copies of all ECHOs and cardiology consultations performed 
on subjects who experience a >15% decrease in LVEF from baseline or >10% decrease 
in LVEF from baseline and whose cardiac ejection fraction is <50% will require review 
by a GSK medical monitor.  Instructions for submitting qualifying ECHOs/MUGAs are 
provided in the Study Reference Manual (SRM). 
5.4.1.5. 
Troponin Evaluation and Stopping Criteria 
If post-screening, the local troponin is >Institutional ULN it is recommended that 
subjects undergo urgent evaluation of cardiac ischemia symptoms and ECG should be 
performed to rule out cardiac ischemia. An urgent repeat of troponin value and collection 
of sample for central lab evaluation should be obtained within 24 hours. 
Asymptomatic subject: 
If the second value of troponin is ≤ULN the subject can continue on study with close 
follow up of symptoms, ECG, and further troponin measurements as clinically indicated 
If the second value of troponin remains >ULN treatment with belantamab mafodotin 
should be interrupted. The subject should undergo cardiac evaluation including ECHO 
testing for cardiac function. Any re-start of study treatment must be discussed with the 
GSK medical monitor who will consult with a member of the internal cardiotoxicity 
panel prior to restart.  If the second value of troponin exceeds the threshold for MI 
according to local lab parameters, obtain cardiology consultation immediately. 
Permanently discontinue belantamab mafodotin and withdraw the subject from the study. 
Symptomatic subject: 
Obtain cardiology consultation immediately. Permanently discontinue belantamab 
mafodotin and withdraw the subject from the study. 
5.4.1.6. 
Valvular Toxicity Stopping Criteria 
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by ECHO 
(Grade 2 mitral/tricuspid/aortic valvular toxicity per National Cancer Institute- Common 
Toxicity Criteria for Adverse Events [NCI-CTCAE], version 4.03, [NCI, 2010]) should 
temporarily discontinue study treatment and have a repeat evaluation by ECHO within 
1 week.  ECHO should be repeated every 1 to 2 weeks for 4 weeks or until valve 
recovery to baseline. 


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CCI


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Infusion-Related Reactions Associated with pembrolizumab 
If an IRR occurs during and/or after the infusion of pembrolizumab, refer to Table 6 for 
further guidance. 
5.4.1.9. 
Allergic and Anaphylactic reaction stopping criteria 
All subjects will be monitored carefully for evidence of allergic response. A subject that 
exhibits signs or symptoms of severe hypersensitivity or anaphylaxis will receive 
appropriate medical treatment and be permanently withdrawn from the study.  
Additional stopping criteria in case of significant toxicity are provided in Section 6.5.1 
5.5. 
Subject and study Completion 
5.5.1. 
Subject completion 
For Part 1 and Part 2, a subject is considered to have completed the study if they received 
at least 1 cycle of combination study treatment, and:  
• The subject is followed until death, or  
• The subject is followed until the end of study 
The end of study is defined in Section 5.5.2. The end of study analyses will be performed 
at that time.  
The eCRF should continue to be completed during the follow up period (every 3 months 
(7 days) until the end of study. Please refer to Table 10 for assessments to be completed 
during PFS follow-up visits or OS follow-up. OS follow-up data can be based on 
contacting subjects via phone calls/e-mails/or, other means of communication. Subjects 
who cannot be contacted will be considered lost to follow up. Follow-up data will be 
entered into the eCRF. 
5.5.2. 
End of Study Definition 
A final data cut-off will occur when all participants have either died, progressed, 
withdrawn consent, or have been followed for a minimum of 24 months from the LSFD. 
Following 24 months post LSFD, PACT will be implemented. At this time, the collection 
of data for all recruited participants who no longer receive study treatment will stop 
entirely and clinical trial database will be closed. Those participants still benefiting from 
belantamab mafodotin will continue to receive study drug as assessed by the investigator, 
or can choose to discontinue belantamab mafodotin and only SAEs, overdose and 
pregnancy cases, and pre-specified ocular data will be reported directly to GSK. 
Dispensing of study treatment following 24 months post LSFD, will utilize a manual 
resupply option, and drug accountability assessment will be performed at the site. All 
participants will be monitored and will receive follow-up care in accordance with 
standard local clinical practice. For participants who do continue to receive belantamab 


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mafodotin beyond the time of the final data cut-off, investigators will continue to report 
all SAEs, pregnancy and overdose cases up to 70 days after last dose of study treatment, 
and pre-specified ocular data (see SRM) will be reported until resolution unless the event 
is considered by the investigator to be unlikely to resolve, or the patient is lost to follow 
up. Additionally, any SAE and pre-specified ocular event that are ongoing at the time of 
this data cut-off must be followed up to resolution, unless the event is considered by the 
investigator unlikely to resolve, or the patient is lost to follow-up. GSK retains the right 
to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of 
the study, if judged necessary. 
5.5.3. 
Treatment after the End of Study 
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment. If a subject remains on treatment at the time end of study is 
achieved they may be offered an option to extend treatment.  
6. 
INVESTIGATIONAL PRODUCT 
The term of “Study Treatment” are used throughout the protocol to describe belantamab 
mafodotin and pembrolizumab as the investigational products (IP)  
6.1. 
Investigational Products 
Product name: 
Belantamab Mafodotin 
Pembrolizumab 
[Formulation 
description:] 
Solution containing 20 mg/mL, 
1.5 mL/vial  
Solution containing 100 mg/4 mL 
Dosage form: 
20 mg/mL solution for infusion 
Supplied as frozen liquid.   
Protect from light. 
100 mg/4 mL solution that should 
be stored under refrigeration at 2-
8C (36-46F). 
Protect from light. Do not freeze. Do 
Not Shake. 
Unit dose 
strength(s)/Dosage 
level(s): 
20 mg/mL, 1.5 mL/vial  
100 mg/4 mL 
Route of Administration  
Delivered as IV infusion over at 
least 30 minutes. Infusions may be 
prolonged in the event of an 
infusion reaction. If subjects 
experience clinically significant 
infusion reactions, the infusion rate 
may be slowed for all future 
administrations of study 
treatment(s) for each subject. 
Should a global change in infusion 
rate be required, it will be 
communicated to sites in writing.   
Delivered as 30 min IV infusion 


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Dosing instructions: 
 
Dilute belantamab mafodotin 
solution in normal 0.9% saline to 
the appropriate concentration for 
the dose.  See SRM for detailed 
preparation procedures. 
Dilute pembrolizumab injection 
(solution) prior to intravenous  
Administration in 0.9% 
Sodium Chloride Injection, United 
States Pharmacopeia (USP) or 5% 
Dextrose Injection, USP. See SRM 
for detailed preparation procedures. 
Manufacturer/ Source of 
Procurement: 
GSK/Baxter 
Merck 
6.2. 
Medical Devices 
Not applicable. 
6.3. 
Treatment Assignment 
Dose level allocation will be performed by GSK after subject has given written informed 
consent and has completed the necessary screening assessments.  Eligible subjects will be 
enrolled to receive GSK2857916 at an assigned dose in combination with 200 mg of 
pembrolizumab. 
Additional details are outlined in the SRM. 
6.3.1. 
Study Treatment Administration 
For belantamab mafodotin, please refer to the SRM for additional details on 
administration. For pembrolizumab, the study medical staff should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a window between -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min).  
The Pharmacy Manual contains specific instructions for the preparation of the 
belantamab mafodotin and pembrolizumab infusion and administration of infusion 
solution. 
6.3.1.1. 
Belantamab Mafodotin Administration 
Belantamab mafodotin will be administered to subjects intravenously as mg/kg calculated 
dose at the study site .  The dose to be administered is based on actual body weight 
calculation, and may be reduced for toxicity according to protocol guidelines.  
Administration will be documented in the source documents and reported in the eCRF. 
The time of start and end of infusion will be documented in eCRF. 
Belantamab mafodotin will be administered over at least 30 minutes on Day 1 of each 
cycle at the assigned dose.  Premedication is not required prior to infusion unless deemed 
medically necessary by the investigator, in which case it should be administered 


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according to institutional recommendations. In case of infusion related reactions related 
to belantamab mafodotin the rules outlined in Section 5.4.1.8 and in Table 6 should be 
followed.  
After the infusion of belantamab mafodotin has been completed subject will be required 
to enter at least 1 hour rest period before start of pembrolizumab infusion. In case of IRR 
during belantamab mafodotin infusion, subject needs to recover to Grade 1 or less in 
order to be able to receive pembrolizumab infusion.  
6.3.1.2. 
Pembrolizumab administration 
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week 
treatment cycle after all procedures and assessments have been completed.  
Pembrolizumab will be administered as a dose of 200 mg using a 30 min IV infusion 
after at least approximately 1 hour rest period after completion of belantamab mafodotin 
infusion.  Premedication is not required prior to infusion unless deemed medically 
necessary, in which case it should be administered according to institutional 
recommendations.  
In case of IRR during or after preceding belantamab mafodotin infusion, the 
administration of pembrolizumab will be delayed to allow for recovery to Grade 1 or less. 
In total, the infusion of pembrolizumab may be delayed for up to the allowed +3 day 
window from the scheduled dose date to allow for recovery, and to accommodate 
scheduling conflicts in a given cycle. If the subject does not recover from IRR to Grade 1 
or less within the +3 day window, the dosing of pembrolizumab will be skipped in a 
given cycle, and may be resumed in the next cycle. 
All subjects are required to remain under observation at the study site for at least three 
hours post-infusion of the last study drug administered for the first two study treatment 
dosing visits. At subsequent study treatment dosing visits, for subjects who experience 
infusion-related reactions, the post-infusion observation time should remain as at least 
three hours; for subjects who do not experience infusion reactions, these subjects should 
remain under observation for a time period not shorter than one hour (or longer as per the 
judgement of the investigator or as per institutional guidelines.)  
In case of IRR during pembrolizumab administration –please refer to Table 6 for 
management guidelines. 
Detailed information on the preparation and administration, refer to [Keytruda SmPC, 
2017 and KEYTRUDA PI, 2018]. 
6.4. 
Planned Dose Adjustments 
6.4.1. 
Adjustments due to body weight 
The actual body weight in kg at the baseline (assessed on the Cycle 1 Day prior to 
dosing) will be used for dose calculation of belantamab mafodotin in all subjects during 


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the treatment period.  However, if the change of body weight is greater than 10%, the 
dose should be re-calculated based on the actual body weight on the day of dosing.   
A fixed dose of pembrolizumab will be used during the study. 
6.4.2. 
Intra subject dose escalation 
For subjects enrolled in Part 1 intra-subject dose escalations of belantamab mafodotin 
may be considered on a case-by-case basis, provided that the subject completed at least 2 
cycles at originally assigned dose, has tolerated treatment well, and did not experience 
the treatment related Grade 3 or higher toxicity. A subject’s dose may be increased to that 
of a completed cohort that has not exceeded the maximum pre-specified dose of 
3.4 mg/kg. Approval must be obtained from a GSK Medical Monitor. Dose-escalation 
decisions will be documented on a Dose Escalation/De-escalation Decision Form (see 
SRM). 
6.5. 
Subject Specific Dose Adjustment Criteria 
6.5.1. 
Dose modifications and management for belantamab mafodotin-
related toxicity 
Subjects should have their dose (including the first dose and subsequent doses) delayed 
or reduced for toxicities according to the recommendations as listed in Table 4. Dose 
reductions are only allowed for belantamab mafodotin.  
In individual cases where, in the judgement of an investigator, waiting a full planned 
Cycle (21 days) to resume treatment after delays due to toxicities would be detrimental to 
the subjects’ health, the Medical Monitor should be contacted to discuss an earlier re-
start. An earlier re-start may be considered only for subjects who have recovered from 
toxicity to Grade 1 or less. Dosing cannot occur more frequently than every 21 days (±3 
days).  In such cases, efficacy and safety assessments must remain every 3 weeks from 
the initial efficacy and safety assessments (Cycle 1 Day 1), which may result in 2 
separate visits (1 for disease assessment [Table 8] and 1 for dosing [Table 9]). 
No dose reductions are allowed for pembrolizumab. Dose Modification Guidelines for 
Pembrolizumab-Related Adverse Events are listed in Table 5. 
If belantamab mafodotin is held or discontinued for any toxicity, pembrolizumab is to be 
held or discontinued. 
For drug related toxicities which are not listed in Table 4 and Table 5,  the general rule of 
withholding the dose at Grade 3 or greater toxicity should be followed.  
Resuming treatment will be possible with or without dose reduction after the toxicity has 
resolved to Grade 1 or less, and in agreement between PI and GSK Medical Monitor.  
 


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Table 4 
Dose Modification Guidelines for Belantamab Mafodotin-Related Adverse Events 
Toxicity 
Grade 
Recommendations to belantamab mafodotin 
Recommendations to 
pembrolizumab 
Serum creatinine elevation or 
decrease in eGFR which cannot 
be explained by concomitant 
sepsis, TLS, other severe 
infection with fever or dehydration 
 If absolute serum 
creatinine increase 
from baseline of >0. 
5 mg/dL 
• Repeat serum creatinine within 48 hours  
• If confirmed: withhold therapy, institute treatment and monitoring 
as clinically indicated, and follow for resolution 
• Discuss any further dosing with Medical Monitora 
See Table 5 for guidance on 
pembrolizumab 
Serum creatinine>Grade 3 (acute 
kidney injury) 
 
>3.0mg/dL from 
baseline 
 Or 3.0-6.0xULN  
• 
Provide appropriate medical treatment. 
• Permanently discontinue treatment with belantamab mafodotin  
Resume treatment with 
pembrolizumab only if 
treatment with belantamab 
mafodotin may be continued 
Spot urine (albumin / creatinine 
ratios) 
>2000 mg/g  
(or 224 mg/mmol) 
• Re-test (at least 7 days apart). 
• If not confirmed, continue belantamab mafodotin at current dose 
• If confirmed on re-test and no clear evidence of disease 
progressionc 
o Interrupt treatment with belantamab mafodotin 
o Repeat testing within 4 weeks 
o If spot urine <2000 mg/g (224/mg/mmol) may restart 
belantamab mafodotin with one dose level reduction 
o If spot urine remains >2000 mg/g (224/mg/mmol) 
after 4weeks; permanently discontinue belantamab 
mafodotin  and discontinue study treatment; provide 
treatment as clinically indicated and follow for 
resolution 
Resume treatment with 
pembrolizumab only if 
treatment with belantamab 
mafodotin may be continued 
 
Thrombocytopenia  
(on days of dosing) ) 
3-4 
• 
Withhold treatment until thrombocytopenia recovered to 
Grade 2 or less (≤G2). 
• 
If Grade 3-4 thrombocytopenia is considered disease-related, 
treatment may be continued with dose reduction and more 
Delay treatment until the next 
belantamab mafodotin dose 


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Toxicity 
Grade 
Recommendations to belantamab mafodotin 
Recommendations to 
pembrolizumab 
frequent hematology monitoring, until recovery to Grade 2 or 
less. 
x
Implement supportive treatment (e.g. transfusion) as clinically 
indicated and per local practice. 
Febrile neutropenia 
Defined as: single 
temp of 38.3oC, or 
sustained 38oC for 
>1 hr AND ANC 
<1.0x109/L 
x
Withhold belantamab mafodotin and pembrolizumab and 
hospitalize subject with appropriate management, per local 
institutional guidance 
x
Consider additional supportive treatment per local guidance (e.g., 
growth factors) 
x
Upon recovery, consider a dose reduction of belantamab 
mafodotin, if neutropenia was drug related 
x
Delay treatment until the 
next belantamab 
mafodotin dose 
Neutropenia 
≥3 (Defined as ANC 
<1.0x109/L 
x
If noted on Day 1 of any cycle, withhold belantamab mafodotin. 
Repeat hematology (CBC) as clinically indicated until recovery to 
Grade 2 or less.  
x
Resume belantamab mafodotin at pre-hold dose once neutropenia 
recovers to Grade ≤2 
 on Day 1 of the 
subsequent cycle. 
x
Implement supportive care as clinically indicated per local practice 
x
Delay treatment until the 
next belantamab 
mafodotin dose 
In case of 
recurrence of 
frequent episodes of 
neutropenia 
 
 
x
Consider dose reduction of belantamab mafodotin, if it was drug-
related. 
x
Delay treatment until the 
next belantamab 
mafodotin dose 
Belantamab mafodotin Treatment 
Related Corneal eventsb 
Corneal 
Management Care 
Regardless of Grade 
Preservative-free artificial tears:   
x
Increase to 1 drop as frequently as every 2 hours, as needed 
Grade 1 per GSK 
Scale 
x
Continue treatment with current treatment with belantamab 
mafodotin   
x
None 
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Toxicity 
Grade 
Recommendations to belantamab mafodotin 
Recommendations to 
pembrolizumab 
Grade 2 per GSK 
Scale 
• 
If Grade 2 finding (visual acuity and/or exam finding) and the 
subject is asymptomatic, continue dosing with belantamab 
mafodotin.  
• 
If Grade 2 finding (visual acuity and/or exam findings) and the 
patient is symptomatic.  
o DOSE REDUCE and continue treatment.   
o If already on 1.92 mg/kg, subject may continue at current 
dose.   
• 
Upon improvement of either visual acuity or ophthalmic exam 
findings to ≤Grade 1 and improvement in symptoms, dose may be 
re-escalated to previous dose.   
• 
Hold/Delay treatment 
until the next 
belantamab mafodotin 
dose 
Grade 3 per GSK 
Scale  
• 
If Grade 3 finding (exam finding) and the subject is 
asymptomatic: continue dosing with belantamab mafodotin. 
 
• 
If Grade 3 exam finding and the subject is symptomatic or Grade 
3 visual acuity: 
o HOLD belantamab mafodotin . Upon improvement of either 
visual acuity or ophthalmic exam findings to ≤ Grade 2 and 
improvement in symptoms continue treatment with dose 
REDUCTION. 
o If already on 1.92 mg/kg subject may continue at current dose  
• 
If after event resolution eye symptoms are considered stable for at 
least 3 cycles consider re-escalation to previous dose. 
• 
Hold/Delay treatment 
until the next 
belantamab mafodotin 
dose 
Grade 4 per GSK 
Scale  
• 
Hold treatment with belantamab mafodotin. 
• 
Treatment re-start may be possible after discussion and 
agreement between the treating ophthalmologist*, treating 
physician, the GSK Medical Monitor  
• 
*or optometrist, if an ophthalmologist is not available 
• 
Stop treatment with 
pembrolizumab.   
• 
Further treatment only 
possible if belantamab 
mafodotin is allowed to 
restart  


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Toxicity 
Grade 
Recommendations to belantamab mafodotin 
Recommendations to 
pembrolizumab 
Infusion Reactionc 
2 
Stop the infusion, provide medical treatment and continue at slower 
pace after resolution to Grade 0-1 
See Table 6 for guidance on 
pembrolizumab 
 
 
3 
Further treatment with belantamab mafodotin needs to be discussed 
with Medical Monitor. Continuation only allowed after recovery to 
Grade 1 and with pre-medication, and extension of infusion time to 2-
4 hours. Any future infusion needs to be pre-medicated 
4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Continue when toxicity resolves to Grade 0-1 
See Table 5 for guidance on 
pembrolizumab  
Grade 3-4 
Permanently discontinue 
Permanently discontinue 
a. Medical Monitor may consult GSK's nephrotoxicity panel about plans to continue therapy 
b. Corneal toxicity should be graded according to GSK scale for belantamab mafodotin treatment related Corneal Events (Appendix 9). 
c. 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 
 


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6.5.2. 
Dose modification and toxicity management for immune-related 
AEs associated with pembrolizumab 
AEs associated with pembrolizumab combination exposure, including coadministration 
with additional compounds, may represent an immune-related response.  These immune 
related AEs (irAEs) may occure shortly after the first dose or several months after the last 
dose of pembrolizumab combination treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical 
to reduce complications. Based on existing clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab combination 
treatment, 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. Dose modification and toxicity management guidelines 
for irAEs associated with pembrolizumab are provided in Table 5. 
Attribution of Toxicity: 
 
When study interventions are administered in combination, attribution of an adverse 
event to a single component is likely to be difficult. Therefore, while the investigator may 
attribute a toxicity event to the combination, to belantamab mafodotin alone, or to 
pembrolizumab alone, for adverse events listed in Table 5, both interventions must be 
held according to the criteria in [Table 5]. 
Holding Study Interventions: 
 
When study interventions are administered in combination, if the AE is considered 
immune-related, both interventions should be held according to recommended dose 
modifications.  
Restarting Study Interventions: 
 
Subjects may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 5.If the toxicity does not resolve or 
the criteria for resuming treatment are not met, the subject must be discontinued from all 
study interventions.If the toxicities do resolve and conditions are aligned with what is 
defined in Table 5, the combination of belantamab mefodotin and pembrolizumab may be 
restarted at the discretion of the investigator.   


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Table 5 
Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
General instructions: 
1. Severe and life-threatening irAEs, should be treated with IV corticosteroids fllowed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
2. Pembrolizumab must be permanently discontinued if AE does not resolve or the corticosteroid dose is ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment. 
3. The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks.  
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.  
 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
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 to 2 mg/kg prednisone or 
equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
• 
Monitor subjects for signs and symptoms of 
pneumonitis 
• 
Evaluate subjects with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment 
• 
 
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor subjects 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). 
• 
Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis.  
• 
Subjects with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids.  If 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
AST / ALT 
elevation or 
Increased Bilirubin 
Grade 21 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5 to 1 mg/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 32 or 43  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold4 
• Initiate insulin replacement therapy 
for subjects with T1DM  
• Administer an antihyperglycemic in 
subjects with hyperglycemia  
 
• 
Monitor subjects 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 
discontinue4  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with nonselective 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 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Hypothyroidism 
Grade 2, 3 or 4 
Continue  
• Initiate thyroid replacement 
hormones (e.g. levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis; grading 
according to 
increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities  
Grade 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 
Myocarditis 
 
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis 
(previously CTCAE 
v4.0 Grade 1) 
 
Withhold  
• Based on severity of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology, 
or exclude other causes  
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
 Persistent Grade 2 
Withhold 
• Based on severity of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Grade 3 
Withhold or 
discontinue based 
on event5.   
 
Recurrent Grade 4 
or Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal;; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
NOTES: Non-irAE will be managed as appropriate, following clinical practice recommendations.   
1. AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0   5.0 x baseline, if baseline abnormal; bilirubin:>1.5   3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if 
baseline abnormal  
2. AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0   20.0 x baseline, if baseline abnormal; bilirubin:>3.0   10.0 x ULN if baseline normal; >3.0 - 10.0 x 
baseline if baseline abnormal 
3. AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline 
abnormal 
4. The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  If control achieved or ≤ Grade 
2, pembrolizumab may be resumed.  .   
5. Events that require discontinuation include but are not limited to: encephalitis, and other clinically important irAEs (eg. Vasculitis and sclerosing cholangitis). 
6.5.3. 
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 in Table 6.  


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6.6. 
Blinding 
This is an open-label study.  
6.7. 
Packaging and labelling/Preparation/Handling/Storage 
The contents of the label will be in accordance with all applicable regulatory 
requirements.  
Open label vials of belantamab mafodotin solution 20 mg/mL, 1.5 mL, each carton 
contains 1 x vial.  
Open label vials of pembrolizumab solution (100 mg/4 mL), each carton contains 1 x 
vial. 
6.7.1. 
Belantamab Mafodotin 
Preparation 
Belantamab mafodotin Solution for Infusion, 20 mg/mL, 1.5 mL is supplied as a frozen 
liquid. Before use, thaw each vial of belantamab mafodotin and prepare infusion solution.  
Refer to the SRM for further details on preparation of belantamab mafodotin. 
Handling 
Under normal conditions of handling and administration, investigational product (IP) is 
not expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. 
In the case of unintentional occupational exposure notify the study monitor, the GSK 
Medical Monitor and/or the study manager. 
Refer to the SRM for detailed procedures for the disposal and/or return of unused study 
treatment(s). 
Administration 
Belantamab mafodotin is compatible with polyvinylchloride-lined or polyolefin-lined 
intravenous infusion administration sets, 0.2 micron polyethersulfone filters, or optionally 
a polyurethane catheter.  Doses of belantamab mafodotin are to be administered as an IV 
infusion via an infusion pump that can ensure precision to the decimal point of a mL for 
the infusion rate at lower doses. It is recommended to prime the IV tubing with at least 15 
mL prior to dosing. 
 


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Storage 
Belantamab mafodotin must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the belantamab mafodotin 
will be limited to the investigator and authorized site staff.  Belantamab mafodotin must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.   
Belantamab mafodotin is to be stored at a temperature range of -50C to -15C.  
Maintenance of a temperature log is required.  
6.7.2. 
Pembrolizumab 
Preparation 
Pembrolizumab will be provided in a single-use vial at 100 mg/4 mL (25 mg/mL).  
Preparation for intravenous infusion: withdraw the required volume from the vials of 
pembrolizumab and transfer into an intravenous (IV) bag containing 0.9% sodium 
chloride injection, USP or 5% dextrose injection, USP.  The final concentration of the 
diluted solution should be between 1 mg/mL to 10 mg/mL. Refer to the SRM for further 
details on preparation of pembrolizumab. 
Handling 
Under normal conditions of handling and administration, investigational product (IP) is 
not expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. 
In the case of unintentional occupational exposure notify the study monitor, the GSK 
Medical Monitor and/or the study manager. 
Refer to the SRM for detailed procedures for the disposal and/or return of unused study 
treatment(s). 
Administration 
Pembrolizumab infusion solution should be intravenously administered over 30 minutes 
through an intravenous line containing a sterile, non-pryogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter. However, given the variability of infusion 
pumps from site to site, a window between -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes -5 min/+10 min). 
 


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Storage 
The vials of pembrolizumab (100 mg/4 mL) solution should be stored under refrigeration 
at 2-8C (36-46F) in original carton to protect from light. Do not freeze and do not 
shake.  
6.8. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product (IP) and other study treatments dispensed and/or administered to 
study subjects, and the amount received from and returned to GSK, when applicable.  
Product accountability records must be maintained throughout the course of the study.  
Refer to the SRM for further detailed instructions on product accountability. 
6.9. 
Compliance with Study Treatment Administration 
Both study drugs: belantamab mafodotin and pembrolizumab will be administered 
intravenously to subjects at the study site.  The dose of pembrolizumab will be 200 mg. 
The dose of belantamab mafodotin is based on body weight calculation, and will be 
escalated from 2.5 mg/kg to 3.4 mg/kg in Part 1. The dose of GSK1857916 in Part 2 will 
be the RP2D as established in Part 1. The dose of belantamab mafodotin may be reduced 
for toxicity according to protocol guidelines.  
6.10. 
Treatment of Investigational Product Overdose 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported to the sponsor within 24 hours of awareness. 
Events of clinical interest for this trial include:  
1. an overdose of Sponsor's product, as defined below – Treatment of Overdose, 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 made available. It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of 
abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to 
proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this trial. 


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For this study, an overdose of pembrolizumab will be defined as 1000 mg or ≥5 times the 
indicated dose.No specific information on the treatment of overdose of pembrolizumab 
and belantamab mafodotin. 
In the event of an overdose (defined as administration of more than the protocol-specified 
dose) of belantamab mafodotin and pembrolizumab, the investigator should: 
• 
contact the GSK Medical Monitor immediately 
• 
closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until belantamab mafodotin can no longer 
be detected systemically (at least 3 months) 
• 
obtain a plasma sample for pharmacokinetic (PK) analysis within 24 hours of 
the event if requested by the GSK Medical Monitor (determined on a case-by-
case basis) 
• 
document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF 


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6.11. 
Lifestyle and/or Dietary Restrictions 
6.11.1. 
Contraception 
Belantamab mafodotin and pembrolizumab may have adverse effects on a fetus in utero. 
The cytotoxic component of belantamab mafodotin, MMAF, disrupts microtubule 
function, is genotoxic, and can be toxic to rapidly dividing cells, suggesting it has the 
potential to cause embryotoxicity and teratogenicity and should not be administered to 
pregnant or lactating women [GlaxoSmithKline Document Number 2013N175128_09, 
2021]. Furthermore, it is not known if pembrolizumab has transient adverse effects on the 
composition of sperm. 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.  
6.11.1.1. 
Female Subjects 
In order to participate in the study, WOCBP must adhere to the contraception 
requirement (from the day of study medication initiation) during the study and for 9 
months after the last dose of study treatment. If there is any question that a WOCBP will 
not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. Full details are in Appendix 8.  
6.11.1.2. 
 Male Subjects 
Male subjects with female partners of child bearing potential must comply with the 
contraception requirements highlighted in Section 5.1 from the time of first dose of study 
medication until 140 days after the last dose of belantamab mafodotin. Details on 
contraceptive options for subjects with a partner of childbearing potential are in 
Appendix 8.  
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration from 
the time of first dose of study until 6 months after the last dose of study treatment to 
allow for clearance of any altered sperm.   
6.11.1.3. 
Lactation Restrictions 
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for 4 
months following the last dose of study treatment. 
6.11.2. 
Subjects with Contact Lenses 
Contact lenses are prohibited while on the study treatment (from first dosing to the end of 
study treatment). Contact lens use may be restarted after the ophthalmologist (or an 
optometrist if an ophthalmologist is not available) confirms there are no other 
contraindications.  
Use of bandage contact lenses is permitted during study treatment as directed by the 
treating ophthalmologist (or optometrist if an ophthalmologist is not available).  


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6.12. 
Concomitant Medications/Vaccinations and Non-Drug 
Therapies 
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the treatment 
visit.  Any concomitant medication(s), including non-prescription medication(s) and 
herbal product(s), taken during the study will be recorded in the eCRF. Additionally, a 
complete list of all prior anti-cancer therapies will be recorded in the eCRF. 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. The SRM will be 
updated to include this information. Any such changes will be communicated to the 
investigative sites in the form of a letter. 
6.12.1. 
Permitted Medication(s) 
Subjects should receive full supportive care during the study, including transfusion of 
blood products, growth factors, and treatment with antibiotics, anti-emetics, 
antidiarrheals, and analgesics, as appropriate. 
Concomitant therapy with bisphosphonates and RANKL inhibitors are allowed. 
Subjects may receive local irradiation or elective surgery, eg. for pain control after 
discussion with the medical monitor.   
6.12.2. 
Tumor Lysis Syndrome (TLS) Prevention and Treatment 
Recommendations 
Subjects with a high tumor burden with a high proliferative rate might be at risk for TLS 
and should be monitored for clinical and laboratory signs of tumor lysis. Specifically, all 
subjects with elevated uric acid (>8 mg/dL, or >476 mmol/L) should receive prophylaxis 
with allopurinol, or rasburicase. All subjects should be hydrated to reduce risks for renal 
toxicity and tumor lysis syndrome (TLS) with belantamab mafodotin treatment. Adequate 
fluid volume status should be maintained throughout treatment and blood chemistries 
should be monitored as indicated in the Time and Events Tables in Section 7 or more 
frequently if clinically indicated. Prior to the first dose in Cycle 1, all subjects should 
receive at least 250- 500 mL of intravenous normal saline or other appropriate 
intravenous fluid. Additionally, 250-500 mL of intravenous fluid should be given as 
needed following belantamab mafodotin administration. Intravenous hydration should be 
continued, as needed, in subsequent cycles and subjects should be monitored for fluid 
overload during this period. 
If the constellation of clinical and/or laboratory signs tested on Cycle 2 Day 1 indicates a 
possibility of developing TLS, subjects should be hospitalized with frequent monitoring 
of clinical signs and clinical chemistries and treated accordingly. 


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Note: If after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance. Refer to Table 5 for guidelines regarding 
dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
6.12.5. 
Prohibited Medication(s) 
Chronic treatment with oral steroids is prohibited while the subject is on study, unless for 
treatment of acute complications related to study treatment, or pre-medication prior to 
belantamab mafodotin, or pembrolizumab infusion. Steroids may be used to treat infusion 
related reactions. Inhaled steroids are allowed for management of asthma, or COPD.  
Elimination pathways for belantamab mafodotin and cys-mcMMAF have not been 
characterized in humans. Cys-mcMMAF was not an inhibitor, an inducer, or a good 
substrate of cytochrome P450 (CYP) enzymes in vitro. Cys-mcMMAF was shown to be a 
substrate of P-glycoprotein (P-gp), and strong inhibitors of OATP1B1 and OATP1B3 
should be avoided unless considered medically necessary.  
A list of Prohibited Concomitant Medications is provided in SRM, based on known 
interactions or characteristics of each component of the Study Treatment. 
Other Prohibited Therapies: 
• 
Plasmapheresis is prohibited from 7 days prior to study entry through the end of 
study.   
• 
Anti-cancer therapies other than those referred to as Study Treatment that include 
but are not limited to chemotherapy, immunotherapy, biologic therapy, hormonal 
therapy (other than physiologic replacement), surgery, and radiation therapy 
(other than palliative intervention as described in Section 6.12.1). Radiation 
therapy or surgery may be permitted after mutual agreement of the investigator, 
the sponsor and the subject.   
• 
Investigational agents other than pembrolizumab and belantamab mafodotin 
• 
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 (oral) 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. 
 
6.13. 
Continued Access to Study Intervention after the End of the 
Study 
Participants receiving belantamab mafodotin following 24 months post LSFD (at the time 
of study completion) may continue to receive belantamab mafodotin, if, in the opinion of 
their treating physician, they are continuing to derive clinical benefit from continued 
treatment. Study treatment will continue until a study discontinuation criterion (see 
Protocol Section 5.4) as assessed by the investigator has been met. Investigators will 
report all SAEs, overdose and pregnancy cases until 70 days after receipt of their last 


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dose of study treatment and pre-specified ocular data (see SRM) will be reported until 
resolution unless the event is considered by the investigator to be unlikely to resolve, or 
the patient is lost to follow up. Post EOS, data cut-off, recording and follow up of SAEs 
and pre-specified ocular data will be done via paper forms. Drug accountability data will 
also be collected at site. Assessments will revert to standard of care at their particular site. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments being performed. 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
The timing of each assessment is listed in the Time and Events Tables (Table 7, Table 8, 
Table 9, and Table 10).  The timing and number of the planned study assessments may be 
altered during the course of the study based on newly available data (e.g. to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring for the 
following assessments: safety, PK, or other assessments. The change in timing or 
addition of time points for any of the planned study assessments listed above must be 
approved and documented by GSK, but this will not constitute a protocol amendment. 
The IRB or EC will be informed of any safety issues that require alteration of the safety 
monitoring scheme.  The maximum amount of blood collected in Screening and during 
the first Cycle 1 from each subject for the Dose Escalation and for the Dose Expansion is 
no more than 120 mL of blood (the details will be provided in SRM). 
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.  Detailed procedures for obtaining each assessment are provided in 
the SRM.  
 






















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7.1. 
Screening and Critical Baseline Assessments 
The following demographic parameters will be captured during Screening: date of birth, 
gender, race and ethnicity. 
Medical/medication history assessed as related to the eligibility criteria listed in Section 
5. 
Baseline (at Screening and/or on Day 1 prior to belantamab mafodotin infusion) 
assessments obtained will include: 
• Complete physical examination, including height (in cm) and weight (in kg). 
• Vital signs (blood pressure, body temperature, pulse rate) 
• Ocular exam 
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Clinical laboratory tests outlined in Table 11 
• Serum beta-human chorionic gonadotropin (-HCG) pregnancy test for female 
subjects of childbearing potential only 
• 12-lead electrocardiogram (ECG) 
• Echocardiogram (ECHO)  
• Imaging studies CT, MRI or PET-CT (for subjects with extramedullary disease) 
• BM aspirate/biopsy for disease assessment, FISH, BCMA  
• Serum (soluble BCMA, chemokines/cytokines, and anti-drug-antibodies) 
• Plasma cfDNA 
• Review of concomitant medications 
• PRO-CTCAE 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for Screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study. 
Cardiovascular medical history/risk factors will be assessed at baseline. 
7.2. 
Efficacy 
Standard disease assessments for MM will include the following assessments:  
• UPEP (24 hour), with M protein 
• Urine Immunofixation   
• SPEP, with M protein 
• Serum immunofixation 
• Corrected Calcium  
• Quantitative Immunoglobulins (IgG, IgA, and IgM and for subjects with IgD or IgE 
myeloma, quantitative IgD or IgE)  
• Serum kappa and lambda free light chains and FLC ratio 


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• Bone marrow aspirate and/or core biopsy at screening for baseline PC percentage and 
FISH analysis; and for disease response assessment at time of suspected CR/sCR, or 
PD 
• At time of VGPR or CR, MRD testing on bone marrow aspirate  
• Imaging by CT, MRI, CT/PET or X-ray to assess EMP and bone lesions. For sites in 
Germany, only MRI is allowed as imaging modality 
• Skeletal survey (Screening and as clinically indicated). For sites in Germany, only 
MRI is allowed as imaging modality 
Response evaluation will be performed according to the International Myeloma Working 
Group Uniform Response Criteria for Multiple Myeloma 2016 [Kumar, 2016]. 
Clinical activity measured as ORR which is defined as follows: 
The percentage of subjects with confirmed sCR, CR, VGPR, and PR as assessed by 2016 
recommendations of the International Myeloma Working Group (IMWG)) [Kumar, 
2016].  Other assessments of interest like CBR, PFS, TTR, DOR, and OS may also be 
considered. Minimal residual disease negative rate will be assessed in those subjects who 
achieve a VGPR or CR. 
In subjects with extramedullary myeloma- the disease assessments have to include 
imaging (e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI], or 
PET/ CT scan) and physical examination (as indicated for palpable/superficial lesions). 
For subjects with skin only involvement, skin lesions should be measured with a ruler.  
Measurement of tumor size will be determined by the Sum of the Products of the 
maximal perpendicular diameters of measured lesions (SPD).    
Baseline serum disease assessment will be completed during screening period (within 28 
days prior to the fist dose of study medication) and baseline imaging within 28 days prior 
to the first dose of study treatment. On study serum and urine based assessments (M-
protein, FLC, immunofixation) and imaging, for extramedullary disease, will be 
performed as required.  The final assessments will be performed during final study visit 
(End of treatment visit).  See the Time and Events Tables (Table 7, Table 8, and Table 
10) for the schedule of assessments of anti-cancer activity. Assessments must be 
performed on a calendar schedule and should not be affected by dose 
interruptions/delays.  For post-baseline assessments, a window of 3 days is permitted to 
allow for flexible scheduling. For imaging assessments, a window of  Q12 weeks (±3 
weeks) through 1 year and then as clinically indicated. 
In subjects with extramedullary MM: if the last radiographic assessment was more than 8 
weeks prior to the subject’s withdrawal from study and progressive disease has not been 
documented, a disease assessment should be obtained at the time of withdrawal from 
study. 
MRD negativity rate (defined as: the percentage of subjects who are MRD negative by 
clonoSEQ).  During treatment, testing will be performed for subjects achieving VGPR or 
CR. In subjects who have achieved MRD negativity, the testing will be repeated after 6 
and 12 months (provided CR is maintained) from time of first documented negative 


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MRD result to assess sustained MRD negativity. MRD testing will be performed by a 
central lab.   
7.3. 
Safety 
Planned time points for all safety assessments are provided in the Time and Events 
Tables (Table 7, Table 8, Table 9, and Table 10). 
7.3.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
Definition of and Procedures for Recording, Evaluating, Follow-Up and Reporting of an 
AE or SAE can be found in Appendix 7 (Section 12.7) 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE) 
as outlined in Section 7.3.1.2. 
7.3.1.1. 
Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  
All AEs will be collected from the time the first dose of study treatment is administered 
until 45 days following cessation of treatment regardless of initiation of new anticancer 
therapy.  
All SAEs will be collected from the time the first dose of study treatment is administered 
until 45 days following cessation of study treatment. In addition, any SAE assessed as 
related to study participation (e.g., protocol-mandated procedures, invasive tests, or 
change in existing therapy), study treatment or GSK concomitant medication must be 
recorded from the time a subject consents to participate in the study up to and including 
any follow-up contact. All SAEs will be reported to GSK within 24 hours, as indicated in 
Section 7.3.1.7. 
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up. At any time after 45 days the investigator may report any AE that they believe 
possibly related to study treatment. 
Investigator is no longer required to  to review and approve SAEs in InForm within 72 
hours of awareness of event. They will continue to record casuality assessment for SAEs 
in source notes. 
Following 24 months post LSFD, participants still deriving clinical benefit in the opinion 
of their treating physician may continue to receive belantamab mafodotin. For these 
participants, GSK will continue to collect safety information including SAEs, overdose 
and pregnancy cases and pre-specified ocular data via paper forms which will be reported 
directly to GSK. For these participants, SAEs, overdose and pregnancy cases will be 


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reported during the treatment period and for up to 70 days after last dose and pre-
specified ocular data will be reported until resolution unless the event is considered by 
the investigator to be unlikely to resolve, or the patient is lost to follow up. 
 
7.3.1.2. 
Method of Detecting AEs and SAEs 
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include: 
“How are you feeling?”  
“Have you had any (other) medical problems since your last visit/contact?” or for 
pediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?” 
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for pediatric studies, ”Has your child needed to take any medicines, 
other than those provided in this study, since his/her last visit/contact?” 
Definition of an AE 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE).  
 “Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE.  
Events that do not meet the definition of an AE include: 


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
led to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
Definition of an SAE 
An SAE is any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-subject setting. Complications that occur during hospitalization are 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect.  
f. Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may 


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jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.  Examples of such events are invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
g. Protocol-Specific SAEs: 
• 
All events of possible study treatment-induced liver injury with 
hyperbilirubinemia defined as alanine aminotransferase (ALT) 3 times upper 
limit of normal (ULN) and bilirubin ≥2 times ULN (>35% direct) (or 
ALT ≥3 times ULN and international normalization ratio (INR) >1.5, if INR is 
measured) or termed ‘Hy’s Law’ events (INR measurement is not required and 
the threshold value stated will not apply to subjects receiving anticoagulants). 
NOTE:  Bilirubin fractionation should be performed. 
• 
Any new primary cancers 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided. 
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay. 
Any new primary cancer must be reported as a SAE.  
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs. 
7.3.1.3. 
Follow up on AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 7. 


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7.3.1.4. 
Cardiovascular Events 
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:   
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularisation 
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported. 
7.3.1.5. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
a SAE.  Death due to disease under study is to be recorded on the Death eCRF.  
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol design or 
procedures and the disease progression, then this must be reported as a SAE. 
7.3.1.6. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) for belantamab mafodotin are corneal events, 
thrombocytopenia and infusion related reactions. The severity of all AESI will be graded 
utilizing the National Cancer Institute Common Toxicity Criteria for Adverse Events 
(Version 4.03 [NCI, 2010]). Severity of belantamab mafodotin treatment related corneal 
events will also be graded using the GSK scale for corneal events provided in Table 17. 
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the study treatment(s) are provided in Table 4. 
For pembrolizumab, an overdose as defined in Section 6.10 that is not associated with 
clinical symptoms or abnormal laboratory results is an AESI.  
7.3.1.7. 
Regulatory reporting requirements for SAEs 
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 


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GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/EC and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/EC, if appropriate according to local requirements. 
Prompt Reporting of SAEs and Other Events to GSK 
Serious adverse events (SAEs), pregnancies, and liver function abnormalities and any 
other events meeting pre-defined criteria will be reported promptly by the investigator to 
GSK as described in the following table once the investigator determines the event meets 
the protocol definition for that event. 


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Initial Reports 
Follow-up Information on a Previous 
Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE data collection 
tool 
24 hours 
Updated SAE data 
collection tool  
“CV events” and/or 
“death” 
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
 
Initial and follow 
up reports to be 
completed within 
one week of when 
the 
cardiovascular 
event or death is 
reported 
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable 
 
Pregnancy 
24 Hours 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy 
Followup- Form 
Liver chemistry abnormalities: 
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 
3 times ULN and INR 
>1.5, if INR is 
measured)c 
24 hoursa 
SAE data 
collection tool; 
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicableb 
24 hours 
Updated SAE data 
collection tool. 
Updated Liver 
Event eCRFb 
ALT 5 times ULN; 
ALT 3 times ULN with 
hepatitis or rash or 3 
times ULN 4 weeks 
24 hoursa 
Liver Event eCRFb 
24 hours 
Updated Liver 
Event eCRFb 
ALT 3 times ULN and 
<5 times ULN and 
bilirubin <2 times ULN 
24 hoursa 
Liver Event eCRF 
does not need to 
be completed 
unless elevations 
persist for 4 weeks 
or subject cannot 
be monitored 
weekly for 4 
weeksb 
 
 
a. 
GSK to be notified at onset of liver chemistry elevations to discuss subject safety. 
b. 
Liver event documents should be completed as soon as possible 
c. 
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants. 
Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SRM. 


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7.3.2. 
Pregnancy  
Do not collect pregnancy information for female subjects known to be pregnant during 
the screening phase or before exposure to study. 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
If a female subject is of childbearing potential, she must have a serum β-human chorionic 
gonadotropin (β –HCG) pregnancy test performed within 72 hours prior to the first dose 
of study treatment.  Subjects with positive pregnancy test result must be excluded from 
the study.  Subjects with negative pregnancy test result must agree to use an effective 
contraception method as described below during the study and for 4 months following the 
last dose of study treatment. 
Details of all pregnancies in female subjects will be collected after the start of study 
treatment and for 4 months following last dose of belantamab mafodotin. 
Details of all pregnancies for female partners of male subjects will be collected after the 
start of study treatment and 6 months following last dose of belantamab mafodotin. 
If a pregnancy is reported, the investigator must inform GSK within 24 hours of learning 
of the pregnancy and must follow the procedures outlined in Appendix 8. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at the end of relevant systemic exposure (4 months after the last dose of belantamab 
mafodotin) and correspond with the time frame for female subject contraception in 
Section 5.1. 
7.3.3. 
Medical Device Incidents (including malfunctions) 
Not applicable for this study 
7.3.4. 
Physical Exams 
At screening and on dosing days, a full physical examination will include assessments of 
the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  Height and weight will also be measured and 
recorded. 
During interim visits and at the end of study, a brief physical examination will include 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
7.3.5. 
Ocular Examinations and Procedures 
Study sites must establish a close collaboration with an ophthalmologist (or an 
optometrist if an ophthalmologist is not available) who will be responsible for assessing 
subjects while they are on study and managing subjects who develop treatment-related 


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changes in vision associated with belantamab mafodotin. Management of subjects with 
treatment-related changes in vision must be performed in close communication with the 
GSK Medical Monitor and the coordinating ophthalmologist (or an optometrist if an 
ophthalmologist is not available). 
Subjects will be assessed by eye care specialist (ophthalmologist, or an optometrist if an 
ophthalmologist is not available) at screening/baseline.  
A full screening/baseline ophthalmic examination for all subjects must include for both 
eyes (OU): 
1. Best corrected visual acuity 
2. Documentation of manifest refraction and the method used to obtain best 
corrected visual acuity 
3. Current glasses prescription (if applicable) 
4. Selected anterior segment (slit lamp) examination with focus on the cornea and 
lens, including fluorescein staining of the cornea  
5. Intraocular pressure measurement 
6. Dilated funduscopic exam 
The on treatment and follow-up ophthalmic exam should be performed for both eyes 
(OU) as described below and in the Time and Events Tables (Section 7):  
1. Best corrected visual acuity 
2. Documentation of manifest refraction and the method used to obtain best 
corrected visual acuity 
3. Selected anterior segment (slit lamp) examination with focus on the cornea and 
lens, including fluorescein staining of the cornea  
4. Intraocular pressure measurement (if clinically indicated) 
5. Dilated funduscopic exam (if clinically indicated) 
The end of study treatment visit ophthalmic exam should match the baseline (screening) 
exam. 
Additional examinations should be performed at the discretion of the treating eye 
specialist.   
7.3.6. 
ECOG Performance Status 
The performance status will be assessed using the ECOG scale (Appendix 2) as specified 
in the Time and Events Tables (Table 7, Table 8, and Table 10). 
7.3.7. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, temperature, 
and pulse rate.  Vital signs should be measured after resting for at least 5 minutes. Vital 
signs will be measured more frequently if warranted by the clinical condition of the 
subject. On days where vital signs are measured multiple times, temperature does not 
need to be repeated unless clinically indicated.   


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First Infusion: 
Monitoring intervals: Vital signs must be monitored at pre-dose (within 30 minutes prior 
to start of each infusion), and at the end of each infusion, and 1 hour post end of infusion.   
Subsequent Infusions: 
Monitoring intervals:  Vital signs must be monitored at pre-dose (within 30 minutes prior 
to start of each infusion) and at the end of each infusion, and 30 min post the end of 
infusion.   
In case of infusion related reactions or cytokine storm, monitoring will be performed with 
higher frequency (as clinically indicated). 
7.3.8. 
Electrocardiogram 
Triple 12-lead ECGs will be obtained at designated time points specified in the Time and 
Events Table (Table 7, Table 9, and Table 10) during the study using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  At each assessment, a 12-lead ECG will be performed by qualified personnel at 
the site after the subject has at least a 10 minute rest.   
For triplicate ECGs, 3 individual ECG tracings should be obtained as closely as possible 
in succession, but no more than 2 minutes apart.  
The QT interval should be corrected for heart rate by Fridericia’s formula (QTcF).  Refer 
to Section 5.4.1.3 for QTc withdrawal criteria. ECGs will be collected and stored 
centrally. Refer to the SRM for details regarding ECG procedures. 
7.3.9. 
Echocardiogram 
Echocardiograms (ECHOs) will be performed at baseline to assess cardiac ejection 
fraction and cardiac valve morphology for the purpose of study eligibility, as specified in 
the Time and Events Table (Table 7).  Additional ECHO assessments will be performed 
at specified time points indicated in the Time and Events Table (Table 8 and Table 10) or 
if clinically warranted.  The evaluation of the echocardiographer should include an 
evaluation for LVEF and both right and left-sided valvular lesions. 
Copies of all ECHOs performed on subjects will be stored in a central location if further 
evaluation is warranted.  
7.3.10. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments, as defined in (Table 11), should be 
performed according to the Time and Events Table (Table 7, Table 8, Table 9, and Table 
10) Details for the preparation and shipment of samples will be provided in the SRM. 


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Prior to administration of the first dose of study treatment, results of laboratory 
assessments should be reviewed.  Any laboratory test with a value outside the normal 
range may be repeated (prior to the first dose) at the discretion of the investigator. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinical significant by the Investigator (for example SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF.  Refer to the SRM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws.  
All laboratory tests with values that are significantly abnormal during participation in the 
study or within 45 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
Asymptomatic elevations of lactate dehydrogenase (LDH) and creatine kinase (CK) and 
AST have been observed in study BMA117159. Subjects with significant elevations (≥x3 
ULN) should, where possible, have a sample sent for central testing of CK and LDH 
isoenzyme levels. 
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 11. 


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Table 11 
List of Clinical Laboratory Tests 
Hematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
Red blood cell (RBC) Count 
MCV 
Neutrophils 
White blood cell (WBC) Count 
(absolute)  
MCH 
Lymphocytes 
Hematocrit 
MCHC 
Monocytes 
Hemoglobin 
 
Eosinophils 
 
 
Basophils 
Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate aminotransferase (AST) 
Total and direct bilirubin 
Creatinine 
Chloride 
Alanine aminotransferase (ALT) 
Uric Acid 
Glucose 
Total carbon 
dioxide (CO2)/ 
bicarbonate  
Gamma glutamyl transferase (GGT) 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
Magnesium 
Phosphorous 
Creatine kinase (CK) 
LDH 
Troponin 
BNP 
T3, T4 and TSH 
 
Routine Urinalysis
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
24-hour urine protein  
Spot urine (albumin / creatinine ratio)1 
Other screening tests
Hepatitis B (HBsAg) 
Hepatitis B core antibody (HBcAb) 
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C PCR test 
should be performed) 
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential 
only) 
FISH analysis2
Other Laboratory Tests
eGFR 
Pregnancy test (urine 
or blood – according 
to local practice) 
IgG, IgM, IgA 
C-reactive protein 
(CRP) 
Beta2 microglobulin 
Kappa, lambda free 
LC, FLC ratio 
ADA 
Genetic Sample3 
Immunofixation 
Serum Protein 
Electrophoresis 
(SPEP)  
Urine Protein 
Electrophoresis 
(UPEP) 
MRD testing 
Serum M-protein calculation  
Corrected calcium 
with albumin 
LDH and CK 
isoenzymes4  
 
Biomarker Measurements
Soluble BCMA (sBCMA) 
(serum) 
Serum 
cytokines/chemokines 
cfDNA (plasma) 
Peripheral blood 
mononuclear cell  
Whole Blood RNA 
 
 
 


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1. Obtained from first void 
2. FISH testing at least for: t(4;14), t(14/16), 17p13del. Biopsy samples from within 60 days prior to first dose are acceptable. 
3. Informed consent for optional sub studies (e.g. genetic research) must be obtained before collecting a sample 
4. Subjects with significant elevations (≥x3 ULN) and performed by central laboratory  
7.3.11. 
Suicidal Risk Monitoring 
Not applicable for this study 
7.3.12. 
Patient-Reported Outcome Version of the Common Term Criteria 
for Adverse Events (PRO-CTCAE) 
The PRO-CTCAE is a patient-reported outcome measure developed to evaluate 
symptomatic toxicity in subjects on cancer clinical trials [Basch, 2014].  The PRO-
CTCAE was designed to be used as a companion to the CTCAE, the standard lexicon for 
adverse event reporting in cancer trials.  The PRO-CTCAE includes an item library of 
124 items representing 78 symptomatic toxicities drawn from the CTCAE.  PRO-CTCAE 
provides a systematic yet flexible tool for descriptive reporting of symptomatic treatment 
side effects in cancer clinical trials.  In the present study, a subset of items selected from 
the PRO-CTCAE Version 1.0 Item library will be administered.  The PRO-CTCAE will 
be administered to select subjects based on the availability of translated versions. 
7.3.13. 
Visual Function Questionnaires (VFQ) and Ocular Surface 
Disease Index (OSDI). 
The impact of potential ocular toxicity will be assessed with the use of a visual function 
questionnaire. The visual function questionnaire will include select items from the NEI-
VFQ-25 and OSDI.  The NEI-VFQ-25 consists of a base set of 25 vision-targeted 
questions representing 11 vision-related constructs, plus an additional single-item general 
health rating question [Mangione , 2001].  The NEI-VFQ-25 generates the following 
vision-targeted sub-scales: global vision rating (1), difficulty with near vision activities 
(3), difficulty with distance vision activities (3), limitations in social functioning due to 
vision (2), role limitations due to vision (2), dependency on others due to vision (3), 
mental health symptoms due to vision (4), driving difficulties (3), limitations with 
peripheral (1) and color vision (1), and ocular pain (2). In addition to the 25 items from 
the NEI-VFQ-25, additional questions will be administered to further assess the impact of 
ocular toxicity on visual function. 
The OSDI is a 12-item questionnaire designed to assesses both the frequency of dry eye 
symptoms and their impact on vision-related functioning [Schiffman, 2000]. The OSDI 
has demonstrated good reliability, validity, sensitivity, and specificity, and can be used as 
a complement to other clinical and subjective measures of dry eye disease by providing a 
quantifiable assessment of dry eye symptom frequency and the impact of these symptoms 
on vision-related functioning.  
All subjects will use the Self-Administered version, unless their vision prevents them 
from being able to complete the questionnaire on their own.  Subjects who are not able to 
complete the questionnaire on their own and require assistance should use the Interviewer 
Administered format.  If the Interviewer Administered format is being used, it should be 
read to the subjects verbatim, and subject responses should be recorded directly without 


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any interpretation.  For any additional assessments conducted via telephone (either during 
participation in the treatment period or during follow-up), the Interviewer Administered 
format should be used.   
The NEI-VFQ-25 and OSDI will be administered to subjects in different regions based 
on the availability of translated versions. 
7.4. 
Pharmacokinetics 
7.4.1. 
Blood Sample Collection for Pharmacokinetics 
Blood samples for pharmacokinetic (PK) analysis of belantamab mafodotin (ADC and 
total monoclonal antibody [mAb]), cys-mcMMAF and corresponding blood samples for 
sBCMA as well as pembrolizumab will be collected at the time points indicated in Table 
12. The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring and need to be accompanied by 
a corresponding sBCMA sample. Note that sBCMA samples will also be collected 
independent from PK samples, as described in the Time and Events table. Samples for 
pembrolizumab will be collected and stored. Pembrolizumab PK samples will only be 
analysed if clinical observations warrant it (e.g. to rule out or confirm suspicion of DDI). 
Each PK sample should be collected as close as possible to the planned time relative to 
the dose (i.e., time zero) administered to the subject on PK days. The actual date and time 
of each blood sample collection will be recorded. All PK, sBCMA, and anti-drug 
antibody (ADA) samples once collected (regardless of dosing) may be analyzed if the 
sample date and time have been recorded.  
Table 12 
Pharmacokinetic and sBCMA blood sampling times 
Cycle Day 
Sampling Times 
Belantamab 
Mafodotin 
sBCMA 
Pembrolizumab 
Sampling window 
C1D1 
Pre-dose 
belantamab 
mafodotin 
X 
X 
 
Within 30 minutes 
prior to start of 
infusion 
EOI belantamab 
mafodotin  
X 
X 
 
Within 30 min after 
EOI 
Pre-dose 
Pembrolizumab1 
 
 
P 
Within 30 minutes 
prior to start of 
infusion 
EOI Pembrolizumab1 
 
 
P 
Within 30 min after 
EOI 
2 hr SOI belantamab 
mafodotin 
X 
X 
 
15 min 
24 hr SOI 
belantamab 
mafodotin 
X 
X 
 
1 hr 
C1D4 
Any time 
X 
X 
 
1 day 
C1D8 
Any time 
X 
X 
 
+3 days 
C2D1 & C5D1 
Pre-dose 
belantamab 
mafodotin 
X 
X 
 
Within 30 minutes 
prior to start of 
infusion 


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Cycle Day 
Sampling Times 
Belantamab 
Mafodotin 
sBCMA 
Pembrolizumab 
Sampling window 
EOI belantamab 
mafodotin 
X 
X 
 
Within 30 min after 
EOI 
Pre-dose 
Pembrolizumab1 
 
 
P 
Within 30 minutes 
prior to start of 
infusion 
EOI Pembrolizumab1 
 
 
P 
Within 30 min after 
EOI 
C8D1 & C11D1 
Pre-dose 
belantamab 
mafodotin 
X 
X 
X 
Within 30 minutes 
prior to start of 
infusion 
EOI belantamab 
mafodotin 
X 
X 
 
Within 30 min after 
EOI 
C14D1 and 
every 3 cycles 
thereafter (i.e., 
C17, 20, until 
EOT) 
Pre-dose 
belantamab 
mafodotin 
X 
X 
X 
Within 30 minutes 
prior to start of 
infusion 
End of 
Treatment 
 
X 
X 
X 
 
EOI = end of the infusion; SOI = start of the infusion, EOT = end of treatment;  
X = time relative to belantamab mafodotin dose; P = time relative to pembrolizumab dose 
1. 
To be obtained pre- and post- first dose of pembrolizumab irrespective of any dose delay 
Details on PK blood sample collection including blood volumes, processing, storage and 
shipping procedures are provided in the SRM. 
7.4.2. 
Pharmacokinetic Sample Analysis 
Plasma analysis will be performed under the control of the GSK Bioanalysis 
Immunogenicity and Biomarkers (BIB) group, the details of which will be included in the 
SRM.  Concentrations of belantamab mafodotin (ADC and total mAb) and cys-
mcMMAF will be determined in plasma samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site (detailed 
in the SRM). 
Once the plasma has been analysed for belantamab mafodotin (ADC and total mAb) any 
remaining plasma may be analysed for other compound-related metabolites and the 
results reported under a separate GSK BIB protocol.  
If analysis is warranted, concentrations of pembrolizumab in serum will be performed 
under the control of Merck, the details of which will be included in the SRM.  Raw data 
will be archived at Merck’s data repository, OpenLab (detailed in the SRM). 
7.5. 
Biomarkers 
7.5.1. 
sBCMA Analysis 
To measure any changes in soluble BCMA (sBCMA) concentration during the study, 
serum will be collected at the time points specified in the Time and Events Tables (refer 
to Table 9 and Table 10) and per PK Table 12.  


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7.5.2. 
Cytokine and Chemokine Analysis 
Cytokines in the blood have been found to correlate with tumor pathway activation.  A 
broad panel of cytokines/chemokines will be evaluated as outlined in the Time and 
Events Table (refer to Table 9).  
7.5.3. 
Subject Stratification/Predictive Biomarkers 
This is an open-label and single-arm study, no subject stratification will be performed. 
BCMA exhibits varied expression across haematological malignancies and therefore, 
BCMA expression at baseline may be an important predictor of response to belantamab 
mafodotin in combination with pembrolizumab. Though the majority of MM subjects 
express BCMA, the intensity of expression varies. To evaluate whether BCMA 
expression has utility in patient stratification, BCMA protein expression will be measured 
by IHC in malignant plasma cells at baseline, and other timepoints if available, and will 
be correlated with clinical outcomes and potentially other biomarker or disease 
assessments. Because BCMA can also be detected in circulation, the soluble form 
(sBCMA) has the potential to serve as a surrogate marker of BCMA at the cell surface. 
This study will correlate subjects sBCMA levels with BCMA cell surface expression and 
clinical response.  
Any blood and bone marrow samples collected during this study may be used for the 
purposes of measuring novel biomarkers to identify factors that may influence scientific 
advances in multiple myeloma, hematological malignancies and/or medically related 
conditions, as well as the biological and clinical responses to belantamab mafodotin in 
combination with pembrolizumab. If relevant, this approach may be extended to include 
the identification of biomarkers associated with AEs. 
Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to belantamab mafodotin in combination with pembrolizumab is observed. 
Samples will be collected at the time points indicated in the Time and Events Tables 
(Table 7, Table 8, Table 9 and Table 10). The timing of the collections may be adjusted 
on the basis of emerging data from this study or other new information, in order to ensure 
optimal evaluation of the pharmacodynamic and/or biomarker endpoints. Novel or 
emerging candidate biomarkers associated with the biological response to advanced 
multiple myeloma, hematological malignancies and/or medically related conditions, as 
well as biological and clinical responses to belantamab mafodotin in combination with 
pembrolizumab, may also be evaluated. These analyses may include but are not limited 
to: 
• Tumor/bone marrow BCMA receptor expression by IHC and/or by RNA analyses.     
• Soluble factors, including circulating cfDNA, blood and derivatives including 
cytokine/chemokine analysis of serum 
• Immune cell characterization and/or profiling of peripheral blood and/or bone marrow 
aspirate samples by protein and/or RNA analyses 
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• RNA/DNA/gene and/or protein analysis of tumor tissue/bone marrow aspirates or 
samples in circulation 
7.5.4. 
Tumor Biomarker Analysis 
To further characterize the subject population, biomarkers (e.g. expression of genes and 
proteins) related to the activity of the investigational compound may be assessed in 
malignant cells.  
BCMA expression in plasma cells from bone marrow aspirates or trephines will be 
evaluated at baseline, and other timepoints if available, by IHC. Analysis of the immune 
context (immune cell characterization) of bone marrow aspirate samples may also be 
performed to analyse the tumor microenvironment. Additional bone marrow aspirate 
samples may be taken during the treatment period for biomarker research. All bone 
marrow aspirate samples collected may be evaluated for additional DNA/RNA/protein 
biomarker analyses. 
7.5.5. 
Circulating Cell Free DNA (cfDNA) Analysis 
Tumor specific circulating nucleic acid (cfDNA) levels detected in plasma or serum have 
been found to correlate with increasing tumor burden and decline following therapy.  
cfDNA in cancer subjects can harbour many genetic alterations (mutations, microsatellite 
alterations, aberrant methylation), which are generally consistent with the tumor. Tumor-
specific circulating cfDNA has the potential to be a useful biomarker of therapeutic 
response as well as offering a less invasive blood based technique for identifying and 
selecting subjects for certain treatments. Given this promise, cfDNA will be explored to 
determine whether mutations in cfDNA can be identified. This test will also be explored 
to correlate increasing cfDNA levels with increasing tumour burden.  
7.5.6. 
Immunogenicity Assessments 
Serum samples for determination of anti-belantamab mafodotin and anti-pembrolizumab 
antibodies will be taken from all subjects at the time-points specified in the Time and 
Events Table in Table 9. 
Samples will be analyzed for the presence of anti-belantamab mafodotin antibodies using 
validated immunoassays. Samples collected for pembrolizumab will be collected and 
stored. Analysis of pembrolizumab samples will only be performed if considered 
clinically indicated. All samples will be tested in screening assay, and positive samples 
will be further characterized for specificity and antibody titers. Details of blood sample 
collection (including volume to be collected), processing, storage and shipping 
procedures are provided in the SRM. For each subject, immunogenicity results, including 
the incidence and titers, will be reported. 
7.6. 
Genetics 
Information regarding genetic research is included in Appendix 6 (Section 12.6) 


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An important exploratory objective of the clinical study is genetic research.  Participation 
in genetic research is optional but all subjects who are eligible for the clinical study will 
be given the opportunity to participate. Subjects may decline participation without effect 
on their medical care or care during the clinical study. A separate consent signature is 
required for genetic research. 
Subjects who provide consent will have a blood sample taken for analysis.  The 
presence/absence of genetic variations in host DNA will be analyzed to determine their 
relationship with response (safety, tolerability, pharmacokinetics (PK) and efficacy) to 
treatment with the combination of belantamab mafodotin and pembrolizumab. 
Information regarding genetic research is included in Section 12.6. In approving the 
clinical protocol the IEC/IRB and, where required, the applicable regulatory agency are 
also approving the genetic research described in Section 12.6  unless otherwise indicated.  
Where required by regulatory authorities, approval of the genetic assessments can occur 
after approval is obtained for the rest of the study. If so, then the written approval will 
clearly indicate approval of the genetic assessments is being deferred and the study, 
except for genetic assessments, can be initiated. When genetic assessments will not be 
approved, then the approval for the rest of the study will clearly indicate this and 
therefore, genetic assessments will not be conducted. 
7.7. 
Value Evidence and Outcome 
Three Health-Related Quality-of-Life (HRQoL) assessments will be performed in this 
study.  More details about all patient questionnaires can be found in the SRM.  The 
following assessments will be administered to subjects in different regions based on the 
availability of translated versions. 
7.7.1. 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core module (EORTC QLQ-
C30) 
The EORTC QLQ-C30 is a 30-item questionnaire containing both single- and multi-item 
measures [Aaronson, 1993]. These include five functional scales (Physical, Role, 
Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and 
Nausea/Vomiting), a Global Health Status/QoL scale, and six single items (Constipation, 
Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). Scores for each 
scale and single-item measure are averaged and transformed linearly to a score ranging 
from 0–100. A high score for functional scales and for Global Health Status/QoL 
represent better functioning ability or HRQoL, whereas a high score for symptom scales 
and single items represents significant symptomatology [Proskorovsky, 2014]. 
 
7.7.2. 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 20-item Multiple Myeloma module 
(EORTC QLQ-MY20) 
The EORTC QLQ-MY20 is a supplement to the QLQ-C30 instrument used in patients 
with multiple myeloma [Aaronson, 1993; Cocks, 2007].  The module comprises 20 


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questions that address four myeloma-specific HRQoL domains: Disease Symptoms, Side 
Effects of Treatment, Future Perspective, and Body Image.  Three of the four QLQ-
MY20 domains are multi-item scales: Disease Symptoms (includes bone aches or pain, 
back pain, hip pain, arm or shoulder pain, chest pain, and pain increasing with activity); 
Side Effects of Treatment (includes drowsiness, thirst, feeling ill, dry mouth, hair loss, 
upset by hair loss, tingling hands or feet, restlessness/agitation, acid 
indigestion/heartburn, and burning or sore eyes); and Future Perspective (includes worry 
about death and health in the future, and thinking about illness).  The Body Image scale is 
a single-item scale that addresses physical attractiveness.  As with the QLQ-C30, QLQ-
MY20 domain scores are averaged and transformed linearly to a score ranging from 0–
100.  A high score for Disease Symptoms and Side Effects of Treatment represents a high 
level of symptomatology or problems, whereas a high score for Future Perspective and 
Body Image represents better outcomes [Proskorovsky, 2014].   
7.7.3. 
Exit Interview 
All subjects in Parts 1 and 2 will participate in an Exit Interview.  The Exit Interview will 
be conducted to further evaluate disease and treatment related symptoms and their 
associated impacts on function and health-related quality of life.  The Exit Interview will 
be conducted by a trained interviewer via telephone subsequent to the End of Treatment 
visit.  The Exit Interview should be scheduled to be completed within approximately 21 
days of the end of treatment visit.   
8. 
DATA MANAGEMENT 
• 
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system].   
• 
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data. 
• 
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.   
• 
CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy. 
9. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
Statistical considerations and data analysis may be performed separately and/or combined 
for Part 1 and Part 2. 


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9.1. 
Hypothesis(es) 
9.1.1. 
Part 1: Dose-Escalation Phase 
No formal statistical hypotheses are being tested in Part 1.  Analysis of the data obtained 
from Part 1 will only utilize descriptive methods.   
9.1.2. 
Part 2: Expansion cohort 
The primary goal of Part 2 is to characterize clinical activity of the combination and to 
detect if meaningful response rate (ORR) can be achieved. Based on historical 
information [Lokhorst, 2015] and clinical judgement, the null hypothesis has been 
defined as ORR 40%. The alternative hypothesis has been defined as ORR 60% based 
on clinically meaningful improvement of 20%. 
In Part 2, treatment-related Grade 4 or higher AEs will be continuously monitored 
starting from when 5 subjects are dosed. Based on the 11% Grade 4 or higher AEs 
observed in the FTIH study (BMA117159), it is considered that the combination 
treatment has unacceptable toxicity if observed treatment-related Grade 4 or higher AEs 
is significantly higher than 12% at 1-sided alpha of 0.025. 
9.2. 
Sample Size Considerations 
9.2.1. 
Part 1: Dose-Escalation Phase 
The total number of subjects to be enrolled into Part 1 will depend on the number of 
subjects needed to characterize individual dose cohorts. The sample size is not driven by 
statistical considerations. However, based on assumptions that 2 different dose levels will 
be tested (up to 6 subjects per dose level) it is anticipated that up to 12 evaluable subjects 
will be enrolled in Part 1. 
9.2.2. 
Part 2: Expansion Cohort 
Sample size for Part 2 is estimated based on hypothesis specified in Section 9.1.2 using 
the Predictive Probability design [Lee, 2008]. Details of sample size calculation are 
provided in Appendix 12. The optimal design has Nmax = 28, type I error rate of 0.10 
and power of 80.6%. The expansion cohort may be stopped early for futility if the 
predicted probability of success is less than 1.5%. If the true ORR is 40%, the expected 
sample size is 20 and the probability of early termination is 86.1%; if the true ORR is 
60%, the expected sample size is 28 and the probability of early termination is 15.6%. 
9.3. 
Sample Size Sensitivity 
There is no need to perform sample size sensitivity analysis. 
9.3.1. 
Sample Size Re-estimation or Adjustment 
Sample size re-estimation is not planned for this study. 


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9.4. 
Data Analysis Considerations 
9.4.1. 
Analysis Populations 
All Treated Population:  will consist of all subjects who received at least one dose of 
study drug(s). Safety and clinical activity data will be evaluated based on this population. 
The Pharmacokinetic Population: This will consist of those subjects in All Treated 
Subjects Population from whom at least one PK sample is obtained and analyzed. 
DLT Evaluable Population: will consist of subjects fulfilling the ‘All Treated’ 
population criteria during part 1 (Dose Escalation) and are followed up for a 21-day 
period or withdrawn within 21 days due to an AE meeting the definition of a DLT as 
defined in Section 4.2.3.1.  
All Evaluable Population: This is the population used for decision-making at the futility 
analysis during part 2 (Expansion Cohort). This will be the population for Bayesian 
predictive adaptive design as defined in Section 9.5.2 and summaries of response if data 
warrant. In general, subjects are evaluable if they have received at least 1 dose of 
treatment for both drugs and the time from the first dose to the time of data cut-off is 
more than 66 days, i.e., reached the time of three planned disease assessments. Details on 
deriving the evaluable population will be provided in the RAP. 
Additional analysis populations may be defined in the Reporting and Analysis Plan 
(RAP). 
 
9.5. 
Interim Analysis 
9.5.1. 
Part 1: Dose Escalation 
During dose escalation, no formal interim analysis will be performed. Data will be 
reviewed through data visualization tools to inform dose escalation decisions. The mTPI 
design will be utilized to guide dose escalation/de-escalation decisions. More details of 
the dose escalation procedure are described in Section 4.2.3.1. 
After the last cohort of subjects in Part 1 complete the DLT observation period, a formal 
interim analysis will be performed to support the RP2D decision, except for scenarios 
where RP2D is clearly defined by the toxicity profile. Data considered to support RP2D 
decision will include but not be limited to safety, available PK profiles and observed 
signs of clinical activity. Details of the interim analysis will be provided in the RAP. 
9.5.2. 
Part 2: Expansion 
Continuous safety monitoring will be conducted for the expansion cohort starting from 
when 5 subjects are dosed. The observed number of treatment-related Grade 4 or higher 
AEs will be compared against the safety stopping rule in Table 13. Enrollment may stop 
if the safety stopping rule is met based on totality of safety data. For example, if there are 
3 events out of 5 dosed subjects, enrollment may stop after review of all safety data, if 


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there is 2 or fewer events out of 5 dosed subjects, enrollment will continue. Operating 
characteristics for the safety stopping rule are provided in Appendix 11.  
Table 13 
Safety Stopping Rules for the Expansion Cohort 
Number of dosed subjects 
Stop if treatment related Grade 4 or higher 
AEs larger or equal to this number 
5 
3 
6-10 
4 
11-14 
5 
15-19 
6 
20-25 
7 
26-28 
8 
Interim analyses for ORR will start when at least 10 subjects are evaluable as defined in 
Section 9.4.1. Subjects who initially received RP2D in Part 1 may also be included. The 
observed number of subjects with unconfirmed response of PR or better will be compared 
with the stopping boundary in Table 14. Enrolment may stop if the stopping rule is met. 
Final decision will be based on the totality of data. For example, if there are 2 
unconfirmed responses out of 10 evaluable subjects, enrolment may stop after review of 
all available data; if there are 3 or more unconfirmed responses out of 10 evaluable 
subjects, enrolment will continue. 
Table 14 
Decision Making Criteria for Futility Analysis 
Number of 
Evaluable 
Subjects 
 This Number of 
Responses to Stop Early 
for Futility 
Probability of continuing 
enrolling when 
ORR=0.4 
Probability of continuing 
enrolling when 
ORR=0.6 
10 
2 
83.3% 
98.8% 
11 
2 
83.3% 
98.8% 
12 
3 
75.5% 
98.1% 
13 
3 
75.5% 
98.1% 
14 
4 
68.6% 
97.5% 
15 
4 
68.6% 
97.5% 
16 
5 
62.3% 
96.9% 
17 
6 
52.9% 
95.7% 
18 
6 
52.9% 
95.7% 
19 
7 
46.7% 
94.9% 
20 
7 
46.7% 
94.9% 
21 
8 
41.6% 
94.2% 
22 
9 
34.6% 
92.8% 
23 
9 
34.6% 
92.8% 
24 
10 
30.2% 
91.9% 
25 
11 
24.4% 
90.2% 
26 
12 
18.8% 
87.7% 
27 
13 
13.9% 
84.5% 


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Number of 
Evaluable 
Subjects 
 This Number of 
Responses to Stop Early 
for Futility 
Probability of continuing 
enrolling when 
ORR=0.4 
Probability of continuing 
enrolling when 
ORR=0.6 
28 
14 
0.0% 
0.0% 
9.6. 
Primary Analysis 
Primary analysis will be conducted approximately 15 months from the last subject first 
visit (LSFV). If meaningful response rate (ORR) cannot be achieved, participants may 
discontinue the study treatment and will undergo end of treatment and follow-up 
assessments as defined in Section 4.2.2. Statistical considerations and data analysis may 
be performed separately and/or combined for Part 1 and Part 2. 
9.7. 
Final Analysis 
Final analysis of the data captured in Part 1 and Part 2 will be undertaken at the end of 
study (Section 5.5.2).  Data from the two parts may be combined for some analyses at the 
end of the trial, as appropriate.  
9.8. 
Key Elements of Analysis Plan 
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to the original analysis plan described in this protocol will be documented in the 
RAP and final study report. 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.  
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects. Consequently, there will be no 
imputation for missing data.  
Demographic and baseline characteristics will be summarized. 
9.8.1. 
Clinical Activity Analyses 
The primary endpoint ORR and other applicable secondary endpoints (e.g., CBR, DoR, 
TTR, TTP, PFS) will be based on the responses assessed by the investigator.  
At futility interim and the primary analysis, the primary endpoint (ORR) will be analyzed 
based on the All Evaluable population. Otherwise, all efficacy endpoints will be analyzed 
based on the All Treated population unless otherwise specified. The analytical methods 
planned for each endpoint are described in Table 15. 


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Table 15 
Statistical Analysis Methods for Clinical Activity Endpoints (Part 2) 
Endpoint 
Statistical Analysis Methods 
Primary 
Overall Response Rate (ORR) is defined as the percentage of subjects with a 
confirmed PR or better (i.e. PR, VGPR, CR and sCR), according to the International 
Myeloma Working Group (IMWG) Response Criteria). 
The number and percentage of subjects in the following response categories will be 
presented: sCR, CR, VGPR, PR, overall response (sCR+CR+VGPR+PR), minimal 
response (MR), stable disease (SD), progressive disease (PD), and not evaluable 
(NE). The corresponding 95% CI for ORR will also be provided. Subjects with unknown 
or missing responses will be treated as non-responders, i.e., these subjects will be 
included in the denominator when calculating percentages of response. 
Secondary 
Secondary clinical activity endpoints of Part 2 of this study are CBR, DoR, TTR, PFS, 
TTP and MRD Negative Rate. 
Clinical benefit rate (CBR), defined as the percentage of subjects with a confirmed 
minimal response (MR) or better per IMWG. 
Duration of response (DoR) is defined as the time from first documented evidence of 
PR or better until disease progression (PD) per IMWG, or death due to PD among 
subjects who achieve an overall response (i.e. confirmed PR or VGPR or CR or sCR). 
Responders without disease progression will be censored at the censoring time point 
for TTP.  
Time to response (TTR) is defined as the time between the date of first dose and the 
first documented evidence of response (PR or better) for subjects who achieve an 
overall response (i.e. confirmed PR or VGPR or CR or sCR).  
Time to best response, defined as the time between the date of first dose and the 
first best documented response (PR or better) for subjects who achieve an overall 
response (i.e. confirmed PR or VGPR or CR or sCR). 
Progression-free survival (PFS) is defined as the time from first dose until the 
earliest date of disease progression (PD) per IMWG, or death due to any cause. 
Determination of dates of PFS event and dates for censoring will be described in the 
RAP.  
Time to disease progression (TTP) is defined as the time from first dose until the 
earliest date of PD per IMWG, or death due to PD. Determination of dates of TTP 
event and dates for censoring will be described in the RAP.  
For all the TTE endpoints described above, median TTE with 95% CI will be estimated 
employing the Kaplan-Meier method. A Kaplan-Meier survival curve will be generated. 
The number and percentage of subjects who had the event or were censored will also 
be reported. In addition, PFS rate with 95% CI at 6, 
12 and 18 months will be estimated using Kaplan-Meier methods for the PFS endpoint. 
 
OS is defined as the time from first dose until death due to any cause.  Subjects who 
withdraw consent from the study or are lost to follow-up will be censored at the time of 
withdrawal or lost to follow-up. Subjects who are still alive at the clinical cut-off date for 
the analysis will be censored at the last known alive date or last contact date. The last 
contact date will be determined by the maximum collection/assessment date from 


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Endpoint 
Statistical Analysis Methods 
among selected data domains within the clinical database. Survival rate 12, 18 and 24 
months will be reported from Kaplan-Meier analysis as data permits. . 
 
9.8.2. 
Safety Analyses 
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g. laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP. 
9.8.2.1. 
Exposure Duration 
The number of subjects administered study treatment will be summarized according to 
the duration of therapy.   
9.8.2.2. 
Adverse Events 
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system 
organ class.  Adverse events (AEs) will be graded by the investigator according to the 
National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), 
(version 4.03, [NCI, 2010]). In addition, for belantamab mafodotin treatment related 
corneal events, the GSK grading scale for corneal events (Appendix 9) should be used.  
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, and SAEs and AEs leading to discontinuation of study treatment.  Adverse 
events (AEs), if listed in the NCI-CTCAE (version 4.03, [NCI, 2010]) will be 
summarized by the maximum grade.  Otherwise, the AEs will be summarized by 
maximum intensity. 
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following 
AEs of special interest will be summarized separately:  
• Corneal events 
• Thrombocytopenia 
• Infusion related reactions 
The incidence of deaths and the primary cause of death will be summarized. 
9.8.2.3. 
Clinical Laboratory Evaluations 
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to National Cancer Institute-Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE) (Version 4.03, [NCI, 2010]).  Laboratory test results 
outside the reference ranges that do not have associated NCI-CTCAE criteria will be 
summarized using proportions.  Further details will be provided in the RAP. 


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9.8.2.4. 
Other Safety Measures 
Data for vital signs, ECGs, and ECHOs will be summarized based on predetermined 
criteria identified to be of potential clinical concern (PCI).  Further details will be 
provided in the RAP. 
9.8.3. 
Pharmacokinetic Analyses 
9.8.3.1. 
Concentration Time Data  
Linear and semi-logarithmic individual concentration-time profiles and mean and median 
profiles (when applicable) by belantamab mafodotin dose will be plotted for belantamab 
mafodotin (ADC and total mAb), cys-mcMMAF, and pembrolizumab (if tested) in Part 
1. 
Concentrations of belantamab mafodotin (ADC and total mAb), cys-mcMMAF, and 
pembrolizumab (if tested) will be listed for each subject and summarized (when 
appropriate) by planned time point and dose cohort in Part 1 and Part 2. 
9.8.3.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic analyses will be the responsibility of Clinical Pharmacology Modeling 
and Simulation, GSK. 
For Cycle 1, belantamab mafodotin, total mAb, cys-mcMMAF, and pembrolizumab (if 
measured) concentration-time data will be analyzed by standard non-compartmental 
methods, if data permit. Calculations will be based on the actual sampling times recorded 
during the study.  
From the plasma concentration-time data, the following PK parameters will be 
determined for belantamab mafodotin, total mAb, and pembrolizumab (if measured) for 
each participant after each dose of belantamab mafodotin or of pembrolizumab, as data 
permit: 
• 
Maximum observed plasma concentration (Cmax), time to Cmax (tmax), 
concentration at the end of infusion (C-EOI), and concentration prior to next dose 
(Ctrough) 
• 
For Cycle 1:  area under the plasma concentration-time curve from time 0 to the end 
of the dosing interval [AUC(0-)], last time point where the concentration is above 
the limit of quantification (tlast) 
For cys-mcMMAF, Cmax, tmax, C-EOI, tlast, and area under the plasma concentration-
time curve from time 0 to 168 h after dosing [AUC(0-168)] will be computed at Cycle 1, 
as data permit. 
Pharmacokinetic parameters will be listed and summarized descriptively (mean, standard 
deviation, median, minimum, maximum, geometric mean, and the standard deviation, 
CV% and 95% confidence interval of log-transformed parameters) by dose cohort in Part 
1 and Part 2. 


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Belantamab mafodotin data from this study may be analyzed using a population 
pharmacokinetic approach. If performed, the initial analysis will use the most current 
population pharmacokinetic model and will include computation of systemic clearance 
(CL), volume of distribution, and/or terminal phase half-life (t½).  The results of the 
population PK analysis may be provided in a separate report. 
9.8.4. 
Pharmacokinetic/Pharmacodynamic Analyses 
If deemed appropriate and if data permit, exposure-response relationships between 
belantamab mafodotin, cys-mcMMAF, and/or pembrolizumab (if measured) exposure 
measures (e.g., dose, concentration, Cmax, or AUC) and clinical activity (e.g., ORR) 
and/or toxicity may be explored by population methods.  Results of this analysis may be 
provided in a separate report. 
9.8.5. 
Translational Research Analyses 
The results of translational research investigations will be reported either within or 
separately from the main clinical study report (CSR).  All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. 
Further details on the translational research analyses will be addressed in the RAP. 
9.8.5.1. 
Novel Biomarker(s) Analyses 
The results of these biomarker investigations may be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data. 
Additional exploratory analyses may be performed to further characterize novel 
biomarkers. 
9.8.5.2. 
Genetic Analyses 
Further details on genetic analyses will be addressed in Section 7.6 
Exploratory Response Prediction Biomarkers 
Cell surface BCMA and sBCMA pre dosing will be quantified as a potential predictive 
biomarker for clinical activity. Post dosing sBCMA will be quantified to assess dynamics 
during treatment.  
If the data permit, an attempt will be made to identify a statistically and clinically 
meaningful threshold for BCMA expression which serves as an indicator for potential 
efficacy. Full details of analysis approaches will be provided in the RAP.  


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9.8.5.3. 
Exploratory analyses of DNA, and Protein 
Exploratory analyses may be performed on remaining study samples for analyses of 
DNA, RNA and protein to understand changes in response to the combination treatment 
with belantamab mafodotin and pembrolizumab. 
The results of exploratory investigations will be reported separate from the main clinical 
study report (CSR).  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data.  
9.8.6. 
Immunogenicity Assessment 
For each subject, the results and titers of anti-belantamab mafodotin binding antibodies 
will be listed for each assessment time point with time-matched belantamab mafodotin 
plasma concentration.  The frequency and percentage of subjects with positive and 
negative results will be summarized for each assessment time and overall for each subject 
by dose cohort. The detailed information will be included in the RAP. 
10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Posting of Information on Clinicaltrials.gov 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
10.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, GSK will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and applicable country-specific 
regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to, the following: 
• 
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable 
• 
Obtaining signed informed consent 
• 
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC) 
• 
GSK will provide full details of the above procedures, either verbally, in writing, 
or both. 


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• 
Signed informed consent must be obtained for each subject prior to participation 
in the study 
• 
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.   
• 
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated. 
GSK will provide full details of the above procedures, either verbally, in writing, or both. 
Written informed consent must be obtained from each subject prior to participation in the 
study. 
10.3. 
Urgent Safety Measures 
If an event occurs that is related to the conduct of the study or the development of the IP, 
and this new event is likely to affect the study of subjects, the Sponsor, and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard. 
The Sponsor will work with the investigator to ensure the Institutional review board 
(IRB)/ethics committee (EC) is notified. 
10.4. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, Good Clinical Practice (GCP) and GSK 
procedures, the site will be contacted prior to the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.  When reviewing data collection procedures, the 
discussion will include identification, agreement and documentation of data items for 
which the eCRF will serve as the source document. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues. 
Monitoring visits will be conducted in a manner to ensure that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 


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10.5. 
Quality Assurance 
To ensure compliance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and all applicable regulatory requirements, GSK may conduct 
quality assurance audits of the site.  Regulatory agencies may conduct a regulatory 
inspection at any time during or after completion of the study.  In the event of an audit or 
inspection, the investigator (and institution) must agree to grant the auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the time 
of their staff to discuss any findings/relevant issues. 
10.6. 
Study and Site Closure 
The end of the study will be defined as the date of the last visit of the last subject 
enrolled. 
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, International Conference on Harmonization Good Clinical Practice (ICH 
GCP), and GSK Standard Operating Procedures. 
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action. 
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/EC promptly and provide the reason(s) for the suspension/termination. 
10.7. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 


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an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements. 
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site. 
10.8. 
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
The results summary will be posted to the GSK Clinical Study Register no later than 
eight months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing. 
10.9. 
Review Committees 
10.9.1. 
Internal Safety Review Committee 
An Internal Safety Review Committee (iSRC) will be utilized in this study and comprise 
individuals who are not members of the clinical study team. The iSRC are positioned to 
offer an internal, independent review of safety data to protect the interests of subjects and 
ensure their safety. All efforts will be made to maintain the study integrity and validity of 
study data. The schedule of planned reviews of safety data and the analysis plan for iSRC 
review is described in the iSRC Charter, which is available upon request. 


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12. 
APPENDIX 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ADCC 
Antibody dependent cellular cytotoxicity 
ADC 
Antibody drug conjugate 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APRIL 
A proliferation-inducing ligand 
AST 
Aspartate aminotransferase 
ATP 
Adenosine tri phosphate 
AUC 
Area under the curve 
AUC(0-t) 
Area under the concentration-time curve 
AV 
Atrioventricular 
BAFF 
B-cell-activating factor belonging to the TNF family 
BCG 
Bacillus Calmette-Guerin 
BCMA 
B cell maturation antigen 
BP 
Blood Pressure 
BNP 
B-type natriuretic peptide 
BUN 
Blood urea nitrogen 
CBR 
Clinical Benefit Rate 
cfDNA 
Circulating Cell Free deoxyribonucleic acid 
CK 
Creatine kinase 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
CO2 
Carbon dioxide 
CPK 
Creatinine phosphokinase 
CRF 
Case Report Form 
CR 
Complete Response 
CRP
C-reactive protein
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
Computed tomography 
Ctrough 
Concentration at trough 
CV 
Coefficient of variation 
CYP 
Potent cytochrome P450 
DAMPs 
Danger-associated molecular patterns 
DCs 
Dendritic cells 
DDI 
Drug-Drug interaction 
DKA 
Diabetic ketoacidosis 
DLT 
Dose limiting toxicities 
DNA 
Deoxyribonucleic acid 


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DOR 
Duration of Response 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ER 
Endoplasmic reticulum 
EMA 
European Medicines Agency 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire 30-item Core 
Module 
EORTC-QLQ-MY20 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire 20-item Multiple 
Myeloma module 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FISH 
 Fluorescent in situ hybridization 
FLC 
Free light chain 
FNRP 
Female of non-childbearing potential 
FRP 
Female of reproductive potential 
FSH 
Follicle stimulating hormone 
FTIH 
First Time in Human Trial 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GSK 
GlaxoSmithKline 
GVHD 
Graft-versus-host disease 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Surface antigen of Hepatitis B virus 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest non-severely toxic dose 
HRT 
Hormone replacement therapy 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator Brochure 
ICD 
Immunogenic cell death 
ICH GCP 
International Conference on Harmonization Good Clinical 
Practice. 
IFN-γ 
Increased interferon-γ 
IL-2 
Interleukin-2 
IMWG 
International Myeloma Working Group 
IND 
Investigational new drug 
IgG
ImmunoglobulinG 
IgM
ImmunoglobulinM 
IgA
ImmunoglobulinA 


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INR 
International normalization ratio 
IP 
Investigational product 
ITIM 
immunoreceptor tyrosine-based inhibition motif 
IRB 
Institutional review board 
IRR 
Infusion related reaction 
ITSM 
immunoreceptor tyrosine-based switch motif 
IV 
Intravenous 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LSFD 
Last subject first dose 
LSLV 
Last subject’s last visit 
LSLV 
Last subject last visit 
mAb 
Monoclonal antibody 
mTPI 
Modified Toxicity Probability Interval 
MM 
Multiple myeloma 
MMAF 
Monomethyl auristatin-F 
MRI 
Magnetic resonance imaging 
MSDS 
Material Safety Data Sheet 
NCI 
National Cancer Institute 
NEI-VFQ-25 
National Eye Institute 25-Item Visual Function 
Questionnaire 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
NSAIDS 
Non-Steroidal Anti-Inflammatory Drugs 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
OTC 
Over the counter 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PACT 
Post Analysis Continued Treatment 
PCR 
Polymerase chain reaction 
PCI 
Potential clinical concern 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death Ligand 1 
PD-L2 
Programmed cell death Ligand 2 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO-CTCAE 
Patient-Reported Outcome Version Of Common Toxicity 
Criteria for Adverse Events 
PR 
Partial response 
PTS 
Platform Technologies and Science 
QTcF 
Corrected QT interval for heart rate by Fridericia’s 
formula 
RAMOS 
Registration and Medication Ordering System 


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RAP 
Reporting and Analysis Plan 
RBC 
Red blood cell 
REM 
Rapid eye movement 
RIBA 
Recombinant immunoblot assays 
RP2D 
Recommended Phase 2 Dose 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System 
SEB 
Staphylococcal enterotoxin B 
SOI 
Start of infusion 
SOP 
Standard operating procedure 
SPEP 
Serum Protein Electrophoresis
SRM 
Study Reference Manual 
STD10 
Severely toxic dose 10 
T1DM 
Type 1 diabetes mellitus 
TLS  
Tumor Lysis syndrome  
TTP 
Time to Disease Progression 
TTR 
Time to (best) Response 
TNF 
Tumor necrosis factor 
UK 
United Kingdom 
ULN 
Upper limit of normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VGPR 
Very good partial response 
WBC 
White blood cell 
WT 
Wild type 
 
Trademark Information  
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
DARZALEX 
 
Chiron RIBA 
 
 
Flu-Mist 
 
 
Keytruda 
 
 
MedDRA 
 
 
SAS 
 
 
 


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12.3. 
Appendix 3:  Modified Diet in Renal Disease Formula 
MDRD 
eGFR = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American) 
GFR is expressed in mL/min/1.73 m2, SCr is serum creatinine expressed in 
mg/dL, and age is expressed in years.  
The link below will auto-calculate the creatinine clearance: 
http://nephron.org/cgi-bin/MDRD GFR/cgi 


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12.5. 
Appendix 5:  Liver chemistry stopping and monitoring 
criteria and required actions and follow up assessments 
12.5.1. 
Liver chemistry stopping criteria 
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology. 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT-absolute 
ALT  5xULN 
ALT Increase 
ALT  3xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT  3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT   3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• 
Report the event to GSK within 24 
hours 
• 
Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2 
• 
Perform liver event follow up 
assessments  
• 
Monitor the subject until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
• 
Do not restart/rechallenge subject with 
study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (refer to language 
within this appendix)  
• 
If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and may 
• 
Viral hepatitis serology4 
• 
Only in those with underlying chronic hepatitis B 
at study entry (identified by positive hepatitis B 
surface antigen) quantitative hepatitis B DNA and 
hepatitis delta antibody5.   
• 
Blood sample for pharmacokinetic (PK) analysis, 
if it can be obtained within 45 days after the 
last dose6 
• 
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin2xULN 
• 
Obtain complete blood count with differential to 
assess eosinophilia 
• 
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE report form 
• 
Record use of concomitant medications on the 
concomitant medications report form including 


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continue subject in the study for any 
protocol specified follow up assessments  
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up 
assessments within 24 hrs 
• 
Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up 
assessments within 24-72 hrs  
• 
Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
acetaminophen, herbal remedies, other over the 
counter medications 
• 
Record alcohol use on the liver event alcohol 
intake case report form 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G (IgG or gamma globulins). 
• 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution 
to liver injury in subjects with definite or likely 
acetaminophen use in the preceding week 
[James 2009]). NOTE: not required in China  
• 
Liver imaging (ultrasound, magnetic resonance, 
or computerised tomography) and /or liver biopsy 
to evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia) 
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5. If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA 
virus (where needed) [Le Gal , 2005]. 
6. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 
prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s 
best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling 
and shipping are in the SRM.   
 


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Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT 3xULN but <5xULN and 
 bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks 
 
• 
Notify the GSK medical monitor within 24 hours 
of learning of the abnormality to discuss subject 
safety.  
• 
Subject can continue study treatment   
• 
Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
• 
If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline. 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.  
12.5.2. 
Liver Safety Drug Restart or Rechallenge Guidelines 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless: 
• 
GSK Medical Governance approval is granted (as described below), 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the subject 
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments 


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12.5.2.1. 
Rechallenge Following Liver Stopping Events that are Possibly Related 
to Study Treatment 
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies.1 Clinical outcomes vary by drug, 
with nearly 50% fatality with halothane readministered within one month of initial injury. 
However, some drugs seldom result in recurrent liver injury or fatality.   
Risk factors for a fatal drug rechallenge outcome include: 
• 
hypersensitivity1 with initial liver injury (e.g. fever, rash, eosinophilia)  
• 
jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total) 
• 
subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5 
• 
serious adverse event or fatality has earlier been observed with drug 
rechallenges2,3 
• 
evidence of drug-related preclinical liability (e.g. reactive metabolites;  
mitochondrial impairment3) 
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable. 
Approval by GSK for rechallenge with study treatment can be considered where: 
• 
Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available.   
• 
Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.    
• 
If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death.   
• 
The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.   
• 
Study treatment must be administered at the dose specified by GSK. 
• 
Subjects approved by GSK Medical Governance for rechallenge with study 
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liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol. 
• 
If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued.  
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge.  
• 
GSK to be notified of any adverse events, as per Section 7.3.1. 
12.5.2.2. 
Restart Following Transient Resolving Liver Stopping Events NOT 
Related to Study Treatment 
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury. 
Approval by GSK for study treatment restart can be considered where: 
• 
Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN). 
• 
Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 12.5.2 will apply. 
• 
There is no evidence of alcoholic hepatitis. 
• 
Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required. 
• 
If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death. 
• 
The subject must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study 
chart. 
• 
 Study treatment must be administered at the dose specified by GSK. 


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• 
Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 
• 
If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions. 
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 
• 
GSK to be notified of any adverse events, as per Section 7.3.1. 
References:  
• 
1Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714. 
• 
2Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced 
liver injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90.  
• 
3Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222. 
 


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12.6. 
Appendix 6:  Genetic Research 
Genetics – Background 
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2002]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study. 
Genetic Research Objectives and Analyses 
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:  
• 
Response to medicine, including belantamab mafodotin or any concomitant 
medicines; 
• 
Multiple myeloma susceptibility, severity, and progression and related conditions  
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives. 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate. 
Study Population 
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research. 


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Study Assessments and Procedures 
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.   
• 
A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.   
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).  
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product. 
Subjects can request their sample to be destroyed at any time. 
Informed Consent 
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken. 
Subject Withdrawal from Study 
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected: 
• 
Continue to participate in the genetic research in which case the genetic DNA sample 
is retained 
• 
Discontinue participation in the genetic research and destroy the genetic DNA 
sample  


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If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records.  
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.  
• 
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.   
• 
Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate.  
Screen and Baseline Failures 
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files. 
Provision of Study Results and Confidentiality of Subject’s Genetic Data 
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals.  
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care. 
















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12.8. 
Appendix 8:  Contraceptive Guidance and Collection of 
Pregnancy Information Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
• 
Premenarchal 
• 
Premenopausal female with 1 of the following: 
▪ 
Documented hysterectomy 
▪ 
Documented bilateral salpingectomy 
▪ 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the subject’s 
medical records, medical examination, or medical history interview. 
• 
Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 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 (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 


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Contraception Guidance 
a. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
b. 
Highly Effective Methodsb That Have Low User Dependency  
c. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
d. 
Intrauterine device (IUD) 
e. 
Intrauterine hormone-releasing system (IUS)c 
f. 
Bilateral tubal occlusion 
g. 
Vasectomized partner 
h. 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
i. 
Highly Effective Methodsb That Are User Dependent 
j. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
k. 
oral 
l. 
intravaginal 
m. transdermal 
n. 
injectable 
o. 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
p. 
oral 
q. 
injectable 
r. 
Sexual abstinence 
s. 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the subject 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction) 
 


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Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male subject’s 
female partner of a male study subject who becomes pregnant while participating in 
this study, and for 6 months following last dose of belantamab mafodotin. This 
applies only to male subjects who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
Female Subjects who become pregnant 
• 
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study, and for 4 months following last dose of 
belantamab mafodotin.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a subject's pregnancy.  
• 
Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on subject and neonate, which will be 
forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.   
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK. While the investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting.  
Any female subject who becomes pregnant while participating will discontinue study 
intervention.  
 


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12.9. 
Appendix 9: Belantamab Mafodotin associated Corneal 
Event Severity Grading and Mitigation Strategy  
Prophylactic preservative-free artificial tears should be administered in each eye at least 
4-8 times daily, beginning on Cycle 1 Day 1 until the End of Treatment (EOT).  Allow at 
least 5-10 minutes between administration of artificial tears and steroid eye drops.  In the 
event of ocular symptoms (e.g., dry eyes), the use of artificial tears may be increased up 
to every 2 hours as needed. 
While not yet clinically demonstrated, it is theoretically possible that the application of a 
cooling eye mask during belantamab mafodotin administration, and in the first few hours 
after infusion may subsequently decrease ocular side effects.  On the day of infusion at 
the discretion of the subject and the investigator, the following may be considered:  
• 
Beginning with the start of each belantamab mafodotin infusion, subjects may apply 
cooling eye masks to their eyes for approximately 1 hour or as much as tolerated.   
• 
Subjects may continue using the cooling eye mask beyond the first hour for up to 4 
hours.  Further use beyond 4 hours is at the patient’s discretion. 
Subjects must avoid the use of contact lenses during the study. 
An ophthalmology (or optometrist, if an ophthalmologist is not available) consult is 
required for all subjects who develop signs or symptoms of corneal toxicity.  
A summary of prophylactic interventions for corneal toxicity associated with belantamab 
mafodotin is provided in Table 16.  Corneal toxicity must be graded according to the 
guidelines provided in Table 17. Additional guidance on grading visual acuity changes 
provided in Table 18. 
Table 16 
Prophylactic measures for corneal Events associated with 
Belantamab Mafodotin 
Prophylactic 
Measurea 
Dose and Administration 
Timing 
Preservative-free 
artificial tears 
Administer in each eye at least 
4-8 times daily 
Administer daily beginning on Cycle 1 
Day 1 until EOT.   
Cooling eye mask 
May apply cooling eye mask to 
both eyes for approximately 
1 hour or as much as tolerated  
During belantamab mafodotin infusion 
administration in the first hour for up to 
4 hours, as tolerated 
a. 
Dose modifications and treatment for ocular toxicities are discussed in Section 6.5.  
 


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.


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12.10. 
Appendix 10: Country Specific Requirements 
No country-specific requirements exist. 
 
 


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12.11. 
Appendix 11: Operating Characteristics of Safety Stopping 
Rule for Expansion Cohort 
 
 
5
10
15
20
25
0 0
0.2
0.4
0.6
0.8
1 0
Number of Dosed Subjects
Prob. of Stopping
True = 0.1
True = 0.2
True = 0.3
True = 0.4
True = 0.5
True = 0.6


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12.12. 
Appendix 12: Sample Size Calculation for the Expansion 
Cohort 
Sample size is calculated using the Predictive Probability Design for Phase II studies 
software. The optimal design is identified by specifying interim looks starting from a 
minimum of 10 evaluable subjects, “maximizing power under the alternative hypothesis’ 
as the optimizing criterion, Thetha_L(threshold of early futility 
stopping)/Theta_U(threshold of early efficacy stopping)/Theta T(threshold) as default, a 
weakly informative beta prior Beta (0.04, 0.06) representing information from 0.1 subject 
with a mean response of 40%, type I error rate controlled at 0.10, and power of 80%. The 
design with smallest Nmax that controls the type I and type II error rate is the optimal 
design. 
 


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12.13. 
Appendix 13: Data Management/Monitoring 
Source Data Verification/Source Document Review (SDV/SDR) 
During periods in which on-site monitoring is not permitted, GSK will consider remote 
Source Data Verification/Source Document Review (SDV/SDR) where permitted by the 
clinical site/institution and in accordance to with local law and regulatory guidance 
documents. 
Remote SDV/SDR will be proposed to study sites to meet a patient and/or critical data 
quality need, e.g., to assess patient safety or to ensure data integrity. The study specific 
monitoring plan will be updated in accordance with remote monitoring practices adopted 
for the country/study. The subject informed consent will be updated in line with local 
regulations to permit remote monitoring practices. In case of remote SDV/SDR, GSK 
will work with the site to ensure subject privacy. 
eCRF/CRF Final or Interim Sign off Process: 
The Principal Investigator (PI) is responsible for ensuring that the data within the eCRF 
casebook and any other data sources utilized during the study for each study patient is 
complete and consistent with source documents throughout the study (ICH GCP 4.9.1 
and 4.9.2). The PI may sign/re-sign the eCRF from any computer/location by accessing 
the eDC platform) using his/her unique eCRF login credentials. 
Essential Document Sign Off Process: 
If an investigator is unable to print and sign essential documents such as 
Protocol/Amendment signature page then Email approval can be accepted by replying to 
the relevant email that is sent by GSK. Please note that unblinding procedures remain the 
same as those documented in the protocol and other study-related documents. 


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12.14. 
Appendix 14: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
2016N273410_01 
26-SEP-2018 
Amendment No. 1 
Amendment 1 applies to all global sites. The following changes were based on 
review and comments from the FDA:  
• Revised line of setting from 2nd line to 4th line; updated associated sections in the 
synopsis, protocol body, and inclusion/exclusion criteria 
• Revised dose limiting toxicity (DLT) wording as directed by FDA 
• Removed the lowest dose level (1.92 mg/kg) during dose escalation. Maintained 
2.5 and 3.4 mg/kg doses during dose escalation. Due to lowest dose removal, 
revised study number to 40 overall subjects. Associated revisions made in 
statistical section 
• Addition of statement to add clarity that pembrolizumab will be held or 
discontinued when belantamab mafodotin is held or discontinued  
• Addition of Part 2 stopping criteria 
In addition to the requests from the FDA, the following revisions were also included:  
• Update to the Sponsor Information section 
• Addition of EudraCT number 
• Inclusion of additional wording to the Rationale and Background section to 
further support combination with pembrolizumab and to support move to 4th line 
therapy 
• Revision of dose escalation objective/endpoints to move overall response rate to 
secondary from exploratory and addition of minimal residual disease negativity 
rate (based on current guidelines); revision of dose expansion 
objectives/endpoints to add clarity to endpoints, add ocular findings, add 
additional clinical activity secondary endpoints, and revise the questionnaire in 
exploratory section from MDASI-MM to EORTC-QLQ-C30 and EORTC-QLQ-
MY20; updated associated sections of protocol to reflect changes  
• Updates/revisions to the inclusion/exclusion criteria to incorporate changes to the 
standard language for belantamab mafodotin and pembrolizumab 
• Revised contraception language for both male and female to follow belantamab 
mafodotin standard language in Inclusion/Exclusion criteria and protocol 
sections; revisions to the pregnancy section due to change in standard language 
• Increased the maximum number of combination cycles from 32 to 35 to be in line 
with standard pembrolizumab language and to be in line with 2-year treatment; 
update of associated study schematic 
• Revision to the follow-up definition; addition of progression free survival follow-
up visits  
• In addition to the FDA mandated DLT revisions, added clarity to DLT definition, 
revised wording to existing DLTs and added new DLTs  
• Revisions/updates to the corneal event language, supportive care, monitoring and 
mitigation language throughout the document, inclusive of changes to Appendix 9 


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• Revision of statistical model in dose escalation from Bayesian Logistic 
Regression Model to modified mTPI; revision to various calculations associated 
with change to this model and to change in subject number; revisions to statistical 
sections of protocol, including revision to clinical activity analyses section 
• Updates to the background/data for belantamab mafodotin from first time in 
human study BMA117159 
• Updated background information related to pembrolizumab to be in line with 
changes to standard language and to address the MM study information from 
KEYNOTE 183 and 185; Revision of Benefit:Risk statement based on this 
information 
• Updated Risk assessment and mitigation table 
• Revisions to subject completion language and study completion language 
• Revisions to Investigational Product section to be in line with standard language 
• Updates to the belantamab mafodotin and pembrolizumab Dose Modification 
tables based on current standard language  
• Revised the Table and Events section by splitting one table into multiple tables 
based on phase of study. Added in eGFR, Spot Urine, Skeletal survey, revisions 
to PK and ADA assessments; replaced MDASI-MM with EORTC questionnaires, 
removed INR/PTT, TBNK and CK-MB. On-treatment assessments linked to 
weekly schedule and/or dosing of combination treatment; addition of PFS follow-
up column and clarification of OS follow-up 
• Removal of Sentinel Event language from protocol 
• Addition of adverse events of special interest section 
• Addition of specific requirements for ocular examinations and procedures 
• Removed TBNK from Biomarker sections, other wording revisions in this section 
• Revision of All Evaluable Subjects population 
• Addition of an Internal Safety Review Committee  
• Appendices updates including revision to abbreviations, update of liver chemistry 
stopping criteria formatting, removal of International Myeloma Working Group 
Uniform Response Criteria for Multiple Myeloma appendix, removal of appendix 
listing P-gp inhibitors, revisions to contraception and corneal event appendices 
due to updates to standard language  
• Other minor clarifications/revisions were added 
2016N273410_02 
26-FEB-2020 
Amendment No. 2 
Amendment 2 applies to all global sites. The following changes were based on 
review and comments from global agencies, inclusion of items noted in protocol 
clarification letters, revisions due to discrepancies, revision of study drug related 
language and other clarifications noted since Amendment #1:  
• Update to Author list, sponsor signatory, and sponsor contact list 
• Universal update to document to clarify name of GSK2857916 as belantamab 
mafodotin 
• Based on emerging data, removal of mandated steroid eye drops throughout 
protocol, inclusive of Appendix 9 
• Updated timelines for requirement of contraception for females and males based 
on additional data collected and Investigator Brochure; added statements that use 
should be consistent with local regulations; inclusive of Appendix 8  


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• Due to emerging data, modified the timings of ocular exams after the 4th dose of 
belantamab mafodotin 
• Removal of detailed non-clinical pharmacokinetics and addition of cross 
reference to revised Investigator Brochure which contains information 
• Revision of effects in human section and addition of pharmacokinetics section 
based on updated data from single agent belantamab mafodotin studies 
• Simplification of dose level reduction language for belantamab mafodotin 
• Revision of Part 1 completion language to clarify belantamab mafodotin RP2D 
decision criteria 
• Based on agency feedback, addition to benefit:risk section and Table to highlight 
risks/mitigations for potential risks associated with the combination of 
belantamab mafodotin and pembrolizumab; Update of belantamab mafodotin and 
pembrolizumab language based on emerging data 
• Clarification of subject completion definition, with definition applying to both 
Part 1 and Part 2 
• Based on agency feedback, addition of belantamab mafodotin administration 
language in applicable sections 
• Based on emerging data for both study treatments, updated belantamab mafodotin 
and pembrolizumab dose modification Tables 
• Added clarification to contact lens use based on emerging data 
• Based on emerging data, revision of prohibited medication section  
• Clarification of clinical stable definition of ocular signs and symptoms 
• Revisions to Time and Events Table 7: clarify pregnancy test language, clarify 
imaging language, addition of cytogenetic tests 
• Revisions to Time and Events Table 8: clarify C1D8 assessment window, 
clarification of AE/SAE language, clarify ocular exam window, revise ocular 
exam timing language, addition of hematology monitoring as per dose 
modification table, clarifications/additions to bone marrow footnotes, including a 
mandated aspirate sample for immune cell characterization/profiling 
• Revisions to Time and Events Table 9: clarify C1D8 assessment window, 
clarification of vital sign windows, clarification of ECG window, removal of 
pharmacokinetics details from footnote and replaced with pharmacokinetics 
section reference, revision of immunogenicity footnote, revision of serum 
cytokine/chemokine footnote with additional samples, revision of cfDNA 
footnote with additional samples, addition of whole blood RNA and 
cryopreserved PBMC samples to increase translational research scope 
• Revisions to Time and Events Table 10: clarification of AE/SAE language, 
update of timing for final pregnancy test (as applicable), addition to bone marrow 
footnotes, including a mandated EOT aspirate sample for immune cell 
characterization/profiling clarification of timing for exit interview 
• Based on emerging data, revision to ocular examination section, with removal of 
some tests/eye segment review, and ocular photography  
• Addition of CK and LDH isoenzyme tests, based on emerging data, revision of 
clinical laboratory Table 
• Addition of pharmacokinetics Table in Section 7.4.1. to provide clarity, removal 
of select belantamab mafodotin and pembrolizumab pharmacokinetic samples; 


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addition of sBCMA collection at each belantamab mafodotin PK collection 
timepoint 
• Revision of biomarker wording to reflect addition of new tests and/or samples  
• Addition of DLT evaluable population to further define Part 1 population 
• Other minor clarifications/revisions were added 
Amendment 3: 27-AUG-2021 (TMF-12902367) 
Overall Rationale for the Amendment:  
This amendment was considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Update to medical 
monitor information and 
SAE reporting 
Medical monitor list is not 
provided as per GSK 
template. Details provided in 
the SRM 
Section 4.5.2. 
Pembrolizumab Dose 
Justification; Section 
4.6. Benefit: Risk 
Assessment; Section 
6.5.2. Dose modification 
and toxicity 
management for 
immune-related AEs 
associated with 
pembrolizumab 
Update to pembrolizumab 
safety language 
Update to pembrolizumab 
ECI-overdose language  
Update to standard text 
based on pembrolizumab 
and belantamab mafadotin 
Investigator Brochures, as 
appropriate 
Updated information as per 
Latest IB Update for 
pembrolizumab (2021) and 
belantamab (2021) 
Section 1. Synopsis; 
Section 9. Statistical 
Considerations And 
Data Analyses, Section 
9.6 Primary Analysis,  
Addition of Primary 
Analysis at approximately 
15 months follow-up from 
LSFV 
To test the hypothesis that a 
meaningful response rate 
(ORR) can be achieved of the 
combination 
Section 7.4.1. Blood 
Sample Collection for 
Pharmacokinetics, 
Section 9.8.3.2. Derived 
Pharmacokinetic 
Parameters, Section 
9.8.4. Pharmacokinetic/ 
Pharmacodynamic 
Analyses 
Update on planned 
derived pharmacokinetic 
parameters and 
pharmacokinetic/ 
pharmacodynamic 
analyses 
PK parameters will be 
determined for belantamab 
mafodotin, total mAb, and 
pembrolizumab (if measured) 
for each participant after each 
dose of belantamab mafodotin 
or of pembrolizumab. 
Section 12.13. 
12.13.Appendix 13: 
Updates to data 
monitoring wording 
Source Data 
Verification/Source Document 
Review, eCRF/CRF Final or 


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Section # and Name 
Description of Change 
Brief Rationale 
Data 
Management/Monitoring 
Interim Sign off Process and 
Essential Document Sign Off 
Process details added 
Amendment 01 
Where the Amendment Applies: 
Protocol Amendment 01 applies to all sites and countries. 
Amendment Changes with Rationale: 
The original protocol dated 11 May 2017 is replaced by Amendment 01 dated 26 SEP 
2018. 
The following protocol changes have been implemented as a result of comments received 
from the US Food and Drug Administration, which included removal of lower dose level 
as starting dose, revision of DLT definitions, population move to later line of therapy, 
adjustment of subject numbers and addition of Part 2 stopping criteria. The revisions also 
include language updates from Merck to pembrolizumab indications, dose rationale, and 
dose modifications. Additional revisions include revisions to background/rationale 
wording for GSK2857916, update to objective/endpoint wording, inclusion/exclusion 
criteria based on GSK/Merck updated wording, adjustment of contraception language, 
adjustment to maximum study treatment cycles, revisions to corneal event sections, 
updated statistical design wording, non FDA related update of DLT definitions, revisions 
of safety language and monitoring/management language, removal of IMWG response 
Appendix and associated links, removal of P-gp inhibitor appendix with addition of SRM 
for additional information, addition of MRD testing, addition of AE of special interest 
section, removal of sentinel event, update to benefit:risk information, replacement of 
questionnaire in Part 2 and updated Table of Events. Additionally, administrative 
corrections of minor typographical, and/or inconsistent language throughout the protocol 
were made as well as an update to the Reference section.  
Original text is displayed as strikethrough indicates replaced or removed text. New text is 
displayed as underline. If applicable, revisions within the tables will be displayed as text 
or if same revision affects multiple tables, the changes will be summarized; revisions to 
figures will be displayed first by the old figure, and then followed by the new figure. 
Administrative changes will not be displayed in the summary of changes.  


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Role 
Name 
Day Time Phone 
Number and email 
address 
After-hours 
Phone/Cell/ 
Pager Number 
Site Address 
Primary 
Medical 
Monitor  
, 
MD, PhD 
 
,  
MD, PhD 
GlaxoSmithKline 
1250 South Collegeville Road 
Mailstop UP4300 
Collegeville, PA 19426, USA 
Secondar
y Medical 
Monitor 
 
, MD, 
PhD 
 
MD, PhD 
 
GlaxoSmithKline1250 South 
Collegeville Road 
Mailstop UP4300 
Collegeville, PA 19426, USA 
SAE 
Reporting 
 
, MD, 
PhD 
OAX37649@gsk.com 
 
 
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Reason for change: Provision of additional data obtained to support rationale for 
combination with pembrolizumab.  
3. Section 1 – Objective(s)/Endpoint(s) 
Part 1: Dose Escalation 
Objectives 
Endpoints 
Primary 
• 
To determine safety, tolerability and to 
establish the recommended Phase 2 dose 
(RP2D) of the combination of GSK2857916 
and pembrolizumab in subjects with 
relapsed/refractory (rel/ref) RRMM   
• 
Percent of subjects with adverse events 
(AEs), changes in clinical signs and 
laboratory parameters 
• 
Number of subjects with dose limiting 
toxicities (DLTs) 
Secondary 
• 
To evaluate clinical activity of the combination 
of GSK2857916 and pembrolizumab in 
subjects with RRMM 
• 
Overall Response Rate (ORR), defined as 
the percentage of subjects with a confirmed 
partial response (PR) or better (i.e., PR, very 
good partial response [VGPR], complete 
response [CR] and stringent complete 
response [sCR]), according to the 
International Myeloma Working Group 
(IMWG) Response Criteria [Kumar, 2016] 
• 
To evaluate the pharmacokinetic profile of 
GSK2857916 when administered 
intravenously in combination with 
pembrolizumab1) 
• 
GSK2857916 Pharmacokinetic (PK) 
parameters following IV administration as 
data permit (e.g., area under the curve 
[AUCs], mean maximum concentration 
[Cmax], time of Cmax [tmax], terminal phase 
half-life [t½]) after the first dose; and 
concentration at trough (Ctrough), and end of 
infusion concentration in subsequent cycles, 
when measured 
• 
To assess anti-drug antibodies (ADAs) 
against GSK28579161). 
• 
Incidence and titers of ADAs against 
GSK2857916 
Exploratory 
• 
To evaluate clinical activity of the combination 
of GSK2857916 and pembrolizumab in 
subjects with rel/ref MM 
• 
Overall Response Rate (ORR) defined as % 
of patients achieving  PR 
• 
Clinical Benefit Rate (CBR) defined as % of 
patients achieving  MR  
• 
Duration of Response (DOR) data permitting 
• 
Progression Free Survival (PFS) data 
permitting 
• 
Overall survival (OS) data permitting 
• 
Time to Response (TTR) data permitting 


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Objectives 
Endpoints 
• 
To assess Minimal Residual Disease (MRD) 
in participants who achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity 
rate, defined as: the percentage of subjects 
who are MRD negative in subjects who 
achieve VGPR or CR 
• 
To characterize the relationship between 
clinical response and other biologic intra
tumor or microenvironment characteristics 
(DNA, protein analysis) 
• 
BCMA expression levels on malignant cells, 
and other markers in tumor tissue, serum 
sBCMA levels, serum cytokines,  baseline 
immune status and immune cell 
characterization and their relationship to 
clinical response (Protein, RNA, DNA 
analysis) 
• 
To investigate the relationship between 
genetic variants in the host and response to 
GSK2857916 in combination with 
pembrolizumab  
• 
Possible relationship between host genetic 
variation and response to GSK2857916 in 
combination with pembrolizumab 
• 
To evaluate the tolerability of GSK2857916 in 
combination with pembrolizumab based on 
patient self-report of symptomatic adverse 
effects 
• 
Symptomatic adverse effects as measured by 
the Patient-reported outcome version of the 
Common Term Criteria for Adverse Events 
(PRO-CTCAE) 
• 
Impact of ocular adverse effects on quality of 
life as measured by the Visual Function 
questionnaire(s): National Eye Institute 25-
item Visual Function Questionnaire (NEI-
VFQ-25) and Ocular Surface Disease Index 
(OSDI) 
• 
To evaluate disease and treatment related 
symptoms and associated impacts on 
function and health-related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered only in case of unexpected clinical findings.  
Part 2: Expansion 
Objectives 
Endpoints 
Primary 
• 
To assess the clinical activity of the 
combination treatment with 
GSK2857916 and pembrolizumab 
in subjects with rel/ref RRMM   
• 
Overall Response Rate (ORR), defined as the 
percentage of participants with a confirmed PR or better 
(i.e., PR, VGPR, CR and sCR), according to the IMWG 
Response Criteria [Kumar, 2016] 
Overall Response Rate (ORR) defined as % of patients 
achieving  PR 
Secondary 
• 
To further evaluate confirm safety 
of GSK2857916 administered in 
combination with pembrolizumab in 
subjects with RR rel/ref MM 
• 
Number of subjects with AEs, changes in clinical signs 
and laboratory parameters 
• 
Ocular findings on ophthalmic exam 


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Objectives 
Endpoints 
• 
To further characterize the clinical 
activity of the combination 
treatment with GSK2857916 and 
pembrolizumab in subjects with 
rel/ref RRMM 
• 
Clinical Benefit Rate (CBR) defined as % of patients 
achieving  MR   
• 
Duration of Response (DOR) data permitting 
• 
Progression Free Survival (PFS) data permitting 
• 
Overall Survival (OS) data permitting 
• 
Time to Response (TTR) data permitting 
• 
Clinical benefit rate (CBR), defined as the percentage 
of participants with a confirmed minimal response (MR) 
or better per IMWG  
• 
Duration of response (DoR), defined as: the time from 
first documented evidence of PR or better to the time 
when disease progression (PD) is documented per 
IMWG, or death due to PD among subjects who 
achieve an overall response, i.e. confirmed PR or 
better. 
• 
Time to response (TTR), defined as: the time between 
the date of first dose and the first documented evidence 
of response (PR or better) among subjects who 
achieved a confirmed response of PR or better. 
• 
Time to best response, defined as the time between the 
date of first dose and the first best documented 
response (PR or better) among subjects who achieve a 
confirmed response of PR or better. 
• 
Progression-free survival (PFS), defined as: the time 
from first dose to the earliest date of PD per IMWG, or 
death due to any cause. 
• 
Time to disease progression (TTP), defined as: the time 
from first dose until the earliest date of PD per IMWG, 
or death due to PD. 
• 
Overall Survival (OS), defined as the time from first 
dose to death due to any cause 
• 
To evaluate the pharmacokinetic 
profile of GSK2857916 when 
administered intravenously in 
combination with pembrolizumab1 
• 
Pharmacokinetic (PK) parameters following IV 
administration as data permit (e.g., area under the 
curve [AUCs], mean maximum concentration [Cmax], 
time of Cmax [tmax], terminal phase half-life [t½]) after 
the first dose; concentration at trough (Ctrough), and 
end of infusion concentration in subsequent cycles, 
when measured 
• 
To assess anti-drug antibodies 
(ADAs) against GSK28579161 
• 
Incidence and titers of ADA to GSK2857916 
Exploratory 
• 
To assess Minimal Residual 
Disease (MRD) in participants who 
achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity rate, 
defined as: the percentage of subjects who are MRD 
negative in subjects who achieve VGPR or CR 


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Objectives 
Endpoints 
• 
To characterize the relationship 
between clinical response and 
other biologic intra tumor or 
microenvironment characteristics 
(DNA, protein analysis) 
• 
BCMA expression levels on malignant cells and other 
markets in tumor tissue, serum sBCMA levels baseline 
immune status, serum cytokines, and immune cell 
characterization and their relationship to clinical 
response (Protein, RNA, DNA analysis) 
• 
To investigate the relationship 
between genetic variants in the 
host and response to GSK2857916 
in combination with pembrolizumab 
• 
Possible relationship between host genetic variation 
and response to GSK2857916 in combination with 
pembrolizumab 
• 
Plasma concentrations of 
GSK2857916 when administered 
intravenously in combination with 
pembrolizumab1) 
• 
 GSK2857916 end of infusion concentration and 
concentration at trough 
• 
To explore the effect of the 
combination therapy of 
GSK2857916 with pembrolizumab 
on symptoms and health-related 
quality of life HRQoL in subjects 
with rel/ref RR MM 
• 
Changes from baseline in symptoms and health-related 
quality of life as measured by the European 
Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core Module 
(EORTC-QLQ-C30) and European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire 20-item Multiple Myeloma Module 
(EORTC-QLQ-MY20) MD Anderson Symptom 
Inventory Multiple Myeloma (MDSI MM) module 
• 
To evaluate the tolerability of 
GSK2857916 in combination with 
pembrolizumab based on patient 
self-report of symptomatic adverse 
effects 
• 
Symptomatic adverse effects as measured by the PRO-
CTCAE 
• 
Impact of ocular adverse effects on quality of life as 
measured by the Visual Function questionnaire(s): NEI-
VFQ-25 and OSDI 
• 
To evaluate disease and treatment 
related symptoms and associated 
impacts on function and health-
related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered if unexpected clinical findings have been identified.  
Reason for change: Revision of Objective/Endpoints to revise secondary endpoint for 
dose escalation, add MRD for response endpoints, replace MDASI-MM with EORTC 
questionnaires, add clarity to primary and secondary endpoints for dose expansion, and 
revise biomarker wording.   
4.  Section 1 – Type and Number of Subjects 
The study will enroll adult subjects with RR rel/ref MM, who have undergone stem cell 
transplant, or who are considered transplant ineligible. Subjects must have been, and who 
have been previously treated with at least 32 prior lines that include the following: , 
containing 3 classess of anti myeloma drugs: an alkylating agent, AND an 
immunomodulatory imide drug -IMiD (eg i.e. lenalidomide or pomalidomide), AND a 


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proteasome inhibitor -PI (eg i.e. bortezomib, ixazomib or carfilzomib) and an anti-CD38 
antibody alone or in combination. Line of therapy are defined by consensus panel of the 
International Myeloma Workshop [Rajkumar, 2011]. In addition, subject must be 
prgressing on, or within 60 days since the most recent therapy (as defined by IMWG).  
Overall, it is estimated that up to 408 evaluable subjects will be enrolled in this two-part 
study (up to 128 in Part 1, and 2830 in Part 2).  
Reason for change: Revision of the targeted population and number of subjects due to 
FDA comments and adjustment to proposed dose level due to FDA comments.  
5.  Section 1 – Key Inclusion Criteria 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
• Provide signed written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form 
• Male or female, 18 years or older (at the time consent is obtained) 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
• Have confirmed diagnosis of Multiple Myeloma and have undergone stem cell 
transplant, or are considered transplant ineligible 
• Histologically or cytologically confirmed diagnosis of MM as defined according 
to IMWG, 2014 [Rajkumar, 2014], and  
o Has undergone stem cell transplant or is areconsidered transplant 
ineligible, and  
o Haves been treated with at least 32 prior lines of prior anti-myeloma 
treatments, including 3 classess of drugs: an alkylating agent, AND an 
IMiID (eg. lenalidomide or pomalidomide), AND a proteasome inhibitor 
(eg., bortezomib, ixazomib or carfilzomib) and an anti-CD38 antibody, 
alone or in combination. Line of therapy are defined by consensus panel of 
the International Myeloma Workshop [Rajkumar, 2011].  In addition, 
subject must be progressing on, or within 60 days since the most recent 
treatment (as defined in International Myeloma Working Group Uniform 
Response Criteria, 2011 [Rajkumar, 2011] 
• In addition to the criteria above, subjects in Part 2 must have Has measurable 
disease defined as one of the following: 
a) 
Serum M-protein 0.5 g/dL (5 g/L).  
b) 
Urine M-protein ≥200 mg/24h.  
c) 
Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an 
abnormal serum free light chain ratio (<0.26 or >1.65)  
d) 
Biopsy proven plasmacytoma (should be measured within 28 days of 
Screening Visit) 
• Subjects with a history of autologous stem cell transplant (SCT) are eligible for 
study participation provided the following eligibility criteria are met: 
a) 
Transplant was > 100 days prior to study enrolment. 
b) 
No active infection (s). 
c) 
Subject meets the other eligibility criteria outlined in this protocol. 




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A WOCBP must have a negative highly sensitive serum pregnancy test (as 
required by local regulations) within 72 hours before the first dose of study 
intervention.  
Additional requirements for pregnancy testing during and after study 
intervention are located in Appendix 8. 
The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy. 
• Male Subjects: 
• Male subjects are eligible to participate if they agree to the following during 
the intervention period and for at least 140 days after the last dose of study 
intervention:  
• Refrain from donating sperm 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent  
OR 
• Must agree to use contraception/barrier as detailed below 
▪ Agree to use a male condom and female partner to use an additional 
highly effective contraceptive method with a failure rate of <1% per 
year as described in Appendix 8 when having sexual intercourse 
with a woman of childbearing potential who is not currently 
pregnant. 
A female subject is of non childbearing potential or women of childbearing potential 
must have a negative serum pregnancy test within 72 hours prior to the first dose 
of study treatment and agree to use effective contraception during the study and 
for 120 days following the last dose of study treatment.  
Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception from the time of first dose of 
study treatment until 140 days after the last dose of study treatment to allow for 
clearance of any altered sperm.  
Reason for change: Revision of Inclusion Criteria due to update in line of therapy and 
update of contraception language. 
 6.  Section 1 – Key Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
• Systemic anti-myeloma therapy or an investigational drug within 14 days or five 
half-lives, whichever is shorter, preceding prior to the first dose of study drug or  
• pPlasmapheresis within 7 days prior to the first dose of study drug 


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• Prior treatment with a monoclonal antibody within 30 days of receiving the first 
dose of study drugs 
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., 
CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a 
Grade 3 or higher immune related adverse event (irAE)  
• Current corneal epithelial disease except mild punctate keratopathy 
• Use of an investigational drug within 14 days or five half-lives, whichever is 
shorter, preceding the first dose of study drug 
• History of an allogeneic stem cell transplant within last 5 years 
• Evidence of active mucosal or internal bleeding 
• Any major surgery within the last four weeks prior to the first dose of study 
therapy 
• Presence of active renal condition (infection, requirement for dialysis or any other 
condition that could affect subject’s safety). Subjects with isolated proteinuria 
resulting from MM are eligible, provided they fulfil criteria for the adequate renal 
functions defined in the inclusion criteria 
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions (including lab abnormalities) 
• Has received prior radiotherapy within 2 weeks of start of study therapy. Subjects 
must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central 
nervous system (CNS) disease 
• History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
• Current active liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal 
or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver 
disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or 
otherwise stable chronic liver disease per investigator’s assessment) or 
hepatobiliary involvement of malignancy is acceptable if subject otherwise meets 
entry criteria 
• Malignancies other than disease under study are excluded, except for any other 
malignancy from which the participant has been disease-free for more than 2 
years and, in the opinion of the principal investigators and GSK Medical Monitor, 
will not affect the evaluation of the effects of this clinical trial treatment on the 
currently targeted malignancy (RRMM). In addition, subjects with curatively 
treated non-melanoma skin cancer are allowed 
• Has known active CNS metastases and/or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate provided they are 
radiologically stable, i.e., without evidence of progression for at least 4 weeks by 
repeat imaging (note that the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid treatment for at 
least 14 days prior to first dose of study therapy Subjects with previous or 
concurrent malignancies are allowed only if the second tumor is not contributing 
to the subject’s illness. 


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Protocol Amendment 04 
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form of immunosuppressive therapy within 7 days prior the first dose of study 
therapy 
• Has known psychiatric or substance abuse disorders that would interfere with the 
subject’s ability to cooperate with the requirements of the study 
• Has had an allogenic tissue/solid organ transplant 
Reason for change: Revision of Exclusion Criteria due to updates to the GSK and 
Merck standard language.  
7.  Section 1 – Study Treatment and Duration 
Study Treatment and Duration 
Product name: 
GSK2857916 
Pembrolizumab 
[Formulation 
description:] 
20mg/mL, 1.5 mL/vial 
100 mg/4mL 
Route of Administration  
Delivered as 30 min IV infusion. 
Refer to Study Reference Manual 
(SRM) for details. 
Delivered as 30 min IV infusion 
Treatment Duration 
GSK2857916 and pembrolizumab will be administered via intravenous (IV) infusion on 
day 1 of each 21-day cycle (once every 3 week Q3W dosing schedule). Subjects enrolled 
in Part 1 and 2 will be treated until disease progression, intolerable toxicity, informed 
consent withdrawal, or for a maximum of 32 35 cycles (approximately 2 years, See 
Combination Treatment Schematic below).  
Old Figure:  
 
New Figure:  


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Subjects who achieve complete response (CR/sCR) are allowed to have early treatment 
discontinuation under following conditions: subjects have attained a CR/sCR and have 
been treated for at least 8 cycles with the combination of GSK2857916 and 
pembrolizumab and had at least 2 treatment cycles with both study drugs beyond the date 
when the initial CR is declared.  
The subjects who have early treatment discontinuation will not be allowed to re enter the 
study treatment at later time. 
After treatment discontinuations all subjects will be followed up every 3 months for 12 
months for PFS and OS. Subjects who discontinued treatment for reasons other than PD 
will be followed up every 3 weeks until confirmed PD, initiation of a new anticancer 
therapy or death. All subjects with confirmed PD will be followed for OS every 3 months 
until the end of study. End of study is defined as when all subjects have been followed for 
36 months from first dose of study treatment or died or withdrew consent or are lost to 
follow-up. The next subsequent therapy will be collected for all subjects who have 
confirmed PD before initiation of new anticancer therapy. 
Part 1: Dose Escalation  
Part 1 dose escalation will characterize the safety and tolerability of escalating doses of 
GSK2857916 in combination with 200 mg pembrolizumab to establish the RP2D.  The 
following dose levels of GSK2857916 in combination with 200 mg pembrolizumab are 
planned to be studied: 1.92 mg/kg, 2.5 mg/kg (dose level [DL] 1) and 3.4 mg/kg (DL2) 
(as outlined in Dose Escalation Schematic for Part 1 below). Additionally, other 
intermediate dose levels may also be explored. Dose level 1.92 mg/kg may be tested if 
dose level 2.5 mg/kg is not cleared. During the dose escalation, at least 3 evaluable 
subjects will be studied per dose level. In Part 1, any subject who received at least one 
treatment cycle of the combination will be evaluated for DLTs.  Subjects who have 
received only GSK2857916 or have been withdrawn from the study for reasons other 
than toxicity but prior to completion of DLT observation period will be replaced. 
Old Dose Escalation Schematic for Part 1 


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New Dose Escalation Schematic for Part 1 
 
Reason for change: Update to number of total cycles based on actual 24 month calendar 
and in line with maximum dosing from Merck language. Revisions of schematics to 
match revised plan. Revision of starting dose based on guidance from FDA. Removal of 
option to discontinue treatment if CR/sCR achieved based on program language.  
8.  Section 1 – Dose Limiting Toxicity Criteria (Part 1 only) 
The DLT observation window will be 21 days (=1 cycle). Any subject in Part 1 who 
received at least one treatment cycle of the combination of GSK2857916 and 
pembrolizumab will be evaluated for DLTs using National Cancer Institute (NCI) 
CTCAE Version 4.03 [NCI, 2010]. In addition, for GSK2857916 treatment related 
corneal events, the GSK grading scale for corneal events (Appendix 9) should be used for 
evaluation of DLT. 
A DLT is defined as an AE that meets at least one of the criteria defined below and is 
considered by the investigator to be clinically relevant and attributed (definitely, 
probably, or possibly) to the study therapy during the 21 day DLT observation period.  
 
An event will be considered a DLT if its relationship to the investigational agents cannot 
be ruled out, occurs within the DLT reporting period, and meets one of the following 
criteria:  
1. Any Grade 4 non-hematologic toxicity 
2. Any Grade 3 or greater non-hematologic toxicity, with the following exceptiosn (i.e., 
the following will not be considered a DLT): Grade 3 diarrhea, nausea, or vomiting 
that responds to standard of care within 72 hours; Grade 3 hypertension (controlled 
following addition of 1 antihypertensive medication); and Grade 3 tumor lysis 
syndrome not resolving with appropriate supportive treatment within 48 hours, or 
resulting in a delay in initiating cycle 2 by 14 days or more 
3. Any Grade 3 or greater non-hematologic laboratory value if either: 
• The laboratory abnormality persists for >48 hrs despite supportive treatment, or 
• The abnormality leads to hospitalization 
4. Hematologic toxicity:  
• Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 
• Grade 4 thrombocytopenia of any duration 


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CCI - This section contained Clinical Outcome Assessment data collection 
questionnaires or indices, which are protected by third party copyright laws and therefore 
have been excluded.


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During an ongoing enrolment in Part 2, futility analysis will be performed once 
approximately 15 subjects in Part 2 are evaluable for futility. Subjects are considered 
evaluable if they are in the all treated population, have received at least 2 doses of 
combination treatment, and have had at least one disease assessment post 2nd dose. 
Subjects are also considered evaluable if they are in the all treated population and have 
progressed or died or have permanently discontinued the study treatment. 
Reason for change: Update to language to clarify analysis population and update to 
subject number due to removal of lowest dose level. Removed analysis information from 
this section as should be in analysis section. 
10.  Section 1 – Corneal Supportive Guidelines for Corneal Toxicity (GSK2857916) 
Corneal events toxicity, which commonly manifests as a superficial microcystic 
keratopathy, haves previously been observed with antibody drug conjugates, including 
those conjugated to MMAF.  It is required that sites establish a close collaboration with 
an ophthalmologist (or optometrist, if ophthalmologist is not available) who will be 
responsible for assessing subjects on study and managing subjects who develop a corneal 
eventtoxicity in close communication with the GSK Medical Monitor and the possibly a 
GSKcoordinating ophthalmologist.  
Subjects will be assessed by ophthalmologists (or /optometrists, if ophthalmologist is not 
available) at baseline, and then every three weeks.  If there is no change in vision and no 
corneal signs consistent with toxicity at time of the cycle 4 exam, subjects may have their 
ophthalmologic exams decreased to once every 3 months.  If a subject subsequently 
develops a change in visual acuity or other ocular symptoms, the subject should be 
evaluated by an eye care professional.  Intraocular pressure must be monitored if steroid 
eye drops are used for more than 7 days. prior to each dose of cycles 1 4.  If 
asymptomatic and without signs consistent with corneal toxicity at time of the cycle 4 
exam, subjects may have their ophthalmologic exams decreased to once every 4 cycles.  
If a subject subsequently develops signs / symptoms, or they require additional treatment, 
e.g. topical steroid for more than 7 days, additional assessment by an ophthalmologist / 
optometrist will be implemented. 
Further information regarding corneal event associated with GSK2857916, including a 
grading scale and prophylactic measures are in Appendix 9. 
Reason for change: Update to language regarding corneal events.   
11.  Section 1 – Clinical Activity Assessment 
Standard disease assessments for MM will include laboratory tests (serum and urine M 
protein test, sFLC, and corrected calcium), bone marrow core biopsy and aspirate (in case 
of suspected CR or to demonstrate progression), immunohistochemistry (IHC) of bone 
marrow samples to confirm stringent CR) or imaging, and minimal residual disease by 
Next Generation Sequencing (NGS; in subjects with achieve confirmed VGPR or CR). 
Response evaluation will be performed according to the International Myeloma Working 
Group Uniform Response Criteria for Multiple Myeloma 20161 [Kumar, 2016 Rajkumar, 


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2011]. Clinical activity measured as Overall Response Rate (ORR) is defined as the 
percentage of subjects with confirmed stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), and partial response (PR). Other 
assessments of interest like clinical benefit rate (CBR), PFS, TTR, DOR, and OS will 
also be analyzed. Minimal residual disease negative rate will be assessed in those subjects 
who achieve a VGPR or CR.  
Reason for change: Update to language due to change in response criteria and deletion 
of clinical activity as information is in other section of synopsis.    
12.  Section 1 – Pharmacokinetic assessments  
Blood PK samples will be collected during the trial and analysed for GSK2857916 (ADC 
and total antibody) and cyc-mcMMAF concentration. Blood samples for pembrolizumab 
measurements will be collected and stored, but will only be analyzed in case of 
unexpected clinical findings. 
Reason for change: Clarification of analytes.  
13.  Section 1 – Value Evidence and Outcome  
Subjects enrolled in Part 2 only will self-complete additional questionnaires to assess the 
The symptoms related to multiple myeloma and its treatment, and the impact of these 
symptoms on daily functioning. Symptoms will be assessed using two questionnaires: 
EORTC-QLQ-C30 and EORTC-QLQ-MY20 the MD Anderson Symptom Inventory  
Multiple Myeloma (MDASI MM) module.  Subjects enrolled in Part 2 only will self
complete the MDASI MM module at the specified visits. 
Reason for change: Change in the questionnaire used for this analysis.  
14.  Section 1 – Statistical Analysis  
For part 1, nNo formal statistical hypotheses are being tested.  In Part 1, after each dose 
level, the Bayesian Logistic Regression Model (BLRM) with overdose control will be 
used to predict probability of toxicity of the next planned dose based on observed dose-
limiting toxities (DLTs) in previous cohorts.  tThe dose escalation decisions will be 
guided by the Modified Toxicity Probability Interval (mTPI) approach, made based on 
this recommendation, as well as the totality of the safety data. After the last cohort of 
subjects in Part 1 completes the 21-day DLT observation period, a formal interim 
analysis will be performed to support the RP2D decision, except for scenarios where 
RP2D is clearly defined by the toxicity profile. 
The primary goal of Part 2 is to confirm safety and to characterize clinical activity of the 
combination and to detect if meaningful overall response rate (ORR) can be achieved. 
Based on historical information [Lokhorst, 2015] and clinical judgement, the null 
hypothesis has been defined as ORR  40% for the purpose of this study. The alternative 
hypothesis has been defined as ORR  60%. A decision will be made using the specified 
stopping rules in the protocol. Descriptive statistics will be used to report the observed 


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ORR in the expanded cohort. Overall response rate will be defined as percentage of 
subjects achieving sCR+CR+VGPR+PR per IMWG Uniform Response Criteria [Kumar, 
2011]. 
A Bayesian predictive adaptive design [Lee, 2008] allowing the trial to be monitored 
more frequently at multiple stages will be used. For Part 2 expansion cohort, starting with 
13 subjects and allowing for a maximum sample size of 30, this design will have a type I 
error rate α of 0.092 and 80.9% power when the true response rate is 60%. The trial is 
designed to stop early for futility if the predictive probability of success is about 3.0% or 
less.  Futility analysis will be performed once approximately 15 subjects in Part 2 are 
evaluable. Futility will be determined by comparing numbers of responses (defined as PR 
or greater) and evaluable subjects with the stopping rules specified in the protocol. 
During part 2 of the study, treatment-rated Grade 4 or higher AEs will be continuously 
monitored starting from when 5 subjects are dosed. If observed toxicity level is 
significantly higher than 12% at 1-sided alpha of 0.025, the study may be terminated 
early based on totality of safety data. The 12% threshold is chosen based on 11% Grade 4 
or higher AE observed in study BMA117159.  
For Part 2, futility analyses for ORR will start when 10 subjects are evaluable. 
Enrollment may stop if the stopping rule is met based on totality of data. 
Final analysis of the data captured in Part 1 and Part 2 will be undertaken after all 
subjects meet at least one of the following criteria: have reached the end of study or died. 
End of study is defined as when all subjects have been followed for 36 months from first 
dose of study treatment or died or withdrew consent or are lost to follow-up or the safety 
stopping criteria is met, whichever occurs first. have received all prespecified treatments 
(32 cycles) or have progressed; or has died; or has been permanently withdrawn from the 
study for toxicity or other resons. 
Reason for change: Revisions to statistical calculations and wording based on change to 
subject number, switch to mTPI design and clarification of end of study definition.  
15.  Section 2.1 Study Rationale  
Multiple myeloma (MM) is an incurable malignancy and accounts for 1% of all cancers 
and for 10% of all hematologic malignancies. Worldwide, approximately 103,000 new 
cases are diagnosed annually, and an estimated 30,330 new cases and 12,650 deaths will 
occur in the U.S. in 2016 [Siegel, 2016].  Approximately 20,000 people will be diagnosed 
with MM each year in the United States [Rajkumar, 2011].  Despite significant advances 
with current novel therapies and hematopoietic stem cell transplantation (HSCT), novel 
therapies like second- and third-generation proteasome inhibitors (PIs), 
immunomodulatory drugs (IMiDs), and recent addition of monoclonal antibodies 
(mAbs),  cannot achieve cure, and most MM patients will relapse and ultimately develop 
resistance to existing therapies will die of relapse [Laubach, 2014]. Thus, there is a need 
to develop treatments with novel mode of action (MOA) which could potentially prevent 
the cross resistance to existing therapies. new treatments are urgently needed. 


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Before the introduction of daratumumab, patients with disease refractory to both IMiDs 
and PIs had a median overall survival (OS) ranging from 9 months [Kumar, 2012] to 12 
months [San Miguel, 2013].  
Daratumumab [DARZALEX, 2017], is a human IgGk monoclonal antibody that was 
granted accelerated approval as monotherapy for the treatment of relapsed/refractory 
multiple myeloma (RRMM) in the US in November 2015 based on the results from a 
Phase II monotherapy study (n=106) which reported 29.2% overall response rate (ORR) 
and median progression free survival (mPFS) of 3.7 months in patients with RRMM 
[Lonial, 2016].  The median number of prior lines of treatment reported in this study was 
5. 
Daratumumab has also been approved in combination with lenalidomide/ dexamethasone 
or bortezomib/dexamethasone for patients who were previously treated with at least one 
prior line of therapy, and in combination with pomalidomide and dexamethasone for 
patients previously treated with at least 2 prior lines of therapy based on improvement in 
mPFS and ORR [DARZALEX, 2017; Janssen-Cilag International NV, 2016]. 
While the data with daratumumab indicates that prolongation of PFS can been achieved, 
patients continue to relapse after treatment with daratumumab; additional treatment 
options to control the disease are needed.  Patients with RRMM who relapse after 
daratumumab, IMiD, and PI based therapies, have few treatment options available.   
B cell maturation antigen (BCMA also referred to as TNFRSF17 or CD269) is a member 
of the tumor necrosis factor (TNF) receptor superfamily and regulates a variety of 
cellular functions. BCMA is expressed in mature B lymphocytes and binds to two TNF 
family ligands BAFF (B-cell-activating factor belonging to the TNF family) and APRIL 
(a proliferation-inducing ligand) which influence B cell survival and proliferation.  Mice 
deficient for BCMA are viable, have normal B cell development, and exhibit normal 
humoral responses [Xu, 2001]. BCMA is widely expressed on malignant plasma cells in 
MM and to a lesser degree in other B cell malignancies [Tai, 2006].  A soluble form of 
BCMA has been identified in serum from MM patients and shown to correlate with 
progressive disease [Sanchez, 2016].  Since all malignant plasma cells express various 
levels of BCMA, MM has a biologically based rationale as a key indication for anti-
BCMA therapy. All patients with MM are expressing various levels of BCMA on the 
surface of the tumor cells, therefore MM is a good target disease for anti BCMA therapy.  
GSK2857916 is a humanized immunoglobulin G1 (IgG1) antibody-drug conjugate 
(ADC) that binds specifically to B cell maturation antigen (BCMA).  The parent antibody 
(GSK2857914) competes with the BCMA ligands APRIL and BAFF and is conjugated to 
the microtubule inhibitor monomethyl auristatin-F (MMAF), resulting in an ADC 
molecule.  The conjugate is produced in an afucosylated form to generate enhanced 
antibody-dependent cellular cytotoxicity (ADCC).  In addition, when MM cells 
expressing BCMA are exposed to GSK2857916, immunogenic cell death (ICD) markers 
are induced. Exposure of dendritic cells to tumor cells undergoing ICD may result in 
antigen-specific T-cell response, enabling the patient’s own immune response against the 
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Of the four proposed mechanisms of action (MOA) for GSK2857916, the ADC and 
ADCC MOAs have been linked to efficacy in non-clinical models:  in vitro and in vivo 
against multiple myeloma cell lines, and ex vivo against primary patient myeloma 
samples.  Inhibition of BCMA signaling has been demonstrated biochemically; however, 
functional effects on myeloma cells have not been demonstrated. ICD markers on cells 
are induced by GSK2857916 both in vivo and in vitro, but effects on efficacy have not 
been established in non-clinical models.  These different mechanisms may enable 
GSK2857916 to deliver anti-tumour activities targeting both dividing and nondividing 
tumour cells and associate the cell kill with an adaptive immune response; these MoA 
characteristics clearly differentiate GSK2857916 from existing approved treatments 
[GlaxoSmithKline Document Number 2013N175128_05. 
GSK2857916 is a humanized (IgG1) antibody drug conjugate (ADC) which binds 
specifically to BCMA. The parent anti BCMA antibody (J6M0) is conjugated to the 
microtubule inhibitor monomethyl auristatin F (MMAF) via a protease resistant 
maleimidocaproyl (mc) linker to produce the GSK2857916 ADC molecule.  Upon 
binding to the cell surface, GSK2857916 is rapidly internalized and active drug (cys
mcMMAF) is released inside the cell. GSK2857916 has also been produced in an 
afucosylated form to generate an enhanced antibody dependent cellular cytotoxicity 
(ADCC) response upon binding to FcRIIIa receptors on the surface of human effector 
cells. This dual mechanism of action may improve efficacy by targeting dividing (ADC) 
and non dividing tumor cells (ADCC). All patients with MM are expressing various 
levels of BCMA on the surface of the tumor cells, therefore MM is a good target disease 
for anti BCMA therapy. GSK2857916 is currently being tested in First Time in Human 
Trial (FTIH), and doses from 0.03 mg/kg up to 4.6 mg/kg have been tested, with no 
DLTs reported. Signals of clinical activity have been observed in patients.  
Many tumors, including MM are usinguse various escape mechanisms to evade the 
immune control and to promote tumor growth and clonal tides [McLaughlin, 2016].  One 
of those mechanisms is the expression of PD-1 ligands (PD-L1). Recent advances in 
cancer treatment include successful checkpoint blockade by using antibodies binding to 
PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab). The anti-PD-1 and anti-PD-L1 
antibodies have a good favorable safety profile in the clinic and have resulted in durable 
responses in a variety of cancers, including melanoma, kidney cancer, lung cancer, and 
Hodgkin lymphoma. The agents continue to be evaluated in various solid tumors and 
hematological malignancies, alone or in combination with other therapies [Dolan, 2014]. 
There is also growing body of data demonstrating broad expression of PD-1 and its 
ligands in the microenvironment of multiple myelomaMM, and indicating an important 
role of the PD-1 pathwayin the immune evasion by MM. [Liu, 2011; Kuranda, 2010; 
Atanackovic, 2014; Benson, 2010]. Although, so far, anti-PD-1 treatment alone has not 
been effective in MM [Lesokhin, 2014; Suen, 2006].  
The KEYNOTE-023 study examined whether an anti-PD-1 treatment (Keytruda 
[pembrolizumab]) in combination with immunomodulatory agents may create synergism, 
in this case lenalidomide and dexamethasone. Lenalidomide doses of 10 mg and 25 mg 
were examined, with the 25 mg dose further explored. Of the subject’s evaluable for 
efficacy (N=40), 88% of subjects had a decrease in M protein. The ORR for this 
population was 50%, including a 38% ORR for subjects who were lenalidomide 


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refractory [Mateos, 2016]. Based on these findings, the KEYNOTE-183 and KEYNOTE-
185 studies were initiated, exploring combinations of pembrolizumab with IMiDs.  
Following review of both studies by data monitoring committees, KEYNOTE-183 and 
KEYNOTE-185 were placed on full clinical hold. In both studies, it was determined that 
the benefit-risk was unfavorable for the combination of pembrolizumab with IMiDs. The 
US FDA also placed Cohort 1 (combination with lenalidomide and dexamethasone) of 
KEYNOTE-023 on full clinical hold as a result of the data from KEYNOTE-183 and 
KEYNOTE-185.  
This study will evaluate the safety and anti-myeloma activity of GSK2857916 in 
combination with pembrolizumab.  Safety will be closely monitored with dose 
modification guidelines in Section 6.5. GSK will also use an internal Safety Review 
Committee (iSRC) as described in Section 10.9.1 for review of safety. We hypothesize 
that given the immunogenic properties of the cell death induced by GSK2857916 an 
augmented anti-tumor activity will be observed in MM subjectspatients, when treated 
with combination of GSK2857916 and pembrolizumab. 
Reason for change: Inclusion of background information for revision to later line of 
therapy based on FDA comments and update to standard Merck language.  
16.  Previous Section 2.2 Brief Background 
Removal of section 
Currently, blockade of PD 1/PD L1 signalling pathway has been proven one of the most 
promising immunotherapeutic strategies against cancer. Pembrolizumab (one of the PD 1 
inhibitors) has gained regulatory approval by FDA and EMA and is successfully used for 
treatment of selected solid tumors.  
Given the immunogenic properties of the cell death induced by GSK2857916 (internal 
GSK data) we hypothesize that anti myeloma activity of GSK2857916 can be further 
enhanced by combining it with a PD 1 inhibitor, pembrolizumab. The aim of this 
approach is to achieve additive, or possibly synergistic anti MM activity in patients 
which may transform into a long lasting benefit.  
Reason for change: Consolidation of language.  
17.  Section 2.23.1 – Nonclinical Pharmacology 
GSK2857916 is an antibody drug conjugate (ADC) consisting of an Fc enhanced, 
humanized anti BCMA monoclonal antibody (mAb) that is conjugated to monomethyl 
auristatin F (MMAF). Upon binding to the cell surface, GSK2857916 is rapidly 
internalized and active cytotoxic drug (cys mcMMAF) is released inside the cell.  
Additionally, the antibody is afucosylated which increases binding to FcRIIIa receptors 
and enhances recruitment and activation of immune effector cells, which can kill tumor 
cells by antibody dependent cellular cytotoxicity (ADCC). The dual mechanism of action 


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of GSK2857916 is designed to enable anti-tumor activity of cells by ADCC activity 
(non dividing), as well as ADC activity (dividing cells). 
Reason for change: Consolidation of language.  
18.  Section 2.23.5 – Effects in Humans (GSK2857916) 
GlaxoSmithKline (GSK) initiated the clinical development of GSK2857916 in July 2014, 
with the FTIH study (BMA117159) in subjects with RRrel/ref MM and other advanced 
hematologic malignancies expressing BCMA (ClinicalTrials.gov Identifier: 
NCT02064387).  As of the data cut from 26 June 2017, a total of 73 subjects with 
RRMM have been treated with at least one dose of GSK2857916.October 14, 2016, 51 
subjects have received at least one dose of GSK2857916. Thirty eight subjects patients 
were treated in Part 1 (dose escalation): 0.03 mg/kg (n=1), 0.06 mg/kg (n=1), 0.12 mg/kg 
(n=4), 0.24 mg/kg (n=4), 0.48 mg/kg (n=4), 0.96 mg/kg (n=3), 1.92 mg/kg (n=4), 2.5 
mg/kg (n=8), 3.4mg/kg (n=3), and 4.6mg/kg (n=6). Since the RP2D (3.4 mg/kg) selection 
(August 11, 2016), an additional 3521 subjects have been enrolled into Part 2 (expansion 
cohort). Of these 35 subjects,40% had receive prior daratumumab. The ORR for this sub-
population was 43% [Trudel, 2017]. 
The most frequently-reported AEs (≥15.0%) in the All Treated Population included: 
vision blurred (37%), nausea (36%), fatigue (33%), anemia (29%), dry eye (29%), 
thrombocytopenia (26%), aspartate aminotransferase increased (25%), chills (23%), 
platelet count decreased (23%) pyrexia (22%), cough (18%), photophobia (16%), back 
pain (15%), headache (15%), and upper respiratory tract infection (15%). 
In the Part 2 population, 59% (20/35) of subjects had 5 or more prior treatment lines. 
Among the subjects in Part 2 (N=35), the most frequently reported AEs Overall, the most 
common AEs (≥15.0%) included: were as follows: vision blurred (46%), platelet count 
decreased (37%), dry eye (34%), anemia (29%), aspartate aminotransferase increased 
(29%), increased cough (26%), chills (23%), nausea (23%), photophobia (23%), pyrexia 
(23%), fatigue (20%), thrombocytopenia ic events (4720%), back pain (17%), and 
diarrhea (17%). ocular toxicity related events (43%), nausea (37%), fatigue (33%), 
pyrexia (27%), anemia (25%), chills (24%), and AST increased (24%).  The most 
frequent Grade 3 or 4 AEs occurring in >10% of subjects were thrombocytopenia (37%) 
and anemia (14%). Most of reported adverse events are reversible without sequelae. As 
of 26 June 2017, a total of 14 (40%) patients in Part 2 had an SAE and there were no fatal 
SAEs. The related SAEs are described below. 
• 
Infusion-Related Reaction (IRR): Two patients experienced serious, Grade 3 
infusion-related reactions during the first infusion that were characterized by 
tachycardia, hypertension and pyrexia. These subjects subsequently received pre-
medication and IRRs did not recur.  
• 
Intracranial Hemorrhage: A patient with a history of intracranial bleeding 
experienced a Grade 2 intracranial hemorrhage with concomitant Grade 4, 
thrombocytopenia. At the same time, the patient’s disease was starting to progress; 
the patient was taken off study and salvage chemotherapy was started. 


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• 
Pericardial Effusion: A Grade 4 pericardial effusion consistent with tamponade was 
found prior to Cycle 9 during a routine study echocardiogram in an asymptomatic 
patient who had a concurrent upper respiratory tract infection.  The fluid was 
evacuated, and the effusion was resolving at the time of data cut-off. The patient 
received three more cycles of treatment after this event.  This SAE is listed as “not 
resolved” at the time of data cut, however a subsequent echocardiogram has 
confirmed no evidence of a pericardial effusion.   
• 
Lung Infection and Pyrexia: A patient experienced a Grade 2 lung infection 
resulting in a dose delay.  Approximately three months later, the patient developed a 
Grade 2 fever resulting in hospitalization.  The fever resolved the same day; the 
patient was not neutropenic.  
To date, GSK28579165 was well tolerated in humans with no Grade 5 events. Overall, 
GSK2857916 has a manageable safety profile with thrombocytopenia / platelet count 
decreased and corneal events as the most commonly reported events, as described in the 
following subsections.   
2.2.5.1 Thrombocytopenia 
A total of 36 patients (49%) in the All treated population, and 20 patients (57%) in Part 2 
have experienced thrombocytopenia/platelet count decreased.  GSK2857916 may cause 
transient worsening of thrombocytopenia in some patients, but in most cases these events 
are resolved during between-dosing intervals.  In the Part 2 MM population, two serious 
bleeding events were reported: intracranial hemorrhage in a patient with a history of an 
intracranial bleeding and in the setting of disease progression, and hematuria in a patient 
with a large bladder mass in the setting of progressive disease.   
2.2.5.2. 
Corneal Events  
Corneal AEs have been observed with various ADC drugs and represent the most 
commonly reported types of AEs associated with GSK2857916.  As there is no single 
term which appropriately captures these events, the term ‘corneal events’ includes 
reported preferred terms describing events associated with the corneal toxicity related to 
GSK2857916.  The most commonly reported corneal events include vision blurred, dry 
eye, photophobia, and lacrimation increased.  A total of 42 patients (58%) in the all 
treated population, and 22 patients (63%) in Part 2 have experienced corneal events 
which were predominantly low-grade.   
In Part 2, there were three patients with ≥ Grade 3 corneal events: one with Grade 3 
keratitis resulting in a delay and a dose reduction, one with Grade 3 eye pain resulting in 
a delay; and one Grade 3 dry eye resulting in a dose delay.  In Part 2, there were no 
serious corneal events and no patients permanently discontinued study treatment due to a 
corneal event.   
In Part 1, there was one SAE of Grade 3 limbal stem cell deficiency (in a patient at the 
1.92 mg/kg dose) that was characterized by blurred vision and dry eyes.  The events 
resolved after treatment was discontinued, and the patient’s vision returned to baseline.  
Another patient in Part 1 (4.6 mg/kg) discontinued treatment due to the feeling of a 
foreign object in the eye (Grade 2).   


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In addition to the AEs describing corneal events, 89% of patients in Part 2 had corneal 
findings upon examination.  These findings were generally characterized by a superficial 
punctate keratopathy/keratitis, which was often associated with epithelial (microcystic) 
edema and occasional stromal edema or opacities.  Visual acuity declined during 
treatment in most patients experiencing these clinical findings, but improved on average 
to near baseline in patients completing end of study treatment visits (n=13).  Eleven of 
these 13 patients (84.6%) had corneal clinical signs at the end of study treatment visit, 
with most cases (9/11 or 81.8%) considered as having “mild” changes. 
Reason for change: Updated language based on updated information from First Time in 
Human study.   
19.  Section 2.34.1 – Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, 2010].  Accumulating evidence shows 
a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies [Mei , 2014; Salgado, 2015; Schatton, 2014; 
Gooden, 2011; Schreiber, 2011; Bremnes, 2011; Talmadge, 2011; Shirabe 2010; Nosho, 
2010; Bellati, 2009; Oble, 2009; Uppaluri, 2008; Dunn, 2007]. In particular, the presence 
of CD8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells (T-
regs) seem to correlates with improved prognosis and long-term survival in many solid 
malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, including durable objective tumor 
responses in cancers such as melanoma tumors [Nosho,2010; Chang, 2014; Preston, 
2013; Yoon, 2012; Kim, 2013; Mathai, 2012; Liu, 2011; Kirk, 2010]. [Dudley, 2005; 
Hunder, 2008]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control [Pedoeem, 2014].  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 signalling upon engagement of its ligands 
(PD-L1 and/or PD-L2) [Greenwald, 2005; Okazaki, 2001].   
The structures of murine PD-1 has been resolved alone [Zhang, 2004]. and in complex 
with its ligands were first resolved [Lazar Molnar, 2008; Lin, 2008], and more recently 
the NMR based structure of the human PD 1 extracellular region and analyses of its 
interactions with its ligands were also reported [Cheng, 2013].  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 CD3 
zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase 


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(ZAP70), which are involved in the CD3 T cell signaling cascade [Okazaki, 2001; 
Chemnitz, 2004; Sheppard, 2004; Riley, 2009].  The mechanism by which PD-1 down-
modulates T cell responses is similar to, but distinct from that of CTLA-4, because both 
molecules regulate an overlapping set of signalling proteins [Parry, 2005; Francisco, 
2010 Ott, 2013].  As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in RRMM.  
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 [Yao, 2014]. Expression has 
also been shown during thymic development on CD4 CD8  (double negative) T cells 
[Nishimura, 1996], as well as subsets of macrophages [Huang, 2009] and dendritic cells 
[Pena Cruz, 2010]. The ligands for PD 1 (PD L1 and PD L2) are constitutively expressed 
or can be induced in a variety of cell types [Keir, 2008]. 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 [Keir, 2008]. Both ligands are 
type I transmembrane receptors containing both IgV  and IgC like domains in the 
extracellular region and 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 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.  
Although healthy organs express little (if any) PD L1, a variety of cancers were 
demonstrated to express abundant levels of this T cell inhibitor [Karim, 2009; Taube, 
2012], which, via its interaction with the PD 1 receptor on tumor specific T cells, plays a 
critical role in immune evasion by tumors [Sanmamed, 2014].  As a consequence, the 
PD 1/PD L1 pathway is an attractive target for therapeutic intervention in cancer 
[Topalian, 2012]  
Reason for change: Revisions to the standard Merck language.  
20.  Section 2.34.3 – Pembrolizumab Background and Clinical Trials 
 Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with PD-L1 and 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. For more details on specific 
indications refer to the Investigator brochure. 
Keynote-183 was a randomized trial which evaluated pomalidomide and low-dose 
dexamethasone with or without pembrolizumab in subjects with relapsed and refractory 
multiple myeloma. The ORR was 34% in the pembrolizumab containing arm versus 40% 
in the control arm without pembrolizumab; however, there was no difference in time-to-
progression between arms. There were 29 deaths in the pembrolizmab arm compared to 
21 in the control arm, reflecting an overall survival hazard ratio of 1.61 (95% CI: 0.91, 
2.85) [Krauss, 2018]. An analysis conducted with the removal of subjects with high-risk 


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disease characteristics (high-risk cytogenetics, plasmacytoma and quadruple refractory 
status) resulted in a similar number of deaths (n=13) in both arms [Mateos, 2018].  
Keynote-185 was a randomized trial which evaluated lenalidomide and dexamethasone 
with or without pembrolizumab in subjects with newly diagnosed multiple myeloma. The 
ORR was 64% in the pembrolizumab containing arm versus 62% in the control arm 
without pembrolizumab; however, there was no difference in time-to-progression 
between arms. There were 19 deaths in the pembrolizmab arm compared to 9 in the 
control arm, reflecting an overall survival hazard ratio of 2.06 (95% CI: 0.93, 4.55) 
[Krauss, 2018]. 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475 [KEYTRUDA Product Information]. 
Pharmacokinetics of Pembrolizumab 
The pharmacokinetics of pembrolizumab was studied in 2195 patients who received 
doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on 
population pharmacokinetic analyses in patients with solid tumors, the geometric mean 
[% coefficient of variation (CV%)] for clearance, steady state volume of distribution, and 
terminal half life were 202 mL/day (37%), 7.38 L (19%) and 27 days (38%), 
respectively. Steady state concentrations of pembrolizumab were reached by 19 weeks of 
repeated dosing with an every 3 week regimen and the systemic accumulation was 2.2
fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the 
plasma concentration versus time curve at steady state (AUCs) of pembrolizumab 
increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks. 
Pharmacokinetic drug interactions 
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab. 
Toxicity of Pembrolizumab 
The principal nonclinical toxicology findings in monkeys associated with pembrolizumab 
consisted of generalized lymphocytic infiltration consistent with its pharmacologic 
activity, which was not associated with clinical toxicities.  In a human PBMC cytokine 
release assay, pembrolizumab did not cause cytokine release in nonstimulated cultures 
but did cause increases in IL 2, TNF , IFN , IL 6 and IL 17 in staphylococcal 
enterotoxin B (SEB) stimulated cells, suggesting the potential for inappropriate cytokine 
release under stimulated conditions [FDA Pharmacology Toxicology Review, 2014].  
The most commonly reported adverse events (AEs) in clinical trials with pembrolizumab 
include fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia 
and diarrhea [KEYTRUDA Package Insert, 2017]  Serious and fatal AEs associated with 
treatment include immune mediated adverse reactions, which consisted of pneumonitis, 
colitis, hepatitis, hypophysitis, and renal failure due to nephritis and thyroid disorders. 
Genotoxicity, Reproductive Toxicity and Carcinogenicity of pembrolizumab 


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No studies have been performed to test the potential of pembrolizumab for 
carcinogenicity or genotoxicity. Fertility studies have not been conducted with 
pembrolizumab. In 1 month and 6 month repeat dose toxicology studies in monkeys, 
there were no notable effects in the male and female reproductive organs; however, most 
animals in these studies were not sexually mature. 
Based on its mechanism of action, pembrolizumab may cause fetal harm when 
administered to a pregnant woman. Animal models link the PD 1/PDL 1 signaling 
pathway with maintenance of pregnancy through induction of maternal immune tolerance 
to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant 
while taking this drug, apprise the patient of the potential hazard to a fetus. Advise 
females of reproductive potential to use highly effective contraception during treatment 
with Keytruda and for 4 months after the last dose of pembrolizumab [see PI Use in 
Specific Populations (8.1, 8.8)][KEYTRUDA Package Insert, 2017]  
Reason for change: Revisions to the standard Merck language. Summaries added for 
analysis of KEYNOTE-183 and KEYNOTE-185 to provide context and top level data 
from the interim analyses. 
21.  Section 2.45 – Assessment of Nonclinical Data for GSK2857916 when Co-
Administered with Pembrolizumab 
In addition, the starting dose of GSK2857916 in this combination regimen has been 
selected to be 21 dose levels below a dose that has been shown to be well tolerated during 
the GSK2857916 monotherapy dose escalation. The determination of the starting dose is 
based on an assumption that less than 2550% of the declared safe dose of GSK2857916 
should provide a sufficient safety margin when pembrolizumab is added at 200 mg. In 
addition, close clinical monitoring will be implemented 
Reason for change: Update of the number of doses and percentage decrease of starting 
dose based on comments from FDA.  
22.  Section 3 – Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To determine safety, tolerability and to 
establish the recommended Phase 2 dose 
(RP2D) of the combination of GSK2857916 
and pembrolizumab in subjects with 
relapsed/refractory (rel/ref) RRMM   
• 
Percent of subjects with adverse events 
(AEs), changes in clinical signs and 
laboratory parameters 
• 
Number of subjects with dose limiting 
toxicities (DLTs) 
Secondary 
• 
To evaluate clinical activity of the combination 
of GSK2857916 and pembrolizumab in 
subjects with RRMM 
• 
Overall Response Rate (ORR), defined as 
the percentage of subjects with a confirmed 
partial response (PR) or better (i.e., PR, very 
good partial response [VGPR], complete 
response [CR] and stringent complete 
response [sCR]), according to the 


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Objectives 
Endpoints 
International Myeloma Working Group 
(IMWG) Response Criteria [Kumar, 2016]. 
• 
To evaluate the pharmacokinetic profile of 
GSK2857916 when administered 
intravenously in combination with 
pembrolizumab1) 
• 
GSK2857916 Pharmacokinetic (PK) 
parameters following IV administration as 
data permit (e.g., area under the curve 
[AUCs], mean maximum concentration 
[Cmax], time of Cmax [tmax], terminal phase 
half-life [t½]) after the first dose; and 
concentration at trough (Ctrough), and end of 
infusion concentration in subsequent cycles, 
when measured 
• 
To assess anti-drug antibodies (ADAs) 
against GSK28579161). 
• 
Incidence and titers of ADAs against 
GSK2857916 
Exploratory 
• 
To evaluate clinical activity of the combination 
of GSK2857916 and pembrolizumab in 
subjects with rel/ref MM 
• 
Overall Response Rate (ORR) defined as % 
of patients achieving  PR 
• 
Clinical Benefit Rate (CBR) defined as % of 
patients achieving  MR  
• 
Duration of Response (DOR) data permitting 
• 
Progression Free Survival (PFS) data 
permitting 
• 
Overall survival (OS) data permitting 
• 
Time to Response (TTR) data permitting 
• 
To assess Minimal Residual Disease (MRD) 
in participants who achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity 
rate, defined as: the percentage of subjects 
who are MRD negative in subjects who 
achieve VGPR or CR 
• 
To characterize the relationship between 
clinical response and other biologic intra
tumor or microenvironment characteristics 
(DNA, protein analysis) 
• 
BCMA expression levels on malignant cells, 
and other markers in tumor tissue, serum 
sBCMA levels, serum cytokines, baseline 
immune status and immune cell 
characterization and their relationship to 
clinical response (Protein, RNA, DNA 
analysis) 
• 
To investigate the relationship between 
genetic variants in the host and response to 
GSK2857916 in combination with 
pembrolizumab  
• 
Possible relationship between host genetic 
variation and response to GSK2857916 in 
combination with pembrolizumab 
• 
To evaluate the tolerability of GSK2857916 in 
combination with pembrolizumab based on 
patient self-report of symptomatic adverse 
effects 
• 
Symptomatic adverse effects as measured by 
the Patient-reported outcome version of the 
Common Term Criteria for Adverse Events 
(PRO-CTCAE) 
• 
Impact of ocular adverse effects on quality of 
life as measured by the Visual Function 


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Objectives 
Endpoints 
questionnaire(s): National Eye Institute 25-
item Visual Function Questionnaire (NEI-
VFQ-25) and Ocular Surface Disease Index 
(OSDI) 
• 
To evaluate disease and treatment related 
symptoms and associated impacts on 
function and health-related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered only in case of unexpected clinical findings.  
Part 2: Expansion 
Objectives 
Endpoints 
Primary 
• 
To assess the clinical activity of the 
combination treatment with 
GSK2857916 and pembrolizumab 
in subjects with rel/ref RRMM   
• 
Overall Response Rate (ORR), defined as the 
percentage of participants with a confirmed PR or better 
(i.e., PR, VGPR, CR and sCR), according to the IMWG 
Response Criteria [Kumar, 2016]. 
Overall Response Rate (ORR) defined as % of patients 
achieving  PR 
Secondary 
• 
To further evaluate confirm safety 
of GSK2857916 administered in 
combination with pembrolizumab in 
subjects with RR rel/ref MM 
• 
Number of subjects with AEs, changes in clinical signs 
and laboratory parameters 
• 
Ocular findings on ophthalmic exam 
• 
To further assess the clinical 
activity of the combination 
treatment with GSK2857916 and 
pembrolizumab in subjects with 
rel/ref RRMM 
• 
Clinical Benefit Rate (CBR) defined as % of patients 
achieving  MR   
• 
Duration of Response (DOR) data permitting 
• 
Progression Free Survival (PFS) data permitting 
• 
Overall Survival (OS) data permitting 
• 
Time to Response (TTR) data permitting 
• 
Clinical benefit rate (CBR), defined as the percentage 
of participants with a confirmed minimal response (MR) 
or better per IMWG.  
• 
Duration of response (DoR), defined as: the time from 
first documented evidence of PR or better to the time 
when disease progression (PD) is documented per 
IMWG, or death due to PD among subjects who 
achieve an overall response, i.e. confirmed PR or 
better. 
• 
Time to response (TTR), defined as: the time between 
the date of first dose and the first documented evidence 
of response (PR or better) among subjects who 
achieved a confirmed response of PR or better. 
• 
Time to best response, defined as the time between the 
date of first dose and the first best documented 
response (PR or better) among subjects who achieve a 
confirmed response of PR or better. 


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Objectives 
Endpoints 
• 
Progression-free survival (PFS), defined as: the time 
from first dose to the earliest date of PD per IMWG, or 
death due to any cause. 
• 
Time to disease progression (TTP), defined as: the time 
from first dose until the earliest date of PD per IMWG, 
or death due to PD. 
• 
Overall Survival (OS), defined as the time from first 
dose to death due to any cause 
• 
To evaluate the pharmacokinetic 
profile of GSK2857916 when 
administered intravenously in 
combination with pembrolizumab1 
• 
Pharmacokinetic parameters following IV administration 
as data permit (e.g., AUCs, Cmax, time of Cmax [tmax], 
terminal phase half-life [t½]) after the first dose; 
concentration at trough (Ctrough), and end of infusion 
concentration in the subsequent cycles when 
measured. 
• 
To assess anti drug antibodies 
(ADAs) against GSK28579161) 
• 
Incidence and titer of ADA to GSK28579161) 
Exploratory 
• 
To assess Minimal Residual 
Disease (MRD) in participants who 
achieve ≥VGPR or better 
• 
Minimal Residual Disease (MRD) negativity rate, 
defined as: the percentage of subjects who are MRD 
negative in subjects who achieve VGPR or CR 
• 
To characterize the relationship 
between clinical response and 
other biologic intra tumor or 
microenvironment characteristics 
(DNA, protein analysis) 
• 
BCMA expression levels on malignant cells and other 
markets in tumor tissue, serum sBCMA levels baseline 
immune status, serum cytokines, and immune cell 
characterization and their relationship to clinical 
response (Protein, RNA, DNA analysis) 
• 
To investigate the relationship 
between genetic variants in the 
host and response to GSK2857916 
in combination with pembrolizumab 
• 
Possible relationship between host genetic variation 
and response to GSK2857916 in combination with 
pembrolizumab 
• 
Plasma concentrations of 
GSK2857916 when administered 
intravenously in combination with 
pembrolizumab1) 
• 
 GSK2857916 end of infusion concentration and 
concentration at trough 
• 
To explore the effect of the 
combination therapy of 
GSK2857916 with pembrolizumab 
on symptoms and health-related 
quality of life HRQoL in subjects 
with rel/ref RR MM 
• 
Changes from baseline in symptoms and health-related 
quality of life as measured by the European 
Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core Module 
(EORTC-QLQ-C30) and European Organisation for 
Research and Treatment of Cancer Quality of Life 
Questionnaire 20-item Multiple Myeloma Module 
(EORTC-QLQ-MY20) MD Anderson Symptom 
Inventory Multiple Myeloma (MDSI MM) module 


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Objectives 
Endpoints 
• 
To evaluate the tolerability of 
GSK2857916 in combination with 
pembrolizumab based on patient 
self-report of symptomatic adverse 
effects 
• 
Symptomatic adverse effects as measured by the PRO-
CTCAE 
• 
Impact of ocular adverse effects on quality of life as 
measured by the Visual Function questionnaire(s): NEI-
VFQ-25 and OSDI 
• 
To evaluate disease and treatment 
related symptoms and associated 
impacts on function and health-
related quality of life 
• 
Exit Interview 
1. PK and ADA samples for pembrolizumab will be collected and stored during the trial. The analysis will be 
triggered if unexpected clinical findings have been identified.  
Reason for change: Revision of Objective/Endpoints to revise secondary endpoint for 
dose escalation, add MRD for response endpoints, replace MDASI-MM with EORTC 
questionnaires, add clarity to primary and secondary endpoints for dose expansion, and 
revise biomarker wording.   
23.  Section 4.1 – Overall Design 
This is a phase I/II, single arm, open label, two-part study to determine the RP2D of 
GSK2857916 administered in combination with 200 mg of pembrolizumab, and to 
evaluate safety and clinical activity of the combination in subjects with rel/refRRMM. 
The study will be conducted in two parts: Part 1: dose escalation of GSK2857916 with a 
constant dose of pembrolizumab at 200 mg, and Part 2: expansion cohort at RP2D of 
GSK2857916 in combination with 200 mg pembrolizumab.  A total of up to 408 
evaluable subjects with rel/ref RRMM will be enrolled into this study (up to 128 in Part 
1, and 2830 in Part 2). 
Reason for change: Update to overall subject numbers due to removal of lower first dose 
level per FDA comments.    
24.  Section 4.2.1 – Study Treatment 
This is a single arm, open label study. Subjects in Part 1 and in Part 2 will receive 
GSK2857916 and pembrolizumab via IV infusion on day 1 of each 21-day cycle. 
GSK2857916 will be administered first, as approximately 30 min an IV infusion, 
followed by at least 1 hour rest. Refer to the SRM for details on GSK2857916 infusion. 
Provided there is no infusion related reaction (IRR) warranting a prolonged interval 
between dosing, pembrolizumab will be administered as second drug over approximately 
30 min via IV infusion. If a subject develops IRR during or after GSK2857916 infusion, 
he or she will be treated according to institutional guidelines. In such cases the infusion 
of pembrolizumab may have to be delayed until IRR has recovered to Grade 1 or less, 
and investigator considers it safe to continue with infusion with pembrolizumab. The 
infusion of pembrolizumab may be delayed for up to the +3 day window from scheduled 
visit48 hours to allow for recovery of IRR, and to accommodate scheduling conflicts. If a 
subject does not recover from IRR to Grade 1 or less within the +3 day window48 hours, 


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the dosing of pembrolizumab will be skipped in a given cycle, and may be resumed in the 
next cycle. 


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followed for OS and subsequent anti-cancer therapy every 3 months until the end of 
study. End of study is defined in Section 5.5.2.  
After the study treatment discontinuation, subjects will undergo end of study assessments 
30 days (7 days) after the last dosing, or prior to the start of new anti cancer treatment 
(whichever occurs first). All subjects will continue to be followed up every 3 months to 
collect data on PFS, OS, and next treatment for the duration of 1 year after the last dose 
of study treatment. 
All subjects will continue to be followed up every 3 months to collect data on PFS, OS, 
and next treatment for the duration of 1 year after the last dose of study treatment. 
All subjects who permanently discontinue all study treatments without disease 
progression will be followed for progression according to the Time and Events Table 6. 
Follow up will continue until disease progression, death, start of new anti cancer therapy 
or withdrawal of consent, whichever is documented first. 
Reason for change: Update to number of total cycles based on actual 24 month calendar 
and in line with maximum dosing from Merck language. Removal of language allowing 
treatment discontinuation if subject achieves CR/sCR. Addition of option for re-treatment 
if subject meets certain criteria. Adjustment of discontinuation language.  
26.  Section 4.2.3 – Part 1: Dose-Escalation 
Part 1 dose escalation will characterize the safety and tolerability of escalating doses of 
GSK2857916 in combination with 200 mg pembrolizumab to establish the RP2D.  In the 
currently ongoing FTIH study (ClinicalTrials.gov Identifier: NCT02064387), no DLTs 
were observed up to the highestrecently tested dose level of 4.6 mg/kg of GSK2857916 
and 3.4 mg/kg was selected as RP2D dose. The following dose levels of GSK2857916 in 
combination with 200 mg pembrolizumab are to be tested in this study: 1.92 mg/kg, 2.5 
mg/kg and 3.4 mg/kg (as outlined in Figure 2). Additionally, intermediate other dose 
levels may also be tested if emerging data suggests a beneficial risk/benefit profile at 
those dose levels. The RP2D from the monotherapy FTIH study (3.4 mg/kg 
(ClinicalTrials.gov Identifier: NCT02064387)) will not be exceeded in this combination 
study.  During the dose escalation, at least 3 evaluable subjects will be tested per dose 
level, and escalation will be guided by the modified Toxicity Probability Interval (mTPI) 
approachfollow the Bayesian Logistic Regression Model (BLRM) with overdose control 
as outlined in Section 9.5.1. 


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Old Dose Escalation Schematic for Part 1 
 
New Dose Escalation Schematic for Part 1 
 
The mTPI design assumes the true underlying toxicity rate for maximum tolerated dose 
(MTD) of GSK2857916 falls within the range from 25% to 35% and centered at 30%.  
The monitoring rules for guiding dose escalations are provided in Table 1.  Columns 
provide the numbers of subjects treated at the current dose level, and rows provide the 
corresponding numbers of subjects experiencing toxicity.  The entries of the table are 
dose-finding decisions (i.e., E, S, and D) representing escalating the dose, staying at the 
same dose, and de-escalating the dose.  In addition, decision U means that the current 
dose level is unacceptable because of high toxicity; the current dose level and any higher 
dose level should be excluded from the trial.  For example, when one of three subjects 
experiences toxicity, the decision can be located at row 1 and column 3, which is S – to 
stay at the current dose level.  Consequently, the next cohort of subjects will be treated at 
the same dose level currently being used.  If 0 of 3 subjects experiences toxicity, the 
decision is at row 0 and column 3, which is E – to escalate.  Thus, the next cohort of 
subjects will be treated at the next-higher dose level.  If three of three subjects 
experiences toxicity, the decision is DU – to de-escalate to the next-lower dose level, and 
exclude the current dose and any higher dose from the trial, because the high toxicity 
level is unacceptable. In dose escalation (E)/de-escalation (D), no dose skipping is 
allowed. 


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New Table 1  Dose-Escalation Monitoring Rules for Part 1 Using the mTPI Method 
Dose finding Criteria for the Modified Toxicity Probability Interval Dose Finding 
Number of DLTs 
Toxicities 
Number of Subjects treated at current dose 
1 
2 
3 
4 
5 
6 
0 
E 
E 
E 
E 
E 
E 
1 
D 
S 
S 
S 
S 
E 
2 
DU 
D 
S 
S 
S 
3 
DU 
DU 
D 
S 
4 
 
 
 
DU 
DU 
DU 
5 
 
 
 
 
DU 
DU 
6 
 
 
 
 
 
DU 
The table was generated based on a beta/binomial model and precalculated before trial initiation.  
The letters in different colors are computed based on the decision rules under the mTPI method 
and represent different dose-finding actions.  In addition to actions de-escalate the dose (D), stay 
at the same dose (S), and escalate the dose (E), the table includes action unacceptable toxicity 
(DU), which is defined as the execution of the dose-exclusion rule in mTPI.  Excerpted from Ji et 
al . [Ji, 2010] 
After each cohort, the BLRM will be used to calculate the posterior probabilities of DLT 
rate for all potential doses of GSK2857916 in combination with pembrolizumab lying 
within four toxicity intervals (under dosing, target dose range, excessive toxicity, and 
unacceptable toxicity). The four DLT toxicity intervals are defined as follows: 
[0%, 16%) Underdosing 
[16%, 33%) Target toxicity 
[33%, 60%) Excessive toxicity 
[60%, 100%] Unacceptable toxicity 
The recommended dose for next cohort will be based on the following criteria: dose with 
the highest posterior probability of DLT rate lying in the target toxicity interval with the 
additional requirement that the sum of the posterior probabilities of the DLT rate lying in 
the excessive toxicity or unacceptable toxicity range is less than 25%.  Selection of the 
next dose cohort to be enrolled is also subject to the constraint that the next dose level 
can be no more than two times that of the current dose level. Note that de escalation as 
well as escalation is possible using this method. 
The DLT observation period for subjects in Part 1 is 21 days after the first dose of the 
study treatment. The complete safety data from DLT observation period of at least 3 
subjects are needed for dose escalation decisions. Subjects who have only received 
GSK2857916 or have been withdrawn from the study for reasons other than toxicity but 
prior to completion of DLT observation period will be replaced.  
In Part 1, dose escalation/de-escalation decisions will take into account all available 
safety and tolerability data. The decisions will be informed by the BLRM model the 
mTPI approachwith overdose control and will occur following review of these data and 
joint discussion by the GSK Study Team and investigators.  
Although the BLRM will be used to recommend the next dose level, clinical judgment by 
the Medical Monitor and GSK study team  in consultation with the investigators can 
influence the decision about the next dose as deemed appropriate by the emerging clinical 
data as long as adherence to the outlined restrictions is assured: the next dose level cannot 


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be greater than 100% increment of previously tested dose AND the selected dose at any 
time of the trial cannot exceed the RP2D from the FTIH trial. 
The dosing may be adjusted to expand any cohort to further evaluate safety at a given 
dose level, or to add cohorts to evaluate additional, intermediate dose levels of 
GSK2858916 after discussion between GSK study team and investigators. The study 
procedures for these additional subject(s) or cohort(s) will be the same as that described 
in Section 5 and Section 7. The dose of pembrolizumab will be kept constant at 200 mg 
throughout the study. 
Reason for change: Revision of starting dose based on guidance from FDA. Revisions to 
statistical calculations and wording based on change to subject number, switch to mTPI 
design and clarification of end of study definition.  
27.  Section 4.2.3.1 – Dose-Limiting Toxicity Criteria (Part 1 only) 
The DLT observation window will be 21 days (=1 cycle). Any subject in Part 1 who 
received at least one treatment cycle of GSK2857916 in combination with 
pembrolizumab will be evaluated for DLTs.  Subjects who have only received 
GSK2857916 or have been withdrawn from the study for reasons other than toxicity but 
prior to completion of DLT observation period will be replaced.  
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.03 
[NCI, 2010]. In addition, for GSK2857916 treatment related corneal events, the GSK 
Grading Scale (Appendix 9) should be used for evaluation of DLT. 
A DLT is defined as an AE that meets at least one of the criteria defined below and is 
considered by the investigator to be clinically relevant and attributed (definitely, 
probably, or possibly) to the study therapy during the 21 day DLT observation period. An 
event will be considered a DLT if its relationship to the investigational agents cannot be 
ruled out, occurs within the DLT reporting period, and meets one of the following 
criteria:  
• 
Any Grade 4 non-hematologic toxicity 
• 
Any Grade 3 or greater non-hematologic toxicity, with the following exceptions (i.e., 
the following will not be considered a DLT): Grade 3 diarrhea, nausea or vomiting 
that responds to standard of care within 72 hours; Grade 3 hypertension (controlled 
following addition of 1 antihypertensive medication); and Grade 3 tumor lysis 
syndrome not resolving with appropriate supportive treatment within 48 hours or 
resulting in a delay in initiating cycle 2 by 14 days or more 
• 
Any Grade 3 or greater non-hematologic laboratory value if either: 
• 
The laboratory abnormality persists for >48 hrs despite supportive treatment or 
• 
The abnormality leads to hospitalization 
• 
Hematologic toxicity:  
• Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 
• Grade 4 thrombocytopenia of any duration 
• Grade 3 thrombocytopenia associated with clinically significant bleeding 


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires 
or indices, which are protected by third party copyright laws and therefore have been 
excluded.


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activity. If necessary, alternative doses and schedules can be explored to determine 
additional clinically active regimens.  A dose level below the pre specified max dose of 
3.4 mg/kg may be selected as RP2D compelling safety and encouraging clinical activity 
can be demonstrated at dose levels below pre specified max dose of 3.4 mg/kg.  
Part 2:  Expansion 
Once the RP2D has been identified, an expansion cohort (Part 2) will open for enrollment 
of up to 2830 subjects with rel/refRRMM in order to confirm the safety profile and to 
evaluate the clinical activity of the combination. 
During an ongoing enrolment, futility analysis will be once approximately 15 subjects in 
Part 2 are evaluable for futility analysis. The details for defining a subject to be evaluable 
for futility analysis is provided in Section 9.4.1.  
Reason for change: Revision of language to allow flexibility and revision of subject 
numbers. Consolidation of language. 
29.  Section 4.3 – Type and Number of Subjects 
The study will enroll adult subjects with rel/refRRMM, who have undergone stem cell 
transplant, or are considered transplant ineligible, and who have been previously treated 
with at least 32 prior lines that include the following: , containing 3 classes of anti
myeloma drugs: an alkylating agent, AND an IMiD (i.e. lenalidomide or pomalidomide),  
AND a proteasome inhibitor (i.e. bortezomib, ixazomib or carfilzomib) and an anti-CD38 
antibody alone or in combination. Line of therapy are defined by consensus panel of the 
International Myeloma Workshop [Rajkumar, 2011]. In addition, subject must be 
progressing on, or within 60 days since the most recent therapy (as defined by IMWG).  
 Overall, it is estimated that up to 408 evaluable subjects will be enrolled in this two-part 
study (up to 128 in Part 1, and 2830 in Part 2).   
Reason for change: Revision to target treatment line and number of subjects based on 
FDA comments.  
30.  Section 4.3 – Design Justification  
This is the first clinical study in which GSK2857916 will be administered in combination 
with pembrolizumab.  Therefore, a two-part study design is implemented to allow for 
careful safety assessments during dose escalation.  Part 1 will consist of dose escalation 
to establish the RP2D of GSK2857916 in combination with 200 mg of pembrolizumab.  
Once RP2D has been established, Part 2 will enroll an additional 2830 subjects with 
rel/refRRMM to further confirm safety and to assess the clinical activity of the 
combination at the RP2D of GSK2857916.  FA futility analyseis will be conducted from 
afterwhen response data is available from 105 subjects.  Details of the futility analysis 
have beenare described in Section 9.5.2. 


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Reason for change: Consistency of language throughout protocol to address subject 
number change.   
31.  Section 4.5.1. – GSK2857916 Starting Dose Justification  
The starting dose for GSK2857916 will be 2.51.92 mg/kg administered intravenously 
once every 3 weeks (Q3W) on Day 1 of each 21-day Cycle. Careful dose escalation and 
monitoring will be implemented to protect subjects’ safety throughout the study. 
The 2.51.92 mg/kg dose is considered to be appropriate starting dose for combination 
with a fixed dose of 200 mg pembrolizumabwith following justification:  
• 
The starting dose of 2.5 mg/kg is one dose level below the 3.4 mg/kg, which had 
an acceptable safety profile in FTIH trial; 
• 
Based on the non specific clearance mechanism with large capacity of both: 
GSK2857916 and pembrolizumab, the likelihood for drug drug interactions from 
combining GSK2857916 with pembrolizumab is considered to be low.  
• 
According toPer currently available data, it is anticipated that the starting dose of 
2.51.92 mg/kg will be well tolerated and is not expected to result in an excessive 
toxicity, while allowing to derive anti tumor activity;  
• 
Based on the non-specific clearance mechanism with large capacity of both: 
GSK2857916 and pembrolizumab, the likelihood for drug-drug interactions from 
combining GSK2857916 with pembrolizumab is low. 
• 
Doses up to 4.6 mg/kg have been tested and 3.4 mg/kg was selected as the RP2D 
in the ongoing FTIH trial, and did not result in excessive toxicity. The starting 
dose of 1.92 mg/kg is two dose levels below the 3.4 mg/kg which was declared 
safe in FTIH trial. In addition it is less than 25% of the highest tested dose of 4.6 
mg/kg, which did not result in excessive toxicity in humans. 
• 
Careful dose escalation and monitoring will be implemented to protect subjects’ 
safety throughout the study. 
Reason for change: Revision to starting dose and justification based on changes 
suggested by FDA comments.   
32.  Section 4.5.2. – Pembrolizumab Dose Justification  
The dose of pembrolizumab for this studyin this trial is 200 mg every 3 weeks (Q3W). 
Based on the totality of data generated in the Keytruda development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications 
regardless of tumor type. As outlined below, this dose is justified by: administered 
intravenously once every 3 weeks (Q3W) on Day 1 of each 21 day Cycle. 
• 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• 
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 


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• 
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W. 
 
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different 
treatment settings (monotherapy and in combination with chemotherapy). Five studies 
compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, 
KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, 
flat dose-exposure-response relationships were also observed in other tumor types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor 
type. These findings are consistent with the mechanism of action of pembrolizumab, which 
acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable 
overlap in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg 
Q3W dose. Supported by these PK characteristics, and given that fixed-dose has 
advantages of reduced dosing complexity and reduced potential of dosing errors, the 200 
mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols. 
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 Q3W is summarized below. 
In KEYNOTE 001, an open label Phase I study conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti tumor activity 
of pembrolizumab when administered as monotherapy.  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 


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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 
anti tumor 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 Q3W fixed dose regimen 
is considered an appropriate fixed dose for other tumor indications as well.   
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 Q3W as the appropriate dose for pembrolizumab. 
Reason for change: Revisions to the Merck standard language.    
33.  Section 4.6.1. – Risk Assessment 
The risk assessment and risk mitigation plan for GSK2857916 andthe study procedures 
are summarized in Table 2. Refer to Table 5 for pembrolizumab guidance. 


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New Table 21 revisions: Below will highlight major changes per applicable row 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (GSK2857916) 
Corneal events 
toxicity 
Reversible corneal toxicity has been 
observed with various antibody drug 
conjugates (specific corneal changes with 
ADCs conjugated to MMAF). 
Corneal related AEs (blurred vision, dry / 
watery eyes, decreased visual acuity, 
photophobia) are among the most 
common AEs associated with 
GSK2857916 in the clinic.  The majority of 
events have been non-serious and 
transient, some requiring dose delays 
and/or reductions.  Time to recovery is 
variable and in some instances the 
resolution may take several weeks. 
Active monitoring for corneal 
events toxicity according to Table 
4. 
 
ProphylacticPreventive use of 
steroid eye drops as outlined in 
Section 6.12.3 and Appendix 9. 
 
Timely evaluation and 
management by an eye care 
professional ophthalmologist upon 
developing corneal related events 
(see Section 6.5.1 and Appendix 
9.  
 
Recommendations for dose delays 
/ reductions are provided in 
Section 6.5.1.   
 
Infusion related 
reaction 
The majority of IRRs observed in the clinic 
without any premedication to date have 
been G1-2 and non-serious; however, 
there have also been serious IRRs. 
Overall, subjects who experienced an IRR 
during the initial infusion were pre-
medicated prior to subsequent infusions 
and IRRs did not recur. 
Subjects will be closely monitored 
for signs of IRR. Premedication 
prior to first infusion of 
GSK2857916 is not mandatory but 
may be considered based on 
investigator judgement.  
If an infusion-related reaction 
occurs during administration of 
GSK2857916 the management will 
may follow according to guidance 
in Table 4 
3 or local 
standard of care. 
 
Hepatotoxicity 
Non-clinical safety experiments 
demonstrated increased liver weight and 
elevated liver enzymes in rats. Elevations 
in liver enzymes and increased mitotic 
figures in Kupffer cells were observed in 
monkeys. All of these changes were dose 
dependent and reversible.  
 
Non-serious elevations in ALT, AST have 
been observed in the clinic. 
Only subjects with well-preserved 
liver function will be allowed on 
study. Subjects with Hepatitis B 
(HBV) and C will be excluded from 
the trial.  Liver function tests will 
be frequently monitored in all 
subjects on study and in case of 
liver abnormalities management 
will be implemented according to 
clinical practice. Subjects that 
meet liver stopping criteria 
(Section 5.4.1.1) will be withdrawn 
from the study. 






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Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. Provide signed written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form 
2. Male or female, 18 years or older (at the time consent is obtained) 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix 2) 
4. Subjects must:  
• Histologically or cytologically confirmed diagnosis of MM as defined according 
to IMWG, 2014 [Rajkumar, 2014], and have confirmed diagnosis of Multiple 
Myeloma  
• Hhasve undergone stem cell transplant or is to be considered transplant ineligible, 
and  
• Haves been treated with at least 32 prior lines of prior anti-myeloma treatments, 
including 3 classess of drugs: an alkylating agent, AND an IMiID (eg.i.e., 
lenalidomide or pomalidomide), AND a proteasome inhibitor (eg., bortezomib, 
ixazomib or carfilzomib) and an anti-CD38 antibody, alone or in combination. 
Line of therapy are defined by consensus panel of the International Myeloma 
Workshop [Rajkumar, 2011].  In addition, subject must be progressing on, or 
within 60 days since the most recent treatment (as defined be IMWG) 
• In addition to the criteria above, subjects in Part 2 must have Has measurable 
disease defined as one of the following: 
a) Serum M-protein 0.5 g/dL (5 g/L) 
b)  Urine M-protein ≥200 mg/24h 
c) Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an 
abnormal serum free light chain ratio (<0.26 or >1.65) 
d) Biopsy proven plasmacytoma (should be measured within 28 days of 
Screening Visit) 
5. Subjects with a history of autologous stem cell transplant (SCT) are eligible for study 
participation provided the following eligibility criteria are met: 
a) Transplant was > 100 days prior to study enrolment. 
b) No active infection (s). 
c) Subject meets the other eligibility criteria outlined in this protocol. 
6. Subjects after prior allo SCT are allowed if the allo transplant was performed  5 
years ago, and if subject has no active GVHD requiring treatment. 
6. Subject has adequate organ system functions as defined in the Table 32 




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A WOCBP must have a negative highly sensitive serum pregnancy test (as required 
by local regulations) within 72 hours before the first dose of study intervention.  
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 8. 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
9. Male Subjects: 
• Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 140 days after the last dose of study 
intervention:  
• Refrain from donating sperm 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
OR 
• Must agree to use contraception/barrier as detailed below 
• Agree to use a male condom and female partner to use an additional highly 
effective contraceptive method with a failure rate of <1% per year as 
described in Appendix 8 when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant. 
A female subject is of non childbearing potential or women of childbearing potential 
must have a negative serum pregnancy test within 72 hours prior to the first dose 
of study treatment and agree to use effective contraception during the study and 
for 120 days following the last dose of study treatment.  
Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception from the time of first dose of 
study treatment until 140 days after the last dose of study treatment to allow for 
clearance of any altered sperm.  
Reason for change: Revision of Inclusion Criteria due to update in line of therapy and 
update of contraception language. 
36.  Section 5.2 – Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Systemic anti-myeloma therapy or an investigational drug within 14 days or five 
half-lives, whichever is shorter, preceding prior to the first dose of study drug or  
2. pPlasmapheresis within 7 days prior to the first dose of study drug 
3. Prior treatment with a monoclonal antibody within 30 days of receiving the first 
dose of study drugs 


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4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., 
CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a 
Grade 3 or higher immune related adverse event (irAE)  
5. Current corneal epithelial disease except mild punctate keratopathy 
Use of an investigational drug within 14 days or five half lives, whichever is 
shorter, preceding the first dose of study drug 
Any toxicity from previous treatments which has not recovered to  Grade 1 or to 
baseline  
History of an allogeneic stem cell transplant within last 5 years. Subjects with a 
history of an autologous stem cell transplant are NOT excluded if they meet 
Inclusion Criterion #5. 
Evidence of active mucosal or internal bleeding 
6. Any major surgery within the last four weeks prior to the first dose of study 
therapy 
7. Presence of active renal condition (infection, requirement for dialysis or any other 
condition that could affect subject’s safety). Subjects with isolated proteinuria 
resulting from MM are eligible, provided they fulfil criteria given in Table 32  
8. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions (including lab abnormalities) that could interfere with subject’s safety, 
obtaining informed consent or compliance to the study procedures. 
9. Has received prior radiotherapy within 2 weeks of start of study therapy. Subjects 
must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease 
10. History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
11. Current active liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal 
or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver 
disease (with the exception of including Gilbert’s syndrome or asymptomatic 
gallstones or otherwise stable chronic liver disease per investigator’s assessment) 
or hepatobiliary involvement of malignancy is acceptable if subject otherwise 
meets entry criteria 
12. Malignancies other than disease under study are excluded, except for any other 
malignancy from which the participant has been disease-free for more than 2 
years and, in the opinion of the principal investigators and GSK Medical Monitor, 
will not affect the evaluation of the effects of this clinical trial treatment on the 
currently targeted malignancy (RRMM). In addition, subjects with curatively 
treated non-melanoma skin cancer are allowed.  
13. Has known active CNS metastases and/or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate provided they are 
radiologically stable, i.e., without evidence of progression for at least 4 weeks by 
repeat imaging (note that the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid treatment for at 
least 14 days prior to first dose of study therapy Subjects with previous or 
concurrent malignancies are allowed only if the second tumor is not contributing 
to the subject’s illness. The subject must not be receiving active therapy, other 


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replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.   
23. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
chronic form of immunosuppressive therapy within 7 days prior the first dose of 
study therapy 
24. Has known psychiatric or substance abuse disorders that would interfere with the 
subject’s ability to cooperate with the requirements of the study 
25. Has had an allogenic tissue/solid organ transplant 
Reason for change: Revision of Exclusion Criteria due to updates to the GSK and Merck 
standard language. 
37.  Section 5.3 – Screening Failures  
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria. Data for screen failures will be collected in source 
documentation at the site but will not be transmitted to GSK. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened.  Rescreened subjects must be assigned a new unique subject number 
that is different from the initial number. 
Reason for change: Revision language due to update of GSK standard.  
38.  Section 5.4 – Withdrawal/Stopping Criteria  
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity (including but not restricted to meeting stopping criteria for significant toxicity as 
outlined in Section 1), or completion of pre-assigned treatment by reaching a maximum 
of 325 treatment cycles. In addition, study treatment may be permanently discontinued 
for any of the following reasons: 
• 
subjects with CR are allowed to end the treatment sooner if they fulfil the 
criteria outlined in Section 5.4.1.. 
• 
Recurrent Grade 2 pneumonitis  
• 
subject has met any of the protocol defined safety stopping criteria (Section 
5.4.1.) 
• 
deviation(s) from the protocol 
• 
request of the subject or proxy (withdrawal of consent by subject or proxy) 
• 
investigator’s discretion 
• 
concurrent illness that prevents further administration of study treatment(s) 
• 
study treatment must be permanently discontinued in case of pregnancy 
• 
subject is lost to follow-up  
• 
study is closed or terminated 


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The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF)  
If the subject withdraws the consent and discontinues from treatment due to toxicity, 
‘adverse event (AE)’ will be recorded as the primary reason for permanently 
discontinuation on the electronic case report form (eCRF).    
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be re-entered the study.  
After the study treatment discontinuation, subjects will undergo end of treatment 
assessments 30 days (7 days) after the last dosing, or prior to the start of new anti-
cancer treatment (whichever occurs first). Subjects who discontinued treatment for 
reasons other than PD will be followed up every 3 weeks until confirmed PD, until 
initiation of a new anticancer therapy or death. All subjects with confirmed PD will be 
followed for OS and next subsequent anti-cancer therapy every 3 months until the end of 
study. End of study is defined in Section 5.5.2.  
All subjects who discontinue from study treatment will complete safety assessments, and 
will be followed up for PFS, OS, and treatment after study as specified in Time and 
Events Tables (Table 7). 
The following actions must be taken in relation to fora subjects who fails to attend the 
clinic for a required study visit: 
Reason for change: Removal of wording related to discontinuation for achieving CR due 
to update in program language, addition of pneumonitis, addition of statement related to 
pregnancy. Revision of study discontinuation language   
39.  Section 5.4.1 – Early Discontinuation of Study Treatment after Achieving a 
Complete Response (CR)  
Early discontinuation of treatment may be considered for subjects who have attained a 
complete response (CR) and who have been treated for at least 8 cycles with the 
combination of GSK2857916 and pembrolizumab and had at least 2 treatments with both 
study drugs beyond the date when the initial CR is declared.  The assessment for 
stringency will be performed in all subjects achieving CR. For subjects discontinuing 
early due to achieving CR, the reason for treatment discontinuation will be recorded in 
eCRF as: achieving CR, and subject will complete the end of treatment visit, and enter 
the follow up period. Subject will not be allowed to re enter the study at later time 
Reason for change: Deletion of section due to removal of ability to discontinue 
treatment if achieving CR due to program updates.   


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40.  Section 5.4.1 – Safety stopping criteria  
Section 5.4.2.1 Old Figure 
 
 Section 5.4.2.1 New Figure 
 
Addition of Section 5.4.2.2; Renumbered the remainder of the section 
5.4.2.2    Study Treatment Restart or Rechallenge 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless: 
• 
GSK Medical Governance approval is granted (as described below), 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for treatment restart/rechallenge is signed by the subject 
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments. 
Reason for change: Update of the GSK standard language.   
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
➢Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


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41.  Section 5.4.2.8.1 – Infusion-Related Reactions Associated with GSK2857916  
Premedication is not required prior to infusion of GSK2857916 unless deemed medically 
appropriate by the investigator following evaluation of infusion related reactions. 
Premedication should be considered in any subject who experienced an infusion related 
reaction at first or any subsequent infusion with GSK2857916  
If an i Infusion-related reactions should be managed by guidelines provided in Table 4. A 
subject that experiences a Grade 4 IRR after GSK2857916, should be permanently 
withdrawn from the study. occurs during administration of GSK2857916, the infusion 
rate may be reduced or halted at the discretion of the investigator and/or GSK medical 
monitor depending on the severity of the symptoms.  The subject will receive appropriate 
medical treatment.  When the subject’s condition is stable, the infusion may be restarted 
according to the judgment of the investigator. For details on re start guidance and 
stopping criteria please see Table 3.  Upon restart, the infusion rate should be half of the 
infusion rate at the time the infusion was paused. If the IRR occurred during, or 
immediately post GSK2857916 infusion, the pembrolizumab infusion must be delayed to 
allow recovery to G1 or less. The infusion of pembrolizumab may be delayed for up to 48 
hours to allow for recovery of IRR caused by GSK2857916, and to accommodate 
scheduling conflicts. If a subject does not recover from IRR to G1 or less within 48 
hours, the dosing of pembrolizumab will be skipped in a given cycle, and may be 
resumed in the next cycle. 
Blood for serum cytokines should be collected in each subject who developed IRR 
regardless whether the infusion has been completed or not. 
Reason for change: Update of the GSK and Merck standard language.   
43.  Section 5.5 – Subject and study Completion  
5.5.1 Subject completion 
For Part 1: A subject is considered to have completed the study if the subject is treated 
through the DLT determinative period or has a DLT during the DLT determinative 
period, i.e., a completed subject is one who is evaluable for the determination of DLT 
rate. 
For Part 2, a subject is considered to have completed the study if they received at least 1 
cycle of combination study treatment, and:  
• The subject is followed until death, or  
• The subject is followed until the end of study 
A completed subject in Part 1 is a subject who has received at least one dose of study 
treatment, and has completed the End of Study visit.  
A completed subject in Part 2 is one who has completed all pre assigned 32 treatment 
cycles, or has stopped study treatment early due to achieving CR, and has completed the 
End of Study Visit.   


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The end of study is defined in Section 5.5.2. The end of study analyses will be performed 
at that time.  
The eCRF should continue to be completed during the follow up period (every 3 months 
(7 days) until the , up to end of study. Please refer to Table 10 for assessments to be 
completed during PFS follow-up visits or OS follow-up. OS follow-up12 months) with 
survival/progression data can be based on contacting patients via phone calls/e-mails/or, 
other means of communication.  Subjects who cannot be contacted will be considered lost 
to follow up. Follow-up data will be entered into the eCRF. 
5.5.2.   
Study Completion 
The A  end of study is defined as will be considered completed when all subjects have 
been followed for 36 months from first dose of study treatment or died or withdrew 
consent or are lost to follow-up or the safety stopping criteria is met, whichever occurs 
first. having met the study objectives, when the last subject has received their last dose of 
study medication and completed the End of Study visit. 
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s 
last visit.   
The follow up contact will occur via phone calls/e mails, or any other means of 
communication, no visit in the clinic is required. The survival/progression data gathered 
during the contact will be entered into eCRF. 
5.5.3  
Treatment after the End of Study 
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment. If a subject remains on treatment at the time end of study is 
achieved they may be offered an option to extend treatment.  
Subjects’ survival and status of post study treatment will be documented via phone calls, 
and/or medical charts analysis every 3 months (7 days) for the duration of 1 year (12 
months) after the last dose of study treatment 
Reason for change: Revision of the definition of subject completion, end of treatment 
and other language.   


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44.  Section 6.1 – Investigational Products   
Product name: 
GSK2857916 
Pembrolizumab 
Dosage form: 
20 mg/mL solution for infusion 
Supplied as frozen liquid.  
Recommended storage condition is 
(minus 50C to minus 15C).  
Protect from light. 
100 mg/4mL solution that should be 
stored under refrigeration at 2-8C 
(36-46F). 
Protect from light. Do not freeze. Do 
Not Shake. 
Route of Administration  
Delivered as 30 min IV infusion. 
Refer to SRM for details.  
 
Delivered as 30 min IV infusion 
Manufacturer/ Source of 
Procurement: 
GSK/Baxter 
Merck 
Reason for change: Additions of GSK and Merck standard language.    
45.  Section 6.3.1. – Study Treatment Administration 
For GSK2857916, please refer to the SRM for additional details on administration. For 
pembrolizumab, the both study drugs the study medical staff should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a window between -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes  -5 min/+10 min). 
Reason for change: Revision of GSK2857916 language to refer to SRM for infusion 
instructions.     
46.  Section 6.3.1.1 – GSK2857916 Administration    
GSK2857916 will be administered on Day 1 of each cycle at the assigned dose.  as 
approximately 30 min infusion. Premedication is not required prior to infusion unless 
deemed medically necessary by the investigator, in which case it should be administered 
according to institutional recommendations. In case of infusion related reactions related 
to GSK2857916 the rules outlineds in Section 5.4.1.8.1 5.4.2.8.1 and in Table 6 should be 
followed. 
Blood for serum cytokines should be collected in each subject who developed IRR 
regardless whether the infusion has been completed or not. The time of serum collection 
will be documented in eCRF. 
Reason for change: Removal of GSK2857916 infusion timing with move to SRM for 
instructions. Removal of serum cytokine language.    
47.  Section 6.3.1.2. – Pembrolizumab administration    
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week 
treatment cycle after all procedures and assessments have been completed.  


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Pembrolizumab will be administered as a dose of at the flat dose of 200 mg using via 
approximately a 30 min IV infusion after at least approximately 1 hour rest period after 
completion of GSK2857916 infusion.  Premedication is not required prior to infusion 
unless deemed medically necessary, in which case it should be administered according to 
institutional recommendations.  
In case of IRR during or after preceding GSK2857916 infusion, the administration of 
pembrolizumab will be delayed to allow for recovery to Grade 1 or less. In total, the 
infusion of pembrolizumab may be delayed for up to the allowed +3 day window from 
the scheduled dose date48 hours to allow for recovery, and to accommodate scheduling 
conflicts in a given cycle. If the subject does not recover from IRR to Grade 1 or less 
within the +3 day window48 hours, the dosing of pembrolizumab will be skipped in a 
given cycle, and may be resumed in the next cycle. 
All subjects are required to remain under observation at the study site for at least three 
hours post-infusion of the last study drug administered for the first two study treatment 
dosing visits. At subsequent study treatment dosing visits, for subjects who experience 
infusion-related reactions, the post-infusion observation time should remain as at least 
three hours; for subjects who do not experience infusion reactions, these subjects should 
remain under observation for at least one hour or per the judgement of the investigator or 
as per institutional guidelines.  
Reason for change: Revision of Merck standard language and addition of subject 
observation post all infusions.     
48.  Section 6.5. – Subject Specific Dose Adjustment Criteria    
Revisions in this section will be highlighted and full tables may not be reproduced. 
Section 6.5.1. – Dose modifications and managementreductions for GSK2857916-
related toxicity 
In individual cases where, in the judgement of an investigator, waiting a full planned 
Cycle (21 days) to resume treatment after delays due to toxicities would be detrimental to 
the subjects’ health, the Medical Monitor should be contacted to discuss an earlier re-
start. An earlier re-start may be considered only for subjects who have recovered from 
toxicity to Grade 1 or less. Dosing cannot occur more frequently than every 21 days (±3 
days).  In such cases, efficacy and safety assessments must remain every 3 weeks from 
the initial efficacy and safety assessments (Cycle 1 Day 1), which may result in 2 
separate visits (1 for disease assessment [Table 8] and 1 for dosing [Table 9]). 
If GSK2857916 is held or discontinued for any toxicity, pembrolizumab is to be held or 
discontinued. 


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Table 4 – Dose Modification Guidelines for GSK2857916-related AEs 
Toxicity 
Grade 
Recommendations to GSK2857916 
Recommendations 
to pembrolizumab 
Serum creatinine 
elevation or 
decrease in eGFR 
which cannot be 
explained by 
concomitant 
sepsis, TLS, other 
severe infection 
with fever or 
dehydration 
2 If absolute 
serum 
creatinine 
increase from 
baseline of 
>0. 5 mg/dL 
• 
Repeat within 48 hours  
• 
If confirmed: withhold therapy, institute 
treatment and monitoring as clinically 
indicated, and follow for resolution 
• 
Discuss any further dosing with 
Medical Monitora 
• 
When recovered to G1 continue 
GSK2857916, consider 25% dose 
reduction (after discussion with 
Medical Monitor) 
See Table 54 for 
guidance on 
pembrolizumab 
Serum 
creatinine>Grade 
3 (acute kidney 
injury) 
Elevated serum 
creatinine or 
decrease in eGFR 
which cannot be 
explained by 
concomitant 
sepsis, TLS, other 
severe infection 
with fever or 
dehydration 
>43.0 mg/dL 
 Or >3.0x 
baseline or 
hospitalization 
indicated 
• 
Provide appropriate medical treatment. 
• 
Provide appropriate medical 
treatment. 
• 
Permanently discontinue treatment 
with GSK2857916 
• 
Withhold the dosing. Only resume 
treatment with GSK2857916 at 
reduced dose (25 50%) when 
creatinine returns to G1 or less 
Resume treatment 
with pembrolizumab 
only if treatment 
with GSK2857916 
may be continued 
 
Spot urine 
(albumin / 
creatinine ratios) 
>2000mg/g  
(or 224 
mg/mmol) 
• 
Re-test (at least 7 days apart). 
• 
If not confirmed, continue 
GSK2857916 at 100% dose 
• 
If confirmed on re-test and no clear 
evidence of disease progressionc 
1. Interrupt treatment with 
GSK2857916 
2. Repeat testing within 4 weeks 
1. If spot urine <2000mg/g 
(224/mg/mmol) may restart 
GSK2857916 with 25% dose 
reduction 
2. If spot urine remains 
>2000mg/g (224/mg/mmol) 
after 4weeks; Permanently 
discontinue GSK2857916 
and withdraw subject from 
study; provide treatment as 
clinically indicated and follow 
for resolution 
Resume treatment 
with pembrolizumab 
only if treatment 
with GSK2857916 
may be continued 
 


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Toxicity 
Grade 
Recommendations to GSK2857916 
Recommendations 
to pembrolizumab 
GSK2857916 
Treatment Related 
Corneal events 
toxicityb 
Corneal 
Management 
Care 
Regardless of 
Grade 
Steroid Eye Drops:  
• 
If symptoms occur within the 7-day steroid eye drop 
prophylaxis window, increase the frequency to 1 drop 
every 2-4 hours (6-12 times daily) and continue until 
symptom resolution. 
• 
If symptoms occur after the 7-day prophylaxis window is 
complete, re-start ocular steroid drops at 4x daily until 
symptom resolution.   
Preservative-free artificial tears:   
• 
Increase to 1 drop as frequently as every 2 hours, as needed 
Grade 1 per 
GSK Scale  
• 
Continue treatment with current dose 
of GSK2857916  
• 
Consider ophthalmology consult 
• 
If symptoms occur after the mandatory 
7 day prophylactic treatment with 
steroid eye drops is complete, 
consider re starting ocular steroid 
drops at four times daily until 
resolution. If topical steroid use is 
prolonged, i.e. > 7 days, consult 
ophthalmology. 
• 
If symptoms occur within the 7 day 
prophylaxis window with steroid eye 
drops, consider increased frequency of 
steroid eye drops to 1 drop every 2 4 
hours and continue until resolution. If 
topical steroid use is prolonged, i.e. > 
7 days, consult ophthalmology. 
• 
Use of preservative free artificial tears 
may be increased up to every 2 hours. 
• 
None 
Grade 2 per 
GSK Scale 
• 
If either ophthalmic exam finding or 
visual acuity findings are Grade 1, 
continue dosing with GSK2857916 at 
current dose 
• 
If visual acuity and exam findings are 
both Grade 2, HOLD GSK2857916 
• 
Upon improvement of either visual 
acuity or ophthalmic exam findings to 
Grade 1 or baseline, resume with 
current dose 
• 
Continue treatment with current dose 
of GSK2857916 consult 
ophthalmology as soon as possible 
• 
If symptoms occur after the mandatory 
7 day prophylactic treatment with 
steroid eye drops is complete, re start 
ocular steroid drops at four times daily 
until resolution.  
• 
Hold/Delay 
treatment until 
the next 
GSK2857916 
dose None 


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Toxicity 
Grade 
Recommendations to GSK2857916 
Recommendations 
to pembrolizumab 
• 
If symptoms occur within the 7 day 
prophylaxis window with steroid eye 
drops, consider increased frequency 
of steroid eye drops to 1 drop every 2
4 hours and continue until resolution  
• 
Use of preservative free artificial tears 
may be increased up to every 2 hours, 
as needed 
In case of recurring  Grade 2 events, 
consult the MM 
Grade 3 per 
GSK Scale 
• 
Hold GSK2857916 and consult 
ophthalmology as soon as possible 
• 
Upon improvement of either visual 
acuity or ophthalmic exam findings 
to Grade 1 or baseline, resume with 
25% dose reduction (for subjects 
receive 1.92 mg/kg dose, continue 
at 1.92 mg/kg) 
• 
In case of recurring ≥Grade 3 events, 
consult GSK Medical Monitor 
• 
Hold GSK2857916 and consult 
ophthalmology as soon as possible 
• 
If symptoms occur after the mandatory 
7 day prophylactic treatment with 
steroid eye drops is complete, re start 
ocular steroid drops at four times daily 
until resolution  
• 
If symptoms occur within the 7 day 
prophylaxis window with steroid eye 
drops, consider increased frequency 
of steroid eye drops to 1 drop every 2
4 hours and continue until resolution  
• 
Use of preservative free artificial tears 
may be increased up to every 2 hours, 
as needed 
• 
If resolved to  Grade 2 within 14 days 
discuss with MM prior to continuing at 
pre hold dose. 
• 
If resolved to  Grade 2 after 14 days, 
consider 25% dose reduction. 
• 
In case of recurring  Grade 3 events, 
hold GSK2857916 and consult MM 
• 
Hold/Delay 
treatment until 
the next 
GSK2857916 
dose None 
Grade 4 per 
GSK Scale 
• 
Stop treatment with GSK2857916 
• 
Consult ophthalmology immediately 
• 
If symptoms occur after the mandatory 
7 day prophylactic treatment with 
steroid eye drops is complete, re start 
• 
Stop treatment 
with 
pembrolizumab.   
• 
Further 
treatment only 
possible if 


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Toxicity 
Grade 
Recommendations to GSK2857916 
Recommendations 
to pembrolizumab 
ocular steroid drops at four times daily 
until resolution  
• 
If symptoms occur within the 7 day 
prophylaxis window with steroid eye 
drops, consider increased frequency of 
steroid eye drops to 1 drop every 2 4 
hours and continue until resolution 
Additional topical treatment as 
recommended by ophthalmologist 
• 
Use of preservative free artificial tears 
may be increased up to every 2 hours, 
as needed 
• 
Additional topical treatment may be 
prescribed, as if recommended by 
ophthalmologist 
• 
Treatment re-start may be possible 
after discussion and agreement 
between ophthalmologist (or 
optometrist if an ophthalmologist is not 
available), treating physician, GSK 
Medical Monitor and possibly a GSK 
ophthalmologist at the reduced dose in 
only possible after discussion and 
agreement between the treating 
ophthalmologist, the GSK MM and 
possibly a GSK ophthalmologist with 
subject’s re consent 
GSK2857916 is 
allowed to 
restart  
 
Infusion Reactionac 
2 
Stop the infusion, provide medical 
treatment and continue at slower pace 
after resolution to Grade 0-1 
See Table 56 for 
guidance on 
pembrolizumab 
3 
 Further treatment with GSK2857916 
needs to be discussed with Medical 
Monitor. Continuation only allowed after 
recovery to  Grade 1 and with pre-
medication, and extension of infusion time 
to 2-4 hours. Any future infusion needs to 
be pre-medicated 
4 
Permanently discontinue 
Permanently 
discontinue 
a.  Medical Monitor may consult GSK's nephrotoxicity panel about plans to continue therapy 
b.  Corneal toxicity should be graded according to GSK scale for GSK2857916 treatment related Corneal Events 
(Appendix 9) 
c. 
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 
Section 6.5.2. – Dose modification and toxicity management for immune-related AEs 
associated with pembrolizumab  
Table 5 – Dose Modification Guidelines for Pembrolizumab-Related AEs 


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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 or exclude other 
causes 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-
related 
AEs 
Grade 3, or i  
Intolerable/ 
persistent 
Grade 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids  
• 
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
New Section 6.5.3. – Dose modification and toxicity management for 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 in Table 6.  


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.


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• Bilateral tubal ligation or salpingectomy 
• Hysteroscopic tubal occlusion procedure with follow up confirmation of bilateral 
tubal occlusion 
• Hysterectomy 
• Bilateral oophorectomy 
• Post menopause 
• Female 60 years of age or older 
• Menopause is the phase associated with complete cessation of menstrual cycles 
and implies the loss of reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone 
replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g., 
leuprolide treatment). In questionable cases for women under 60 years of age, a 
blood sample with simultaneous follicle stimulating hormone and estradiol falling 
into the central laboratory’s post menopausal reference range is confirmatory 
(these levels need to be adjusted for specific laboratories/assays). 
• Females under 60 years of age, who are on HRT and wish to continue, and whose 
menopausal status is in doubt, are required to use highly effective method to avoid 
pregnancy, as outlined below 
A female of reproductive potential (FRP):  
• Females with functioning ovaries 
• This category include females with oligomenorrhea, females who are peri
menopausal and young female who have begun to menstruate 
• Also note that FRP includes females who are pregnant or nursing. 
Female subjects of reproductive potential must not become pregnant for 14 days prior to 
first dose of study treatment, through the dosing period, and for at 120 days after the last 
dose of study treatment. and so must be sexually inactive by abstinence or use 
contraceptive methods with a failure rate of <1% (See below). 
Abstinence 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post
ovulation methods) and withdrawal are not acceptable methods of contraception.  
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at 120 days after the last dose of study 
treatment. 
The following is the all inclusive list of the highly effective methods with a Failure Rate 
of <1%.  
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile vaginal intercourse on a long term or persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence and withdrawal 
are not acceptable methods of contraception. 
• Contraceptive subdermal implant 
• Intrauterine device or intrauterine system 
• Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
• Injectable progestogen [Hatcher, 2011] 


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• Contraceptive vaginal ring [Hatcher, 2011] 
• Percutaneous contraceptive patches [Hatcher, 2011] 
• Male partner sterilization with documentation of azoospermia prior to the female 
subject’s entry into the study, and this make is the sole partner for that subject 
[Hatcher, 2011].  The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination and/or semen 
analysis or medical history interview provided by her or her partner. 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring subjects understand how to properly use these methods of contraception.  
6.11.1.2. – Male Subjects 
Male subjects with female partners of child bearing potential must comply with the 
followingcontraception requirements highlighted in Section 5.1 from the time of first 
dose of study medication until 140 days after the last dose of GSK2857916. Details on 
contraceptive options for subjects with a partner of childbearing potential are in 
Appendix 8.  
• Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s review of subject’s medical records, medical 
examination and/or semen analysis or medical history interview.  
• Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of falture per year, as tated in the 
product label:  
• Contraceptive subdermal implant 
• Intrauterine device or intrauterine system 
• Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
• Injectable progestogen [Hatcher, 2011] 
• Contraceptive vaginal ring [Hatcher, 2011] 
• Percutaneous contraceptive patches [Hatcher, 2011] 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration from 
the time of first dose of study until 140 days after the last dose of study treatment to allow 
for clearance of any altered sperm. 
6.11.2. – Subjects with Contact Lenses 
Subjects should avoid use of Ccontact lenses are prohibited while on the study treatment 
(from first dosing to the end of study treatment). 
Reason for change: Revision of contraception language and contract lenses language 
based on updated data from GSK2857916 data.  
51.  Section 6.12. – Concomitant Medications/Vaccinations and Non-Drug Therapies     


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Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the treatment 
visitstudy (Final Study Visit).  Any concomitant medication(s), including non-
prescription medication(s) and herbal product(s), taken during the study will be recorded 
in the electronic case report form (eCRF).  Additionally, a complete list of all prior anti-
cancer therapies will be recorded in the eCRF. 
Concomitant dosing of GSK2857916 with P-gp inhibitors should be avoided if possible, 
unless considered medically necessary and with appropriate clinical monitoring. Please 
refer to the SRM for a list of relevant P-gp inhibitors. . 
Elimination pathways for GSK2857916 or cys-mcMMAF in humans have not been 
characterized, and care should be exercised when combined with potent cytochrome P450 
(CYP) inhibitors, CYP inducers, and transporter modulators. Please refer to the SRM for 
further information. 
Reason for change: Revision of P-gp inhibitors to refer to SRM and removal of 
Appendix, addition of CYP restrictions introduced in program with refer to the SRM.  
52.  Section 6.12.1. – Permitted Medication(s)     
Subjects should receive full supportive care during the study, including transfusion of 
blood products, growth factors, and treatment with antibiotics, anti-emetics, 
antidiarrheals, and analgesics, as appropriate. 
Chronic treatment with oral steroids is prohibited while the subject is on study, unless 
used as a short course for treatment of acute complications related to study treatment, or 
pre medication prior to GSK2857916, or pembrolizumab infusion. Steroids may be used 
to treat infusion related reactions. Inhaled steroids are allowed for management of 
asthma, or COPD exacerbations. 
Concomitant therapy with biphosphonatesbisphosphonates and RANKL inhibitors areis 
allowed. 
Subjects may receive local irradiation or elective surgery, eg. for pain control after 
discussion with the medical monitor. or stability control  
Reason for change: Revision of GSK standard language and to reduce duplication.   
53.  Section 6.12.3. – Supportive Care Guidelines for Corneal EventsToxicity      
Corneal eventstoxicity, which commonly manifests as a superficial microcystic 
keratopathy, has previously been reported with antibody drug conjugates, including those 
conjugated to MMAF [Tannir, 2014; Eaton, 2012; Younes, 2012].  It is required that the 
sites establish a close collaboration with an ophthalmologist (or optometrist, if 
ophthalmologist is not available) who will be responsible for assessing subjects on study 
and managing subjects who develop corneal toxicity in close communication with GSK 
Medical Monitor and possibly a GSK ophthalmologist.  


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Subjects will be assessed by ophthalmologists (or /optometrist, if an ophthalmologist is 
not available) at baseline, and then every three weeks.  If there is no change in vision and 
no corneal signs consistent with toxicity at time of the cycle 4 exam, subjects may have 
their ophthalmologic exams decreased to once every 3 months.  If a subject subsequently 
develops a change in visual acuity or other ocular symptoms, the subject should be 
evaluated by an eye care professional.  Intraocular pressure must be monitored if steroid 
eye drops are used more than 7 days. prior to each dose of cycles 1 4.  If asymptomatic 
and without signs consistent with corneal toxicity at time of the cycle 4 exam, subjects 
may have their ophthalmologic exams decreased to once every 4 cycles.  If a subject 
subsequently develops signs / symptoms, or they require additional treatment, e.g. topical 
steroid for more than 7 days, additional assessment by an ophthalmologist/optometrist 
will be implemented. 
Subjects who have signs or symptoms of corneal toxicity present at end of study will 
continue to be followed monthly for up to 12 months, or until deemed clinically stable by 
an ophthalmologist (or optometrist, if ophthalmologist is not available), whichever comes 
first. 
Reason for change: Update to GSK language related to treatment of corneal guidelines.  
54.  Section 6.12.4. – Supportive Care Guidelines for Pembrolizumab      
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of 
AEsadverse events with potential immunologic etiology are outlined along with the dose 
modification guidelines in 6.5.2. below. , 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 for dose 
modification.4 Table 5 for guidelines regarding dose modification and supportive care. 
below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
Table 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
Reason for change: Update to Merck standard language.  




















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• Quantitative Immunoglobulins (IgG, IgA, and IgM and for subjects with IgD or IgE 
myeloma, quantitative IgD or IgE),  
• Serum kappa and lambda free light chains and FLC ratio, 
• Bone marrow aspirate and/or core biopsy at screening for baseline PC percentage and 
FISH analysis; and for disease response assessment at time of suspected CR/sCR, or 
PD, 
• At time of VGPR or CR, MRD testing on bone marrow aspirate,  
• Imaging by CT, MRI, CT/PET or X-ray to assess EMP and bone lesions. For sites in 
Germany, only MRI is allowed as imaging modality 
• Skeletal survey (Screening and as clinically indicated). For sites in Germany, only 
MRI is allowed as imaging modality 
Response evaluation will be performed according to the International Myeloma Working 
Group Uniform Response Criteria for Multiple Myeloma 20161 [Kumar, 2016]. 
Clinical activity measured as Overall Response Rate (ORR) which is defined as follows: 
The percentage of subjects with confirmed stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), and partial response (PR) as assessed 
by 20116 recommendations of the International Myeloma Working Group (IMWG)) 
[Kumar, 2016].  Other assessments of interest like clinical benefit rate (CBR), PFS, TTR, 
DOR, and OS may also be considered. Minimal residual disease negative rate will be 
assessed in those subjects who achieve a VGPR or CR. 
In subjects with extramedullary myeloma- the disease assessments have to include 
imaging (e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI], or 
PET/et CT scan) and physical examination (as indicated for palpable/superficial lesions). 
For participants with skin only involvement, skin lesions should be measured with a 
ruler.  Measurement of tumor size will be determined by the Sum of the Products of the 
maximal perpendicular diameters of measured lesions (SPD).    
Baseline serum disease assessment will be completed during screening period (within 
2814 days prior to the fist dose of study medication) and baseline imaging within 2821 
days prior to the first dose of study treatment. On study serum and urine based 
assessments (M-protein, FLC, immunofixation) and imaging, for extramedullary disease, 
will be performed as required. every 21 days (at the start of each cycle), or every 4 cycles 
(in case of imaging for extramedullary disease). The final assessments will be performed 
during final study visit (End of treatment visit).  See the Time and Events Tables (Table 
7, Table 8, and Table 10) for the schedule of assessments of anti-cancer activity.  
Assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions/delays.  For post-baseline assessments, a window of 3 days is 
permitted to allow for flexible scheduling.   
In subjects with extramedullary MM: if the last radiographic assessment was more than 8 
or 9 weeks prior to the subject’s withdrawal from study and progressive disease has not 
been documented, a disease assessment should be obtained at the time of withdrawal 
from study. 


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MRD negativity rate (defined as: the percentage of subjects who are MRD negative by 
clonoSEQ).  During treatment, testing will be performed for subjects achieving VGPR or 
CR. In subjects who have achieved MRD negativity, the testing will be repeated after 6 
and 12 months (provided CR is maintained) from time of first documented negative 
MRD result to assess sustained MRD negativity. MRD testing will be performed by a 
central lab.   
Reason for change: Revision of section to clarify the efficacy measures, update IMWG 
to 2016 criteria and to clarify timelines for assessments.     
58.  Section 7.3.1.1. – Time Period and Frequency of Detecting AEs and SAEs 
All AEs will be collected from the time the first dose of study treatment is administered 
until 4590 days following cessation of treatment, or 30 days following cessation 
regardless of initiation oftreatment if the subject initiates new anticancer therapy 
All SAEs will be collected from the time the first dose of study treatment is administered 
until 90 days following cessation of treatment, or 45 days following cessation of study 
treatment if the subject initiates new anticancer therapy, whichever is earlier. over the 
same time period as stated above for AEs.   In addition, any SAE assessed as related to 
study participation (e.g., protocol-mandated procedures, invasive tests, or change in 
existing therapy), study treatment or GSK concomitant medication must be recorded from 
the time a subject consents to participate in the study up to and including any follow-up 
contact.  All SAEs will be reported to GSK within 24 hours, as indicated in Section 
7.3.1.6. 
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 4530 days the investigator may report any AE that they 
believe possibly related to study treatment. 
Reason for change: Update of the GSK safety standard language and adjustment based 
on Merck standard language.     
59.  Section 7.3.1.2.3  Sentinel Events (Removal of Section)  
A Sentinel Event is a GSK defined SAE that is not necessarily drug related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  The GSK Medical Monitor is accountable for reviewing 
all SAEs for possible Sentinel Events which is mandated at GSK.  The GSK medical 
monitor may request additional clinical information on an urgent basis if a possible 
Sentinel Event is identified on SAE review.  The current GSK defined Sentinel Events 
are listed below: 
• 
Acquired Long QT Syndrome 
• 
Agranulocytosis/Severe Neutropenia  
• 
Anaphylaxis & Anaphylactoid Reactions  
• 
Hepatotoxicity 


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• 
Acute Renal Failure 
• 
Seizure 
• 
Stevens Johnson syndrome/Toxic epidermal necrosis 
Reason for change: Removal of section due to update of GSK standard language. 
60.  Section 7.3.1.6. – Adverse Events of Special Interest  
Adverse events of special interest (AESI) for GSK2857916 are corneal events, 
thrombocytopenia and infusion related reactions. The severity of all AESI will be graded 
utilizing the National Cancer Institute Common Toxicity Criteria for Adverse Events. 
Severity of GSK2857916 treatment related corneal events will also be graded using the 
GSK scale for corneal events provided in Table 16. Guidelines for dose modifications 
and interruptions for management of common toxicities associated with the study 
treatment(s) are provided in Table 4. 
For pembrolizumab, an overdose as defined in Section 6.10 that is not associated with 
clinical symptoms or abnormal laboratory results is an AESI. 
Reason for change: Addition of section to clarify AEs of importance for GSK2857916 
and pembrolizumab.  
61.  Section 7.3.2. – Pregnancy Testing and Reporting  
Do not collect pregnancy information for female subjects known to be pregnant during 
the screening phase or before exposure to study. 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
If a female subject is of childbearing potential, she must have a serum β-human chorionic 
gonadotropin (β –HCG) pregnancy test performed within 7214 hoursdays prior to the 
first dose of study treatment.  Subjects with positive pregnancy test result must be 
excluded from the study.  Subjects with negative pregnancy test result must agree to use 
an effective contraception method as described below during the study until 120 days 
following the last dose of study treatment. 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until approximately 120 days. 
If a pregnancy is reported, the investigator must inform GSK within 24 hours of learning 
of the pregnancy and must follow the procedures outlined in Appendix 8. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 


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Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at the end of relevant systemic exposure plus an additional 30 days and correspond with 
the time frame for female subject contraception in Section 5.1. 
Reason for change: Update to the pregnancy language for GSK2857916.  
62.  New Section 7.3.5. – Ocular Examinations and Procedures 
A full baseline ophthalmic examination for all subjects must include: 
1. Best corrected visual acuity 
2. Documentation of manifest refraction used to obtain best corrected visual acuity 
3. Current glasses prescription (if applicable) 
4. Pupillary light reflex 
Extraocular muscle movements (graded from one to four with (+) sign indicating over 
action, (-) sign indicating under action and 0 representing normal movements 
5. Intraocular pressure measurement & time checked 
6. Full anterior segment examination including fluorescein staining of the cornea: 
• Anterior segment exam (slit lamp) includes: orbit/lids/adnexa, conjunctiva, sclera, 
cornea, anterior chamber, iris, lens and anterior vitreous 
7. Anterior segment photography of a fluorescein stained cornea 
8. Dilated funduscopic exam: fundus photography with interpretation 
The on treatment and follow-up ophthalmic exam must include everything except the 
dilated funduscopic/ fundus photography, anterior segment photography, and extraocular 
muscle movements (all of which must be performed as clinically indicated) and current 
glasses prescription (if applicable).  The last follow-up visit should also include anterior 
segment photography of a fluorescein stained cornea. Representative images will be 
collected and stored centrally. 
The end of study treatment visit ophthalmic exam should match the baseline (screening) 
exam. 
Additional examinations should be performed at the discretion of the treating eye 
specialist.  
Reason for change: Addition of detailed ocular examination wording to clarify 
requirements related to corneal event management.  
63. Section 7.3.8. – Electrocardiogram 
Triple 12-lead electrocardiogram (ECGs) will be obtained at designated time points 
specified in the Time and Events Table (Table 7, Table 8 and Table 10) during the study 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and corrected QT (QTc) intervals.  At each assessment, a 12-lead ECG will be 
performed by qualified personnel at the site after the subject has at least a 105 minute 
rest.   


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For triplicate ECGs, 3 individual ECG tracings should be obtained as closely as possible 
in succession, but no more than 2 minutes apart. The full set of triplicate ECGs should be 
completed in 4 minutes or less. 
The QT interval should be corrected for heart rate by Fridericia’s formula (QTcF).  Refer 
to Section 5.4.1.3 for QTc withdrawal criteria. ECGs will be collected and stored 
centrally. Refer to the Study Procedures Manual (SPMSRM) for details regarding ECG 
procedures. 
Reason for change: Additional instructions added for ECG tracing and clarification of 
central collection.    
64.  Section 7.3.9.10. – Clinical Safety Laboratory Assessments 
Table 11: Addition of bicarbonate as option for Total carbon dioxide, removal of CK-
MB, removal of albumin from 24-hour urine protein; addition of spot urine (albumin / 
creatinine ratio) with relevant footnote, addition of Hepatitis B core antibody, removal of 
INR and PTT, removal of peripheral blood biomarker sample.   
Reason for change: Revision of Table 11 due to changes in laboratory tests.   
65.  Section 7.3.12.13. – Visual Function Questionnaire 
The NEI-VFQ-25 and OSDI will be administered to subjects in different regions based 
on the availability of translated versions. 
Reason for change: Clarification that Visual Function questionnaires to be administered 
dependent on available translated versions.  
66.  Section 7.4. – Pharmacokinetics 
7.4.1. – Blood Sample Collection for Pharmacokinetics 
Blood samples for pharmacokinetic (PK) analysis of GSK2857916 (ADC and total 
monoclonal antibody[mAb]), cys-mcMMAF and pembrolizumab will be collected at the 
time points indicated in Time and Events Table (Table 9 and Table 10). The actual date 
and time of each blood sample collection will be recorded.  The timing of PK samples 
may be altered and/or PK samples may be obtained at additional time points to ensure 
thorough PK monitoring. Samples for pembrolizumab will be collected and stored. 
Pembrolizumab PK samples will only be analysed if clinical observations warrant it (e.g. 
to rule out or confirm suspicion of DDI). 
Blood samples of approximately 4 mL for pharmacokinetic (PK) analysis of 
GSK2857916 (ADC and total mAbantibody), cys-mcMMAF, and along with a further 3 
mL of blood sample for potential PK analysis for pembrolizumab will be collected at the 
time points indicated in the Time and Events Tables (Table 9).  Each PK sample should 
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administered to the subject on PK days.  The actual date and time of each blood sample 
collection will be recorded. 
Details on PK blood sample collection including blood volumes, processing, storage and 
shipping procedures are provided in the Study Procedures Manual (SPMSRM). 
7.4.2. – Pharmacokinetic Sample Analysis 
Plasma analysis will be performed under the control of GSK Platform Technologies and 
Science-Bioanalysis Immunogenicity and Biomarkers (PTS-BIB) group, the details of 
which will be included in the SRM.  Concentrations of GSK2857916 (ADC and total 
mAbantibody) and cys-mcMMAF will be determined in plasma samples using the 
currently approved bioanalytical methodology.  Raw data will be archived at the 
bioanalytical site (detailed in the SRMStudy Procedures Manual). 
Once the plasma has been analysed for GSK2857916 (ADC and total mAbantibody) any 
remaining plasma may be analysed for other compound-related metabolites and the 
results reported under a separate GSK PTS-BIBIVIVT protocol.  
If analysis is warranted, concentrations of pembrolizumab in serum will be performed 
under the control of Merck, the details of which will be included in the SRMStudy 
Procedures Manual.  Raw data will be archived at Merck’s data repository, OpenLab 
(detailed in the SRMStudy Procedures Manual). 
Reason for change: Clarification that addition of cys-mcMMAF levels in these samples, 
update of abbreviations and clarification of BIB group name.  
67.  Section 7.5. – Biomarkers 
7.5.1. – sBCMA Analysis 
To measure any changes in the levels of soluble BCMA (sBCMA) during the study, 
Target engagement with soluble BCMA will be assessed.  Sserum will be collected to 
measure concentrations of free and GSK2857916 boundsBCMA at the time points 
specified in the Time and Events Tables (refer to Table 69 and Table 10). 
Old Section 7.5.2  Activated TBNK cells  
Whole blood will be collected and analysed for % and absolute counts of monocytes, T, 
B and NK cells as well as the expression of activation markers CD107 and CD69 on 
these cell types. In addition, baseline measurements of peripheral blood mononuclear 
cells and cytokines/chemokines will help inform on subject immune status. The analysis 
may also be conducted on bone marrow aspirates at baseline and correlation between 
baseline immune status and clinical outcome assessed.  


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New Section 7.5.2 – Cytokine and Chemokine Analysis  
Clusters of markers Cytokines circulating in the blood have been found to correlate with 
tumor pathway activation.  A broad panel of cytokines/chemokines will be evaluated at 
various timepointscycle 1 as outlined in the Time and Events Table (refer to Table 9). and 
correlated with clinical outcome to treatment with GSK2857916. In addition to 
measuring total cytokine levels in serum, activated lymphocytes and monocytes 
producing involved in the cytokine production will be determined via intracellular 
cytokine assay  
New Section 7.5.3 – Subject Stratification/Predictive Biomarkers  
This is an open-label and single-arm study, no subject stratification will be performed. 
BCMA exhibits varied expression across haematological malignancies and therefore, 
BCMA expression at baseline may be an important predictor of response to GSK2857916 
in combination with pembrolizumab. Though majority of MM subjects express BCMA, 
the intensity of expression varies. To evaluate whether BCMA expression has utility in 
patient stratification, malignant plasma cells at baseline will be measured for BCMA 
expression by IHC and/or flow cytometry and the expression correlated with clinical 
outcome. Because BCMA can also be detected in circulation, the soluble form (sBCMA) 
has the potential to serve as a surrogate for cell surface BCMA marker. This study will 
correlate patient sBCMA levels with cell surface expression and clinical response to 
support future validation of sBCMA as a patient selection marker, if data warrants.  
Any Bblood and bone marrow samples will becollected during this study andmay be used 
for the purposes of measuring novel biomarkers to identify factors that may influence 
advanced multiple myeloma, hematological malignancies and/or medically related 
conditions, as well as the biological and clinical responses to GSK2857916 in 
combination with pembrolizumab.  If relevant, this approach may be extended to include 
the identification of biomarkers associated with AEs 
These analyses may include but not be limited to: 
• Tumor/plasma cellbone marrow BCMA receptor expression by flow and/or IHC.     
• Soluble factors, including circulating cfDNA analysis of tumor tissue and plasma and 
cytokine/chemokine analysis of plasma serum 
• Additional soluble measurements to include serum levels of freesBCMA  
• Activated peripheral blood mononuclear cell (PBMC) count analysis of whole blood 
and intracellular cytokine assessment 
• RNA/DNA/gene and protein analysis of tumor tissue/bone marrow aspirate samples 
New Section 7.5.4 – Tumor Biomarker Analysis  
In order toTo further characterize the subject population, biomarkers (e.g. expression of 
genes and proteins) related to the activity of the investigational compound willmay be 
assessed in malignant cells.  
BCMA expression in the plasma cells of bone marrow aspirates or trephfines will be 
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of freeBCMAreceptors. Analysis of the immune context (immune cell characterization) 
of the bone marrow aspirate samples may also be performed to analyse the tumor 
microenvironment.  IHC and flow cytometry markers may include but not be limited to:  
BCMA, Blimp1, CD138, and CD38.  Additional bone marrow aspirate samples may be 
taken during the treatment period for biomarker research. All Additionally, bone marrow 
tumor tissue or aspirate samples collected may be evaluated for any DNA /RNA changes 
additional DNA/RNA/Protein biomarker analyses. correlating with response 
New Section 7.5.5 – Circulating Cell Free DNA (cfDNA) Analysis  
Additionally, bone marrow tumor tissue may be evaluated for any DNA/RNA changes 
correlating with response.  Tumor specific circulating nucleic acid (cfDNA) levels 
detected in plasma or serum have been found to correlate with increasing tumor burden 
and decline following therapy.  Futhermore, cfDNA in cancer subjects can harbour many 
genetic alterations (mutations, microsatellite alterations, aberrant methylation), which are 
generally consistent with the tumor.  Thus, tTumor-specific circulating cfDNA has the 
potential to be a useful biomarker of therapeutic response as well as offering a less 
invasive blood based technique for identifying and selecting subjects for certain 
treatments.  Given the promise of cfDNA blood based test for subject selection,this 
promise, cfDNAthis test will be explored to determine whether mutations in cfDNA 
correlate with that in the tumor tissue from which it is derivedcan be identified. This test 
will also be explored to correlate increasing cfDNA levels with increasing tumour 
burden.  
Reason for change: Revisions of Biomarker section including removal of the TBNK 
section, removal of peripheral blood sample and other updates.  
68.  Section 7.7. – Value Evidence and Outcome 
Three Health-Related Quality-of-Life (HRQoL) assessments will be performed in this 
study.  More details about all patient questionnaires can be found in the SRM.  The 
following assessments will be administered to subjects in different regions based on the 
availability of translated versions. 
Section 7.7.1 - European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core module (EORTC QLQ-C30) MD 
Anderson Symptom Inventory – Multiple Myeloma (MDASI-MM) Module  
The EORTC QLQ-C30 is a 30-item questionnaire containing both single- and multi-item 
measures [Aaronson, 1993]. These include five functional scales (Physical, Role, 
Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and 
Nausea/Vomiting), a Global Health Status/QoL scale, and six single items (Constipation, 
Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). Scores for each 
scale and single-item measure are averaged and transformed linearly to a score ranging 
from 0–100. A high score for functional scales and for Global Health Status/QoL 
represent better functioning ability or HRQoL, whereas a high score for symptom scales 
and single items represents significant symptomatology [Proskorovsky, 2014]. 


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Effects of Treatment, Future Perspective, and Body Image.  Three of the four QLQ-
MY20 domains are multi-item scales: Disease Symptoms (includes bone aches or pain, 
back pain, hip pain, arm or shoulder pain, chest pain, and pain increasing with activity); 
Side Effects of Treatment (includes drowsiness, thirst, feeling ill, dry mouth, hair loss, 
upset by hair loss, tingling hands or feet, restlessness/agitation, acid 
indigestion/heartburn, and burning or sore eyes); and Future Perspective (includes worry 
about death and health in the future, and thinking about illness).  The Body Image scale is 
a single-item scale that addresses physical attractiveness.  As with the QLQ-C30, QLQ-
MY20 domain scores are averaged and transformed linearly to a score ranging from 0–
100.  A high score for Disease Symptoms and Side Effects of Treatment represents a high 
level of symptomatology or problems, whereas a high score for Future Perspective and 
Body Image represents better outcomes [Proskorovsky, 2014]. 
Reason for change: Change in questionnaire from MDASI-MM to EORTC-QLQ-C30 
and EORTC-QLQ-MY20.   
69.  Section 9.1.2. – Part 2: Expansion cohort 
The primary goal of Part 2 is to characterize clinical activity of the combination and to 
detect if meaningful response rate (ORR) can be achieved. Based on historical 
information [Lokhorst, 2015] and clinical judgement, the null hypothesis has been 
defined as ORR ≤40%for the purpose of this study. The alternative hypothesis has been 
defined as ORR ≥60% based on clinically meaningful improvement of 20%. A test will 
be performed using the stopping rules provided in Section 9.5.2. Descriptive statistics 
will be used to describe the observed ORRs in the expanded cohorts. 
In Part 2, treatment-related Grade 4 or higher AEs will be continuously monitored 
starting from when 5 participants are dosed. Based on the 11% Grade 4 or higher AEs 
observed in the FTIH study (BMA117159), it is considered that the combination 
treatment has unacceptable toxicity if observed treatment-related Grade 4 or higher AEs 
is significantly higher than 12% at 1-sided alpha of 0.025.  
Reason for change: Clarified that the increase of alternative hypothesis relates to clinical 
improvement and addition of FDA requested stopping criteria for Part 2.  
70.  Section 9.2. – Sample Size Considerations  
Part 1: Dose-Escalation Phase 
The total number of subjects to be enrolled into Part 1 will depend on the number of 
subjects needed to characterize individual dose cohorts. The sample size is not driven by 
statistical considerations. However, based on assumptions that 23 different dose levels 
will be tested (up to 6 subjects per dose level) it is anticipated that up to 1218 evaluable 
subjects will be enrolled in Part 1. 


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Part 2: Expansion Cohort  
Sample size for Part 2 is estimated based on hypothesis specified in Section 9.1.2 using 
the Predictive Probability design [Lee, 2008]. Details of sample size calculation are 
provided in Appendix 12. The optimal design has Nmax = 28, type I error rate of 0.10 
and power of 80.6%. The expansion cohort may be stopped early for futility if the 
predicted probability of success is less than 1.5%. If the true ORR is 40%, the expected 
sample size is 20 and the probability of early termination is 86.1%; if the true ORR is 
60%, the expected sample size is 28 and the probability of early termination is 15.6%. 
 
Once the RP2 dose is established, at least 13 and up to 30 subjects in total will be 
enrolled into the Part 2 of the study. The enrollment may be stopped according to the 
decision rules defined in Table 12. The sample size and stopping rules are based on the 
methodology of Lee et al. [Lee, 2008]. The assumptions underlining the design are 
detailed below: 
The null hypothesis is: H0: ORR≤40% 
The alternative hypothesis is: HA: ORR≥60% 
Overall response (ORR) will be defined as sCR+CR+VGPR+PR per standard evaluation 
criteria for definition of response assessments and criteria.   
For expansion cohort, starting with 13 subjects and allowing for a maximum sample size 
of 30, this design will have a type I error rate α of 0.092 and 80.9% power when the true 
response rate is 60%. The trial is not designed to stop early for efficacy, but is designed 
to stop early for futility if the predictive probability of success is 3.0% or less. The type I 
error rate, power, and predictive probability of success to stop early for futility were 
derived from explicitly stating the minimum and maximum sample size, futility stopping 
rate and selection of the optimizing criterion as the maximization of the power under the 
alternative hypothesis. The Bayesian prior used in determining the design was Beta (0.04, 
0.06), a distribution with a mean response rate of 40%. Under the null hypothesis, if the 
true response rate is 40%, the expected sample size of the design is 20 subjects and 
probability of early termination (PET) is 87.4%. Under the alternative hypothesis, if the 
true response rate is 60%, the expected sample size of the design is 29 subjects in the 
expansion cohort and PET is 15.7%.  
 
Reason for change: Based on FDA comment, removed original starting dose; section 
revised due to sample size adjustment and corresponding calculations.  
71.  Section 9.4.1. – Analysis Populations  
All Evaluable Subjects Population: This is the population used for decision-making at 
the futility analysis during part 2 (Expansion Cohort). This will be the population for 
Bayesian predictive adaptive design as defined in Section 9.5.2 and summaries of 
response if data warrant. In general, subjects are evaluable if they have received at least 1 
dose of treatment for both drugs and the time from the first dose to the time of data cut-
off is more than 66 days, i.e., reached the time of three planned disease assessments. 
Details on deriving the evaluable population will be provided in the RAP. Subjects are 
considered evaluable if they are in the all treated population, have received at least 2 
doses of treatment, and have had at least one disease assessment post 2nd dose. Subjects 


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are also considered evaluable if they are in the all treated population and have progressed 
or died or have permanently discontinued from the study treatment 
Reason for change: Revised definition to allow flexibility based on possible delays with 
dosing based on FTIH experience.   
72.  Section 9.5 – Interim Analysis 
Section 9.5.1. – Part 1: Dose Escalation  
During dose escalation, no formal interim analysis will be performed. Data will be 
reviewed through data visualization tool to inform dose escalation decisions. The mTPI 
design will be utilized to guide dose escalation/de-escalation decisions. More details of 
the dose escalation procedure are described in Section 4.2.3.1. 
After the last cohort of subjects in Part 1 complete the DLT observation period, a formal 
interim analysis will be performed to support the RP2D decision, except for scenarios 
where RP2D is clearly defined by the toxicity profile. Data considered to support RP2D 
decision will include but not limited to safety, available PK profile and observed signs of 
clinical activity. Details of the interim analysis will be provided in the RAP. 
While no formal interim analysis is planned for Part 1, safety data will be examined on an 
ongoing basis to support dose escalation decisions. Prior to determining the GSK2857916 
dose in combination with 200 mg pembrolizumab for the next cohort, analysis of safety 
data from previous dose cohort will be performed. The anlaysis will be performed after at 
least 3 evaluable subjects have been studied per dose level.  To facilitate dose 
escalation/de-escalation decisions, a Bayesian logistic regression model (BLRM) may be 
utilized to predict the probability of DLT at the dose levels to be tested. Specifically, a 
BLRM for combination treatment will be fitted on the dose limiting toxicity data (i.e., 
absence or presence of DLT) accumulated throughout the dose escalation to model the 
dose toxicity relationship of GSK2857916 in combination with pembrolizumab. The 
BLRM analysis will be performed to determine if a next dose-level is expected to be safe 
and to support the dose escalation decision following the completion of each dose cohort. 
Further details regarding such analyses including prior specifications will be provided in 
the Reporting and Analysis Plan (RAP). 
Section 9.5.2.  – Part 2: Expansion   
Continuous safety monitoring will be conducted for the expansion cohort starting from 
when 5 subjects are dosed. The observed number of treatment-related Grade 4 or higher 
AEs will be compared against the safety stopping rule in Table 12. Enrollment may stop 
if the safety stopping rule is met based on totality of safety data. For example, if there are 
3 events out of 5 dosed subjects, enrollment may stop after review of all safety data, if 
there is 2 or fewer events out of 5 dosed subjects, enrollment will continue. Operating 
characteristics for the safety stopping rule are provided in Appendix 11.  


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Table 12 
Safety Stopping Rules for the Expansion Cohort 
Number of dosed subjects 
 
Stop if treatment related 
Grade 4 or higher AEs 
larger or equal to this 
number 
5 
 
3 
6-10 
 
4 
11-14 
 
5 
15-19 
 
6 
20-25 
 
7 
26-28 
 
8 
A Bayesian predictive adaptive design [Lee, 2008] as described in Section 9.2.2 that 
allows the trial to be monitored more frequently at multiple stages will be used.    
For the expansion cohort, based on the size of expansion cohort and on anticipated 
enrollment pace, it is considered that a single futility analysis is practical and sufficient 
once approximately 15 subjects in Part 2 are evaluable for futility analysis. The number 
of best unconfirmed overall responses (PR+VGPR+CR+sCR) observed for the All 
Evaluable Subjects Population will be compared with the stopping rules provided in 
Table 13. Additional futility looks maybe performed, if necessary. These rules are 
intended as a guideline only. Actual decisions will depend on the totality of the data, in 
particular, the depth and duration of response will also be taken into account before 
declaring futility. Should the recommendation to stop for futility be disregarded in favor 
of a decision to continue the trial based on the totality of the data, the overall type I error 
rate of the expansion phase will be inflated.  When the total sample size reaches 30 and 
16 responders are observed, with the assumed beta prior distribution as described in 
Section 9.2.2., the posterior probability of ORR>40% is 92.9%.  
Interim analyses for ORR will start when at least 10 subjects are evaluable as defined in 
Section 9.4.1. Subjects who initially received RP2D in Part 1 may also be included. The 
observed number of subjects with unconfirmed response of PR or better will be compared 
with the stopping boundary in Table 13. Enrolment may stop if the stopping rule is met. 
Final decision will be based on the totality of data. For example, if there are 2 
unconfirmed responses out of 10 evaluable subjects, enrolment may stop after review of 
all available data; if there are 3 or more unconfirmed responses out of 10 evaluable 
subjects, enrolment will continue. 
Table 12 updated to Table 13 due to inclusion of Table 12. Table 13 was updated with 
revised numbers for Decision Making Criteria for Futility Analysis based on the updated 
subject total.  


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Reason for change: Replaced BLRM with mTPI model for Dose Escalation part. Added 
safety monitoring criteria based on rate of Grade 4 treatment related AEs due to FDA 
request to add stopping criteria. Updated Part 2 Table 13 futility wording due to change 
in subject number.   
73.  Section 9.6 – Final Analysis 
Final analysis of the data captured in Part 1 and Part 2 will be undertaken at the end of 
the study (Section 5.5.2).  after all subjects meet at least one of the following criteria: 
have received all prespecified treatment (32 cycles) or has progressed; or has died; or has 
been permanently withdrawn from the study. Data from the two parts may be combined 
for some analyses at the end of the trial, as appropriate. 
Reason for change: Revised criteria for end of study analysis.    
74.  Section 9.7.1. – Clinical Activity Analyses 
The primary endpoint ORR and other applicable secondary endpoints (e.g., CBR, DoR, 
TTR, TTP, PFS) will be based on the responses assessed by the investigator.  
At futility interim, the primary endpoint (ORR) will be analyzed based on the All 
Evaluable population. Otherwise, all efficacy endpoints will be analyzed based on the All 
Treated population unless otherwise specified. 
The analytical methods planned for each endpoint are described in Table 14. 
Table 14 
Statistical Analysis Methods for Clinical Activity Endpoints (Part 2) 
Endpoint 
Statistical Analysis Methods 
Primary 
Overall Response Rate (ORR) is defined as the percentage of subjects with a 
confirmed PR or better (i.e. PR, VGPR, CR and sCR), according to the International 
Myeloma Working Group (IMWG) Response Criteria). 
The number and percentage of subjects in the following response categories will be 
presented: sCR, CR, VGPR, PR, overall response (sCR+CR+VGPR+PR), minimal 
response (MR), stable disease (SD), progressive disease (PD), and not evaluable 
(NE). The corresponding 95% CI for ORR will also be provided. Subjects with 
unknown or missing responses will be treated as non-responders, i.e., these 
subjects will be included in the denominator when calculating percentages of 
response. 
Secondary 
Secondary clinical activity endpoints of Part 2 of this study are CBR, DoR, TTR, 
PFS, TTP and MRD Negative Rate. 
Clinical benefit rate (CBR), defined as the percentage of participants with a 
confirmed minimal response (MR) or better per IMWG 
Duration of response (DoR) is defined as the time from first documented evidence 
of PR or better until disease progression (PD) per IMWG, or death due to PD 
among subjects who achieve an overall response (i.e. confirmed PR or VGPR or 


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CR or sCR). Responders without disease progression will be censored at the 
censoring time point for TTP.  
Time to response (TTR) is defined as the time between the date of first dose and 
the first documented evidence of response (PR or better) for subjects who achieve 
an overall response (i.e. confirmed PR or VGPR or CR or sCR).  
Time to best response, defined as the time between the date of first dose and the 
first best documented response (PR or better) for subjects who achieve an overall 
response (i.e. confirmed PR or VGPR or CR or sCR). 
Progression-free survival (PFS) is defined as the time from first dose until the 
earliest date of disease progression (PD) per IMWG, or death due to any cause. 
Determination of dates of PFS event and dates for censoring will be described in 
the RAP.  
Time to disease progression (TTP) is defined as the time from first dose until the 
earliest date of PD per IMWG, or death due to PD. Determination of dates of TTP 
event and dates for censoring will be described in the RAP.  
For all the TTE endpoints described above, median TTE with 95% CI will be 
estimated employing the Kaplan-Meier method. A Kaplan-Meier survival curve will 
be generated. The number and percentage of subjects who had the event or were 
censored will also be reported. In addition, PFS rate with 95% CI at 6, 
12 and 18 months will be estimated using Kaplan-Meier methods for the PFS 
endpoint. 
 
OS is defined as the time from first dose until death due to any cause.  Subjects 
who withdraw consent from the study or are lost to follow-up will be censored at the 
time of withdrawal or lost to follow-up. Subjects who are still alive at the clinical cut-
off date for the analysis will be censored at the last known alive date or last contact 
date. The last contact date will be determined by the maximum 
collection/assessment date from among selected data domains within the clinical 
database. Survival rate 12, 18 and 24 months will be reported from Kaplan-Meier 
analysis as data permits. 
All subjects who have received study treatment will be evaluated for response according 
to their originally assigned cohort. The overall response rate (ORR) is defined as the 
percentage of subjects with confirmed stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), and partial response (PR) at any time 
as per disease specific criteria. 
 
Subjects with unknown or missing response will be treated as non responders, i.e. these 
subjects will be included in the denominator when calculating the percentage. The 
number and types of responses, as outlined in International Myeloma Working Group 
Uniform Response Criteria, will be listed and summarized separately, as appropriate. 
 
The ORR will be reported at futility and at the time of final analyses. The estimates along 
with 95% exact confidence interval (CI) will be provided.  
 
The clinical Benefit Rate (CBR) is defined as the percentage of subjects with confirmed 
sCR, CR, VGPR, PR and minimal response (MR) at any time as per disease specific 


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criteria. CBR will be reported at futility and at the time of final analyses. The estimates 
along with 95% exact confidence interval (CI) will be provided.  
 
Duration of response (DOR) is defined as time from the first documented evidence of 
response until the first documented sign of disease progression or death for the subset of 
subjects who achieve a response (sCR, CR, VGPR, PR). Duration of response will be 
summarized descriptively, if data warrant, using Kaplan Meier medians and quartiles.  
Details on rules for censoring will be provided in the RAP. 
 
For the analysis of Progression free survival (PFS), PFS Duration is defined from start 
of the treatment to disease progression or death (due to any cause), whichever comes 
first. Further details on rules for censoring will be provided in the RAP.  PFS will be 
summarized by dose using Kaplan Meier quantile estimates along with 2 sided 95% CIs 
at the time of final analysis, if data warrant. 
For the analysis of overall survival (OS), the last date of known contact will be used for 
those subjects who have not died at the time of analysis; such subjects will be considered 
censored. Further details on rules for censoring will be provided in the RAP. OS will be 
summarized by dose using Kaplan Meier quantile estimates along with 2 sided 95% CIs 
at the time of final analysis, if data warrant. 
Reason for change: Revision of wording for clinical activity endpoints, clarification of 
ORR and clarification of included population.    
75.  Section 9.7.2.2. – Adverse Events 
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system 
organ class.  Adverse events (AEs) will be graded by the investigator according to the 
National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), 
(version 4.03, [NCI, 2010]). In addition, for GSK2857916 treatment related corneal 
events, the GSK grading scale for corneal events (Appendix 9) should be used. 
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following 
AEs of special interest will be summarized separately:  
• Corneal events 
• Thrombocytopenia 
• Infusion related reactions 
Reason for change: Addition of specific wording related to corneal events and inclusion 
of AEs which were unintentionally omitted in previous version.  
76.  Section 9.7.3. – Pharmacokinetic Analyses 
9.7.3.1. – RawConcentrations Time Data 


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Linear and semi-logarithmic individual concentration-time profiles and mean and median 
profiles (when applicable) by GSK2857916 dose will be plotted for GSK2857916 
(ADCintact and total mAb), cys-mcMMAF, and for pembrolizumab (if tested) in Part 1. 
Concentrations of GSK2857916 (ADCintact and total mAb), cys-mcMMAF, and 
pembrolizumab (if tested) will be listed for each subject and summarized (when 
appropriate) by planned time point and dose cohort in Part 1 and Part 2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic analysis will be the responsibility of the CPMS Department, QSci, 
GSK. 
For Cycle 1,In Part 1 of the study, GSK2857916 and pembrolizumab (if measured) 
concentration-time data will be analyzed by standard non-compartmental methods, if data 
permitusing WinNonlin. Calculations will be based on the actual sampling times recorded 
during the study. From the concentration-time data, the following GSK2857916 
(ADCintact and total mAb), cys-mcMMAF, and pembrolizumab (if measured) PK 
parameters will be determined as data permit, for each dose of GSK2857916 or for 
pembrolizumab (if measured) and for each subject: In part 1 cycle 1: area under the 
concentration-time curve (AUC(0-t), AUC (0-tau) and/or AUC(0-∞)), maximum 
observed concentration (Cmax), time to Cmax (tmax), last time point where the 
concentration is above the limit of quantification (tlast), terminal phase elimination rate 
constant (λz) and terminal phase half-life (t½). In subsequent cycles (when measured):  as 
well as in part 2: concentration at trough (Ctrough) and end of infusion concentration will 
be summarized. 
PharmacokineticK parameters will be listed and summarized descriptively (mean, 
standard deviation, median, minimum, maximum, geometric mean, and the standard 
deviation, CV% and 95% confidence interval of log-transformed parameters) by dose 
cohort in Part 1 and Part 2. 
GSK2857916 data from this study may be combined with data from other studies and 
analyzed using population pharmacokinetic methods. A nonlinear mixed effects model 
will be used to determine population pharmacokinetic parameters (clearances, CL and 
volumes of distribution, V) and identify important covariates (e.g., age, weight, or 
disease-related covariates). Summary exposure measures (e.g., Cmax, AUC) will also be 
computed.  Results of this analysis may be provided in a separate report. 
GSK2857916 pharmacokinetic resultsPK profile will be assessed versus the expected 
profile based on previousthe data from the FTIH study BMA117159 to evaluate the 
potential impact of pembrolizumab on GSK2857916 pharmacokineticsPK. 
Reason for change: Clarification of analytes measured and addition of wording that 
multi-study analyses may occur.   
 


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77.  Section 9.7.4.2. – Genetic Analyses 
Cell surface BCMA and sBCMA pre dosing will be quantified as a potential predictive 
biomarker for clinical activity. Post dosingfree surface BCMA and BCMA drug 
sBCMAcomplex will be quantified to assess dynamics during treatmentproportion of 
target engagement.  
Measurements of sBCMA will include separate assays for free sBCMA and sBCMA 
complexed with drug. 
Reason for change: Update of wording based removal of separate assays.   
78.  Section 9.7.6. – Immunogenicity Assessment  
For each subject, the results and titers of anti-GSK2857916 binding antibodies will be 
listed for each assessment time point with time-matched GSK2857916 plasma 
concentration.  The frequency and percentage of subjects with positive and negative 
results will be summarized for each assessment time and overall for each subject by dose 
cohort. The detailed information will be included in the RAP. 
Reason for change: Clarification of wording to clarify relationship of ADA and plamsa 
concentrations.    
79.  Section 10.9. – Review Committees 
Section 10.9.1 – Internal Safety Review Committee 
An Internal Safety Review Committee (iSRC) will be utilized in this study and comprise 
individuals who are not members of the clinical study team. The iSRC are positioned to 
offer an internal, independent review of safety data to protect the interests of subjects and 
ensure their safety. All efforts will be made to maintain the study integrity and validity of 
study data. The schedule of planned reviews of safety data and the analysis plan for iSRC 
review is described in the iSRC Charter, which is available upon request. 
Reason for change: Inclusion of internal safety review committee as additional safety 
component.  
80.  Section 12.5. – Appendix 5: Liver chemistry stopping and monitoring criteria 
and required actions and follow up assessments  
Section 12.5.1. – Liver Chemistry stopping criteria 
Summary of changes include revision of liver chemistry criteria to specific GSK Phase 
I/II template information. Previously stopping criteria as specific to ALT-absolute of 
ALT ≥3xULN and specific SAE criteria. Revised stopping criteria include the following: 
ALT ≥5xULN, ALT increase of ALT ≥3xULN for ≥4 weeks, Bilirubin related to ALT 
with ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin), INR related to ALT with 
ALT ≥3xULN and INR >1.5, if INR measured, if ALT ≥3xULN and subject cannot be 


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monitored weekly for 4 weeks, and if ALT ≥3xULN is associated with symptoms 
believed to be related to liver injury or hypersensitivity. Guidance and instructions related 
to monitoring and follow-up have been updated.  
Reason for change: Revision of section to include required Phase I/II wording per GSK 
template.   
81.  Section 12.6. – Appendix 6 – P-gp Inhibitors  
Removal of Appendix. 
Reason for change: To ensure that the list of P-gp inhibitors is as current as possible 
without requiring a protocol amendment, the SRM is instead referenced in the protocol.  
82.  Section 12.7.  Appendix 7  International Myeloma Working Group Uniform 
Response Criteria for Multiple Myeloma  
Removal of Appendix.  
Reason for change: To ensure that the updated criteria are being utilized as written, have 
referred to appropriate reference for 2016 IMWG criteria throughout the document.  
83.  Section 12.8.10 – Appendix 810: Contraceptive Guidance and Collection of 
Pregnancy Information Definitions Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy Information 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
• 
Premenarchal 
• 
Premenopausal female with 1 of the following: 
▪ 
Documented hysterectomy 
▪ 
Documented bilateral salpingectomy 
▪ 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
• 
Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 


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women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
Contraception Guidance 
 
a. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
b. 
Highly Effective Methodsb That Have Low User Dependency  
c. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
d. 
Intrauterine device (IUD) 
e. 
Intrauterine hormone-releasing system (IUS)c 
f. 
Bilateral tubal occlusion 
g. 
Vasectomized partner 
h. 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
i. 
Highly Effective Methodsb That Are User Dependent 
j. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
k. 
oral 
l. 
intravaginal 
m. transdermal 
n. 
injectable 
o. 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
p. 
oral 
q. 
injectable 
r. 
Sexual abstinence 
s. 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
 


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Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction) 
 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male subjects who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
Female Subjects who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical resonas will be 
reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.   
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK. While the investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating will discontinue study 
intervention.  
 
12.10.1   Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) 
The following is the all inclusive list of the highly effective methods for avoiding 
pregnancy that meets the definition specified in GSK SOP_54811 (i.e., have a failure rate 
of less than 1% per year when used consistently and correctly and, when applicable, in 


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accordance with the product label). Therefore, this list is used to comply with GSK 
SOP_54811. 
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.  Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
Contraceptive subdermal implant 
Intrauterine device or intrauterine system 
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]) 
Injectable progestogen [Hatcher, 2011] 
Contraceptive vaginal ring [Hatcher, 2011] 
Percutaneous contraceptive patches [Hatcher, 2011] 
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject [Hatcher, 
2011].  The documentation on male sterility can come from the site personnel’s: review 
of subject’s medical records, medical examination  and/or semen analysis, or medical 
history interview provided by her or her partner. 
 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception. 
12.10.2   Contraceptive requirements for male subjects with female partners of 
reproductive potential (when applicable) 
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until [at least five half lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives] after the last dose of study medication. 
Vasectomy with documentation of azoospermia. The documentation on male sterility can 
come from the site personnel’s: review of subject’s medical records, medical 
examination  and/or semen analysis, or medical history interview.   
Male condom plus partner use of one of the contraceptive options below that meets the 
SOP effectiveness criteria including a <1% rate of failure per year, as stated in the 
product label: 
Contraceptive subdermal implant 
Intrauterine device or intrauterine system 
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]  
Injectable progestogen [Hatcher, 2011] 
Contraceptive vaginal ring [Hatcher, 2011] 
Percutaneous contraceptive patches [Hatcher, 2011] 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception. 
12.10.3    Collection of Pregnancy Information 
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study 
Information will be recorded on the appropriate form and submitted to GSK within 24 
hours of learning of a subject's pregnancy. 


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Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to GSK.  
Generally, follow up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.  
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.   
Any SAE occurring as a result of a post study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 8. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
Any female subject who becomes pregnant while participating 
will be withdrawn from the study 
Reason for change: Revisions to the GSK standard language.  


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84.  Section 12.9.11 – Appendix 911: GSK2857916 associated Corneal Event Severity 
Grading and Mitigation Strategy MITIGATION STRATEGIES FOR FOR 
CORNEAL TOXICITY  
In order to minimize the corneal toxicity, subjects must receive steroid eye drops as 
prophylaxis (such as: prednisolone phosphate 1%, or dexamethasone 0.1%) 1 drop QID 
starting 1 day prior to each GSK2857916 infusion, and continuing for a total of 
consecutive 7 days.  Other equivalent eye drops may be considered after confirming with 
GSK.  Omission or discontinuation of prophylactic steroid eye drops may be allowed 
under certain circumstances (e.g., in the setting of intolerability, contraindication, or 
toxicity secondary to steroid eye drops) upon discussion with the Medical Monitor. 
Prophylactic preservative-free artificial tears should be administered in each eye at least 
4-8 times daily, beginning on Cycle 1 Day 1 until the End of Treatment (EOT).  Allow at 
least 5-10 minutes between administration of artificial tears and steroid eye drops.  In the 
event of ocular symptoms (e.g., dry eyes), the use of artificial tears may be increased up 
to every 2 hours as needed. 
While not yet clinically demonstrated, it is theoretically possible that the application of a 
cooling eye mask during GSK2857916 administration, and in the first few hours after 
infusion may subsequently decrease ocular side effects.  On the day of infusion at the 
discretion of the participant and the investigator, the following may be considered:  
• 
Beginning with the start of each GSK2857916 infusion, subjects may apply cooling 
eye masks to their eyes for approximately 1 hour or as much as tolerated.   
• 
Subjects may continue using the cooling eye mask beyond the first hour for up to 4 
hours.  Further use beyond 4 hours is at the patient’s discretion. 
Subjects must avoid the use of contact lenses during the study. 
An ophthalmology (or optometrist, if an ophthalmologist is not available) consult is 
required for all subjects who develop signs or symptoms of corneal toxicity or require 
steroid eye drops for more than 7 days.  
A summary of prophylactic interventions for corneal toxicity associated with 
GSK2857916 is provided in Table 15.  Corneal toxicity must be graded according to the 
guidelines provided in Table 16.  Additional guidance on grading visual acuity changes 
provided in Table 17. 


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Prophylactic 
Measurea 
Dose and Administration 
Timing 
Steroid eye dropsb 
Prednisolone phosphate 1%, or 
dexamethasone 0.1%, or 
equivalent, 1 drop QID  
Begin 1 day prior to each dose of 
GSK2857916 infusion, and continuing for 
a total of consecutive 7 days 
Preservative-free 
artificial tears 
Administer in each eye at least 
4-8 times daily 
Administer daily beginning on Cycle 1 
Day 1 until EOT.  Allow 5-10 minutes 
between administration of artificial tears 
and steroid eye drops 
Cooling eye mask 
May apply cooling eye mask to 
both eyes for approximately 
1 hour or as much as tolerated  
During GSK2857916 infusion 
administration in the first hour for up to 4 
hours, as tolerated 
a.
Dose modifications and treatment for ocular toxicities are discussed in Section 6.5.  
b.
Omission or discontinuation of prophylactic steroid eye drops may be allowed under certain circumstances (e.g., 
in the setting of intolerability, contraindication, or toxicity secondary to steroid eye drops) upon discussion with the 
Medical Monitor.   
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
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TMF-14344600 
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Protocol Amendment 04 
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84.  Section 12.11 – Appendix 11: Operating Characteristics of Safety Stopping Rule 
for Expansion Cohort 
Figure added to provide visualization for stopping rule as defined in Section 9.5.2. 
Reason for change: FDA requested stopping criteria be established for Part 2 subjects. 
Figure provides characteristics of stopping rules.   
85.  Section 12.12 – Appendix 12: Sample Size Calculation for the Expansion Cohort 
Information and figure providing details for hypothesis of study as described in Section 
9.2.2.  
Reason for change: Additional detail for reviewers.  
 
 


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Role 
Name 
Day Time Phone 
Number and email 
address 
After-hours 
Phone/Cell/ 
Pager 
Number 
Site Address 
Primary 
Medical 
Monitor  
 
 
 MDPhD 
GlaxoSmithKline 
1250 South Collegeville Road 
Mailstop UP4300 
Collegeville, PA 19426, USA 
 
Secondary 
Medical 
Monitor 
 
 
 
MDPhD 
GlaxoSmithKline 
1250 South Collegeville Road 
Mailstop UP4300 
Collegeville, PA 19426, USA 
Email:  
SAE 
Reporting 
 
OAX37649@gsk.com  
 
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TMF-14344600 
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Protocol Amendment 04 
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In adequate organ system function table, revision of footnote 1:  
1. 
Without any Growth factor support (e.g.colony stimulating factors (including 
granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage colony-
stimulating factor [GMCSF], recombinant erythropoietin) or any thrombopoietin receptor 
agonists) within 2 weeks before the first dose of study drugfor the past 14 days, excluding 
erythropoietin. 
Female and Male Inclusion Criteria:  
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described in 
Appendix 8 during the intervention period and for 9 months at least 120 days after the 
last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the 
purpose of reproduction during this period. The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
A WOCBP must have a negative highly sensitive serum pregnancy test (as required 
by local regulations) within 72 hours before the first dose of study intervention of 
dosing on C1D1 and agree to use effective contraception during the study and for 9 
months after the last dose of study medication.  
• Male Subjects: 
• Male subjects are eligible to participate if they agree to the following from the 
time of first dose of study until 6 months after the last dose of study treatment to 
allow for clearance of any altered sperm during the intervention period and for at 
least 140 days after the last dose of study intervention:  
• Refrain from donating sperm 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
OR 
• Must agree to use contraception/barrier as detailed below 
• Agree to use a male condom, even if they have undergone a successful 
vasectomy, and female partner to use an additional highly effective 
contraceptive method with a failure rate of <1% per year as described in 
Appendix 8 when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant. 
• Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies. 
Reason for change: Revision of Inclusion Criteria due to clarification of allowed 
supportive therapy prior to first dose and update of contraception language.  


TMF-14344600 
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Protocol Amendment 04 
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8. Throughout the document: Female and Male contraception requirements:  
Females:  
.. throughout the study period up to 120 days during the study and for 9 months.. 
Males:  
..140 days 6 months 
Reason for change: Update to the contraception timeframe based on emerging PK 
information and agency guidance.  
9. Study Schema and Dose Escalation Schematic Figures in Synopsis and Section 
4.2.1.:  
Replaced GSK2857916 with belantamab mafodotin; as a result, replaced the figures.  
Reason for change: Replaced compound number with generic in figures, not reflected in 
text.  
10. Protocol Synopsis and Section 6.12.3. Corneal Supportive Care Guidelines:  
Subjects will be assessed by ophthalmologists (or optometrist, if ophthalmologist is not 
available) at baseline, and then every three weeks prior to each dose of belantamab 
mafodotin for the first 4 doses. After the 4th dose of belantamab mafodotin, iIf there are 
is no significant ocular symptoms or vision change s, the frequencyin vision and no 
corneal signs consistent with toxicity at time of the cycle 4 exam, subjects may have their 
of ophthalmologic exams may be decreased to once every 36 months until end of study 
treatment.  In case of persistent or newly developed ocular symptoms or vision changes, 
the If a subject subsequently develops a change in visual acuity or other ocular 
symptoms, the subject should will have further ophthalmologic exams, at least every 3 
months until resolution (to Grade 1 or baseline) or more frequently as clinically indicated 
by the be evaluated by an eye care specialistprofessional.  Intraocular pressure must be 
monitored if steroid eye drops are used for more than 7 days. 
Reason for change: Based on benefit/risk after review of data from the primary analyses 
of DREAMM-2 study it has been determined that participant symptoms should determine 
the need for ophthalmology exams, and dose modifications. 
11. Protocol Synopsis Translational Research 
BCMA expression in the plasma cells of from bone marrow aspirates will be evaluated at 
baseline, and at additional timepoints if available, by IHC.  IHC markers may include but 
will not be limited to: BCMA, Blimp1, CD138, and CD38.   
Soluble BCMA (sBCMA) concentrations in serum will be followed evaluated in all 
subjects. 


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Reason for change: Clarification of wording. 
12. Section 2.2.2. Nonclinical Pharmacokinetics:  
Removed the section wording and replaced with:  
Detailed information is available in the Investigator’s Brochure [GlaxoSmithKline 
Document Number 2013N175128_06].   
Reason for change: Reduction of length of document by reference to updated 
Investigator Brochure document that contains the revised information.  
13. Section 2.2.3. Toxicology 
Removed/revised the section wording: 
A range of nonclinical toxicology studies have been conducted to support the intravenous 
administration of belantamab mafodotinGSK2857916 to humans.  Detailed information is 
available in the Investigator’s Brochure [GlaxoSmithKline Document Number 
2013N175128 06].   
Reason for change: Reduction of length of document by reference to updated 
Investigator Brochure document that contains the revised information.  
14. Section 2.2.5 Effects in Humans (belantamab mafodotin) 
Data from two belantamab mafodotin single agent studies conducted in heavily pre-
treated RRMM patients (Q3W schedule via IV administration) is summarized below. 
In the FTIH study BMA117159/DREAMM 1 (NCT02064387), as of 28 August 2018 
primary analysis data cut-off, a total of 73 subjects with RRMM received at least 1 dose 
of belantamab mafodotin frozen drug product ranging from 0.03 mg/kg to 4.6 mg/kg 
once every 3 weeksin BMA117159 [GSK2857916 IB]. Subjects were heavily pre-treated: 
57% of subjects had 5 or more prior lines of therapy. Data from DREAMM 1 
demonstrates a manageable safety profile with thrombocytopenia and corneal events 
being the most frequently reported AEs.  All subjects in Part 2 (MM patient population) 
initiated belantamab mafodotin treatment at 3.4 mg/kg and experienced at least one AE. 
The most common events occurring in ≥30% of subjects were corneal events, 
thrombocytopenia (including the preferred term platelet count decreased), nausea, 
fatigue, anemia, and aspartate aminotransferase increased.  In Part 2, Grade 3/4 AEs were 
reported in 29/35 subjects (83%) and SAEs were reported in 17/35 (49%) subjects.  The 
most common SAEs were lung-associated infections, pneumonia, pyrexia, and IRR. 
Corneal events are the most frequently reported adverse events associated with 
belantamab mafodotin in the clinic, which include keratopathy (microcyst-like superficial 
deposits in the corneal epithelium), blurred vision, dry eyes and photophobia. These 
findings are consistent with those previously reported with other antibody drug-
conjugates utilizing monomethyl auristatin F in terms of manifestation and incidence of 


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events [Donaghy, 2016; Eaton, 2015]. In part 2 of DREAMM 1, corneal events were 
reported in 24/35 (69%) subjects, most commonly blurred vision (18/35; 51%), dry eye 
(13/35; 37%) and photophobia (10/35; 29%). Most subjects experienced Grade 1 or 2 
corneal events (19/35; 54%); 5 (14%) subjects had Grade 3 events. The median duration 
of corneal events for subjects with a resolution date (n = 16) was 35 days (range 5–442). 
Corneal events led to dose reduction in 16 (46%) subjects, and dose interruptions or 
delays in 17 (49%) subjects [Trudel, 2019]. 
Thrombocytopenia/platelet count decreased was reported in a total of 40 subjects (55%) 
in the All Treated Population (N=73), and 22 subjects (63%) in Part 2 (N=35).  
Belantamab mafodotin may cause transient worsening of thrombocytopenia in some 
subjects, but in most cases these events are resolved during between-dosing intervals.  In 
the Part 2 MM population, two serious bleeding events were reported: intracranial 
hemorrhage in a subject with a history of an intracranial bleeding in the setting of disease 
progression, and hematuria in a subject with a large bladder mass in the setting of 
progressive disease. 
As of the efficacy cut-off date of 31 August 2018, a total of 35 subjects were treated at 
the 3.4 mg/kg dose in Part 2 of the ongoing DREAMM 1 study. The ORR was 60% (95% 
CI: 42.1, 76.1): comprised of PR, 6%; VGPR, 40%; CR, 9%; and stringent CR (sCR), 
6%. The median duration of response (DoR) was 14.3 months (95% CI: 10.6, NR). The 
median PFS (mPFS) in this population was 12.0 months (95% CI: 3.1, NR). For subjects 
refractory to both IMiDs and PIs (n = 32/35), the confirmed ORR was 56% (95% CI: 
37.7, 73.6) and mPFS was 7.9 months (95% CI: 2.3, Not Estimable [NE]) [Trudel, 2019].  
A Bayesian logistic regression model (BLRM) was used to determine the dose-response 
relationship for both ORR and ≥Grade 2 corneal event rate (as determined by NCI-
CTCAE Version 4.0) based on data from all 73 subjects with RRMM in DREAMM 1. 
The model showed that the posterior probability of observing an ORR ≥30% is 100% in 
the 3.4 mg/kg dose group and 83% in the 2.5 mg/kg dose group.  Similarly, the posterior 
probability of observing ≥Grade 2 corneal event rate is also higher in the 3.4 mg/kg dose 
group. Based on this analysis, these two doses (2.5 and 3.4 mg/kg) were selected for 
further evaluation. 
The ongoing Phase II study 205678/DREAMM 2 (NCT03525678) is evaluating these 
two IV single agent doses (2.5 and 3.4 mg/kg) administered Q3W until disease 
progression in subjects who have failed at least 3 prior lines of anti-myeloma therapy, 
including an anti-CD38 antibody, and who are refractory to an IMiD and a proteasome 
inhibitor.  A total of 194 subjects received frozen drug product in the main cohort and 24 
subjects received 3.4 mg/kg lyophilized drug product.  Preliminary data from this study 
indicated no new safety signals, and the profile of adverse events was similar to the 
experience in the DREAMM 1 study for both arms. Both dose levels, 2.5 and 3.4 mg/kg, 
were shown to have a positive benefit/risk profile. 
GlaxoSmithKline (GSK) initiated the clinical development of GSK2857916 in July 2014, 
with the FTIH study (BMA117159) in subjects with RRMM and other advanced 
hematologic malignancies expressing BCMA (ClinicalTrials.gov Identifier: 
NCT02064387).  As of the data cut from 26 June 2017, a total of 73 subjects with 


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RRMM have been treated with at least one dose of GSK2857916. Thirty-eight subjects 
were treated in Part 1 (dose escalation): 0.03 mg/kg (n=1), 0.06 mg/kg (n=1), 0.12 mg/kg 
(n=4), 0.24 mg/kg (n=4), 0.48 mg/kg (n=4), 0.96 mg/kg (n=3), 1.92 mg/kg (n=4), 2.5 
mg/kg (n=8), 3.4mg/kg (n=3), and 4.6mg/kg (n=6). Since the RP2D (3.4 mg/kg) selection 
(August 11, 2016), an additional 35 subjects have been enrolled into Part 2 (expansion 
cohort). Of these 35 subjects,40% had receive prior daratumumab. The ORR for this sub
population was 43% [Trudel, 2017]. 
The most frequently reported AEs (≥15.0%) in the All Treated Population included: 
vision blurred (37%), nausea (36%), fatigue (33%), anemia (29%), dry eye (29%), 
thrombocytopenia (26%), aspartate aminotransferase increased (25%), chills (23%), 
platelet count decreased (23%) pyrexia (22%), cough (18%), photophobia (16%), back 
pain (15%), headache (15%), and upper respiratory tract infection (15%). 
In the Part 2 population, 59% (20/35) of subjects had 5 or more prior treatment lines. 
Among the subjects in Part 2 (N=35), the most frequently reported AEs (≥15.0%) 
included: vision blurred (46%), platelet count decreased (37%), dry eye (34%), anemia 
(29%), aspartate aminotransferase increased (29%), increased cough (26%), chills (23%), 
nausea (23%), photophobia (23%), pyrexia (23%), fatigue (20%), thrombocytopenia 
(20%), back pain (17%), and diarrhea (17%).  As of 26 June 2017, a total of 14 (40%) 
patients in Part 2 had an SAE and there were no fatal SAEs. The related SAEs are 
described below. 
• 
Infusion Related Reaction (IRR): Two patients experienced serious, Grade 3 
infusion related reactions during the first infusion that were characterized by 
tachycardia, hypertension and pyrexia.  These subjects subsequently received pre
medication and IRRs did not recur.  
• 
Intracranial Hemorrhage: A patient with a history of intracranial bleeding 
experienced a Grade 2 intracranial hemorrhage with concomitant Grade 4, 
thrombocytopenia.  At the same time, the patient’s disease was starting to progress; 
the patient was taken off study and salvage chemotherapy was started. 
• 
Pericardial Effusion: A Grade 4 pericardial effusion consistent with tamponade was 
found prior to Cycle 9 during a routine study echocardiogram in an asymptomatic 
patient who had a concurrent upper respiratory tract infection.  The fluid was 
evacuated, and the effusion was resolving at the time of data cut off. The patient 
received three more cycles of treatment after this event.  This SAE is listed as “not 
resolved” at the time of data cut, however a subsequent echocardiogram has 
confirmed no evidence of a pericardial effusion.   
• 
Lung Infection and Pyrexia: A patient experienced a Grade 2 lung infection 
resulting in a dose delay.  Approximately three months later, the patient developed a 
Grade 2 fever resulting in hospitalization.  The fever resolved the same day; the 
patient was not neutropenic.  
Overall, GSK2857916 has a manageable safety profile with thrombocytopenia / platelet 
count decreased and corneal events as the most commonly reported events, as described 
in the following subsections.   


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2.2.5.1 Thrombocytopenia 
A total of 36 patients (49%) in the All treated population, and 20 patients (57%) in Part 2 
have experienced thrombocytopenia/platelet count decreased.  GSK2857916 may cause 
transient worsening of thrombocytopenia in some patients, but in most cases these events 
are resolved during between dosing intervals.  In the Part 2 MM population, two serious 
bleeding events were reported: intracranial hemorrhage in a patient with a history of an 
intracranial bleeding and in the setting of disease progression, and hematuria in a patient 
with a large bladder mass in the setting of progressive disease.   
2.2.5.1 Corneal Events  
Corneal AEs have been observed with various ADC drugs and represent the most 
commonly reported types of AEs associated with GSK2857916.  As there is no single 
term which appropriately captures these events, the term ‘corneal events’ includes 
reported preferred terms describing events associated with the corneal toxicity related to 
GSK2857916.  The most commonly reported corneal events include vision blurred, dry 
eye, photophobia, and lacrimation increased.  A total of 42 patients (58%) in the all 
treated population, and 22 patients (63%) in Part 2 have experienced corneal events 
which were predominantly low grade.   
In Part 2, there were three patients with ≥ Grade 3 corneal events: one with Grade 3 
keratitis resulting in a delay and a dose reduction, one with Grade 3 eye pain resulting in 
a delay; and one Grade 3 dry eye resulting in a dose delay.  In Part 2, there were no 
serious corneal events and no patients permanently discontinued study treatment due to a 
corneal event.   
In Part 1, there was one SAE of Grade 3 limbal stem cell deficiency (in a patient at the 
1.92 mg/kg dose) that was characterized by blurred vision and dry eyes.  The events 
resolved after treatment was discontinued, and the patient’s vision returned to baseline.  
Another patient in Part 1 (4.6 mg/kg) discontinued treatment due to the feeling of a 
foreign object in the eye (Grade 2).   
In addition to the AEs describing corneal events, 89% of patients in Part 2 had corneal 
findings upon examination.  These findings were generally characterized by a superficial 
punctate keratopathy/keratitis, which was often associated with epithelial (microcystic) 
edema and occasional stromal edema or opacities.  Visual acuity declined during 
treatment in most patients experiencing these clinical findings, but improved on average 
to near baseline in patients completing end of study treatment visits (n=13).  Eleven of 
these 13 patients (84.6%) had corneal clinical signs at the end of study treatment visit, 
with most cases (9/11 or 81.8%) considered as having “mild” changes. 
Reason for change: Updated language based on updated information from First Time in 
Human study.  
15. Section 2.2.5.1. Pharmacokinetics 
The pharmacokinetics of belantamab mafodotin (antibody-drug conjugate, including the 
complex), total antibody (including the complex), and cys-mcMMAF were investigated 


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in 70 subjects participants after IV administration at doses of 0.03 to 4.60 mg/kg in a 
preliminary analysis of BMA117159 (data as of 26 June 2017).  Maximum 
concentrations of belantamab mafodotin and total antibody were observed at or shortly 
after the end of infusion (EOI), whereas maximum cys-mcMMAF concentrations peaked 
approximately 24 hours after dosing.  There was limited accumulation of belantamab 
mafodotin or cys-mcMMAF during subsequent cycles. [GlaxoSmithKline Document 
Number 2013N175128 06]. 
The pharmacokinetics of belantamab mafodotin were linear over the range of doses 
tested, with exposure of all analytes increasing proportionately with increasing dose and 
were well-described in a preliminary population PK analysis using conventional 
allometry.  On a molar basis, plasma concentrations of cys-mcMMAF were <1% of 
belantamab mafodotin.  Total plasma clearance of belantamab mafodotin was 0.37 L/day, 
and the mean steady-state volume of distribution was 4.2L.  The model-predicted 
terminal phase elimination half-life of belantamab mafodotin was 8.2 days (95% CI: 6.4 
to 10.1), in keeping with the loglinear model estimate (8.7 days). 
Reason for change: Updated language based on updated information from First Time in 
Human study.  
16.  Section 2.4 Assessment of Nonclinical Data for Belantamab Mafodotin when Co-
Administered with Pembrolizumab 
… In addition, the starting dose of belantamab mafodotin GSK2857916 in this 
combination regimen has been selected to be 1 dose level below a dose that has been 
shown to be well tolerated during the belantamab mafodotin GSK2857916 monotherapy 
dose escalation. The determination of the starting dose is based on an assumption that it is 
approximately 25% less than the declared safe dose of GSK2857916 and should provide 
a sufficient safety margin when pembrolizumab is added at 200 mg. In addition, close 
clinical monitoring will be implemented. 
Reason for change: Updated language to simplify the dose reduction wording based on 
dose level.  
17. Section 4.2.3.2 Completion of Dose Escalation and the Recommended Phase 2 
Dose (RP2D)  
The dose escalation will complete when RP2D is determined. A dose level at or below 
the pre-specified max dose of 3.4 mg/kg may be selected as RP2D in combination with 
the fixed dose of 200 mg pembrolizumab.  All available data from Part 1 will be 
analyzed. The totality of the dData considered for RP2D selection will includinge, but not 
be limited to, safety, available PK profile, and observed signs of clinical activity will be 
considered for the RP2D selection of belantamab mafodotin to be admistered in 
combination with pembrolizumab. If necessary, alternative doses and schedules can be 
explored to determine additional clinically active regimens. … 
Reason for change: Revision of language to allow flexibility and revision of subject 
numbers. Consolidation of language.  


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18. Section 4.6.1 Risk assessment 
There is a risk of overlapping toxicities with the combitnation of belantamab mafodotin 
and pembrolizumab. Potential overlapping toxoicities and risk mitigation plans are 
provided in Table 2. The frequency and intensity of these assessments will allow 
Investigators and GSK to identify and to react to potential worsening of toxicities.  


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Table 2 
Risk Assessment and Mitigation Strategy 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential overlapping toxicities for Investigational Product (belantamab mafodotin in combination with pembrolizumabGSK2857916) 
Changes on Ocular 
Corneal examination 
events with 
belantamab mafodotin 
Eye disorders 
associated with 
pembrolizumab 
Belantamab mafodotin: Changes in corneal epithelium on ocular 
examination have been frequently observed with belantamab mafodotin. 
This was most commonly associated with: blurred vision, dry eyes, 
photophobia, and changes in visual acuity.  
Pembrolizumab: Eye disorders including dry eye, uveitis, and rarely 
Vogt-Koyanagi-Harada syndrome have been reported with 
pembrolizumab. 
Reversible corneal toxicity has been observed with various antibody 
drug conjugates (specific corneal changes with ADCs conjugated to 
MMAF). 
Corneal related AEs (blurred vision, dry / watery eyes, decreased visual 
acuity, photophobia) are among the most common AEs associated with 
GSK2857916 in the clinic.  The majority of events have been non
serious and transient, some requiring dose delays and/or reductions.  
Time to recovery is variable and in some instances the resolution may 
take several weeks. 
Active monitoring for corneal events according to Table 4.  
 
Prophylactic use of steroid eye drops as outlined in Section 
6.12.3 and Appendix 9. 
 
Timely evaluation and management by an ophthalmologist 
(or an optometrist if an ophthalmologist is not available) eye 
care professional upon developing corneal related events 
(see Section 6.5.1 and Appendix 9).  
 
Recommendations for dose delays / reductions are provided 
in Section 6.5.1.   
 
Infusion related 
reaction 
Belantamab mafodotin: IRRs were reported in patients treated with 
belantamab mafodotin. Most IRRs observed to date were Grade 1 to 2 
and manageable with medical treatment. 
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 
Subjects will be closely monitored for signs of IRR. 
Premedication prior to first infusion of belantamab 
mafodotinGSK2857916 is not mandatory but may be 
considered based on investigator judgement.  
If an IRRinfusion related reaction occurs during belantamab 
mafodotin administration,  of GSK2857916 the management 
may follow guidance in Table 4 or local standard of care. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
infusion and generally resolve completely within 24 hours of completion 
of infusion. 
The majority of IRRs observed in the clinic without any premedication to 
date have been G1 2 and non serious; however, there have also been 
serious IRRs. Overall, subjects who experienced an IRR during the 
initial infusion were pre medicated prior to subsequent infusions and 
IRRs did not recur. 
Management of pembrolizumab infusion reactions is 
provided in Table 6. 

Thrombocytopenia
Belantamab mafodotin: Thrombocytopenic events of all grades (1-4) 
are among the most common AEs associated with belantamab 
mafodotin.  
 
Pembrolizumab: Thrombocytopenia has been reported with 
pembrolizumab therapy. 
GSK2857916 in the clinic. The majority have been non serious.  There 
has been no clinically significant bleeding reported in association with 
the thrombocytopenic events. 
Hematological panels are assessed frequently. Supportive 
therapy (including transfusions) is provided according to 
standard medical practice, and dose reductions or treatment 
discontinuations are outlined in Section 6.5. 
Neutropenia
Belantamab mafodotin: Neutropenic events, including febrile 
neutropenia have been observed with treatment with belantamab 
mafodotin,  
In a study of belantamab mafodotin in combination with lenalidomide/ 
dexamethasone, two fatal cases of severe infections associated with 
neutropenia have been observed.    
 
Pembrolizumab: Neutropenia has been reported with pembrolizumab 
therapy. 
Non serious and serious neutropenia has been observed in the clinic 
with GSK2857916.  There have been no events of febrile neutropenia 
reported to date. 
Hematological panels are  assessed frequently.  
Consider prophylactic antibiotics, per physician discreation 
and local institutional guidance, in subjects with Grade 3-4 
neutropenia 
 even if afebrile.  
Immediately hospitalize subjects with febrile neutropenia 
and initiation appropriate management, per local institutional 
guidance.  
Consider additional supportive treatment(s) per local 
practice (e.g., therapy (growth factors).  
CCI


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, antibiotics, and active treatment of infections) is provided 
according to standard medical practice, and dDose 
reductions or treatment discontinuations are outlined in 
Section 6.5  
Potential for 
cardiotoxicity related 
to an inflammatory 
response with 
belantamab mafodotin 
Cardiac disorders 
associated with 
pembrolizumab 
Belantamab mafodotin: Nonclinical studies, predominantly in monkey, 
increased activation of macrophages was noted in a number of organs 
at ≥3 mg/kg/week, reflective of a systemic inflammatory response.  
Minimal inflammatory changes (inflammatory cell infiltrate and/or 
haemorrhage) were also noted in hearts (atrial epicardium, ventricle 
endocardium) of single monkeys, which were nonadverse and 
reversible. 
Incidence of cardiac events reported to date with belantamab mafodotin 
was relatively low and mostly grade 1-2.  
 
Pembrolizumab: Cardiac disorders including pericarditis, pericardial 
effusion, and myocarditis, have been reported with pembrolizumab 
therapy. 
Preclinical inflammatory findings were seen in the rat mandibular and 
mesenteric lymph nodes, brachial/sciatic nerves, epididymides, lung, 
thymus, and atrial epicardium. In the monkey, microscopic effects in 
spleen and bone marrow at ≥3 mg/kg/week were reflective of a systemic 
inflammatory response. Electrocardiograms (ECG) were monitored in 
monkeys for up to 24 hours following repeat dosing and did not produce 
any evidence of test article induced electrocardiographic waveform 
abnormalities, arrhythmias or QTc changes. Serum cardiac troponin I 
was also measured in the rat and monkey 3 week studies and no 
treatment related effects were observed. 
Subjects with significant cardiac risk factors will be excluded 
from study participoation.  
Close monitoring of vital signs and ECG, troponin, and 
ECHO will be performed. 
Treatment as medically indicated. Monitoring of other 
cardiac parameters as clinically indicated.  
Dose modifications for myocarditis with pembrolizumab are 
provided in Table 5. 
 


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This potential risk was based on the described preclinical findings, 
however to date, there is no evidence of systemic inflammatory 
response or cardiotoxicity in the clinic 
Laboratory 
abnormalities  
Reports of non serious myalgia and asymptomatic elevations in LDH / 
CK levels have been observed in the clinic. 
Monitoring of LDH, and CK will be performed.   
Hepatotoxicity 
Belantamab mafodotin: In nonclinical studies liver is a target organ for 
toxicity, with increased liver weights and/or raised hepatobiliary enzymes 
and transaminases observed I both rat and monkey. These changes in 
the liver were without clinical consequence in the shorter duration 
studies and in the rat 13-week study. In the monkey 13-week study, 
progression of liver toxicity to include minimal multifocal hepatocellular 
necrosis was observed at all doses administered (≥3 mg/kg/week).  
Mild elevations of liver enzymes have been reported in some patients 
treated with belantamab mafodotin. 
 
Pembrolizumab: Hepatitis has been reported with pembrolizumab 
treatment. 
Non clinical safety experiments demonstrated increased liver weight and 
elevated liver enzymes in rats. Elevations in liver enzymes and 
increased mitotic figures in Kupffer cells were observed in monkeys. All 
of these changes were dose dependent and reversible.  
Non serious elevations in ALT, AST have been observed in the clinic. 
Only subjects with well-preserved liver function per the 
inclusion/exclusion criteria will be allowed on study.  
 
Subjects with Hepatitis B (HBV) and C will be excluded.  
 
from the trialLiver function tests will be frequently monitored. 
in all subjects on study and iIn case of liver abnormalities, 
management will be implemented according to clinical 
practice. Subjects that meet liver stopping criteria (Section 
5.4.1.1) will be withdrawn from the study. 
Nephrotoxicity 
 
Belantamab mafodotin: Non-clinical safety studies have demonstrated 
dose dependent and reversible primary glomerular injury and tubular 
degeneration (in rat and monkey), accompanied by large molecular 
proteinuria (albuminuria) and enzymuria. Single cell necrosis of the 
kidney and bladder urothelium was also noted in the 13-week monkey 
study. Severe tubular degeneration/regeneration and marked 
glomerulonephritis exacerbated by immune complex disease, likely 
Only subjects with well preserved kidney function will be 
allowed on study.  During the study sSubjects will be 
monitored for kidney function by assessing creatinine, 
eGFR, electrolytes, and albumin/creatinine rations (spot 
urine). protein excretion in 24 hr urine collection and albumin 
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associated with ADA, led to the early euthanasia of one monkey 
following 5 weekly doses of 10 mg/kg.  
No significant renal findings were reported from study BMA117159. 
 
Pembrolizumab: Renal disorders, including nephritis and acute kidney 
injury, have been reported with pembrolizumab treatment. 
Non clinical safety experiments have demonstrated primary glomerular 
injury and tubular degeneration (in rat and monkey). The morphologic 
changes were accompanied by large molecular proteinuria 
(albuminuria). The renal changes were dose dependent and reversible. 
No kidney failure has been reported in the clinic to date.  
Subjects will be educated about the need of maintaining 
adequate urinary output.  
 
Management will be implemented according to clinical 
practice.  
 
Dose reductions and treatment stopping criteria will be 
applied according to Section 6.5. 
 
Dose modifications for nephritis and renal dysfunction with 
pembrolizumab are provided in Table 5. 
Pulmonary toxicity 
(pneumonitis) 
 
Belantamab mafodotin: Nonclinical safety experiments have 
demonstrated the presence of progressive microscopic changes in the 
lungs (prominent alveolar macrophages associated with eosinophilic 
material; mixed perivascular/neutrophilic inflammation) in rats at all 
doses tested.   
To date no significant pulmonary toxicity has been reported in clinical 
trials. 
Pembrolizumab: Pneumonitis has been reported with pembrolizumab 
treatment. 
Preliminary non clinical safety experiments have demonstrated the 
presence of microscopic changes in the lungs (prominent alveolar 
macrophages associated with flocculent eosinophilic material; mixed 
perivascular inflammation) in rats at all doses tested. As of to date no 
pulmonary toxicity / cases of pneumonitis have been observed in the 
clinic. 
Monitoring for clinical signs and symptoms potentially 
related to pulmonary toxicity.  Further diagnostic tests and 
management will be implemented immediately according to 
recommendations provided in Section 6.5.1. 
Dose modifications for pembrolizumab are provided in Table 
5. 


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Immunosuppression 
 
In non clinical studies GSK2857916 has been associated with decrease 
in immunoglobulins in monkeys.  An increase in immunoglobulins was 
seen in rats (rats are not an antigen specific species for GSK2857916). 
 
Immunoglobulin levels will be assessed throughout the 
study. Active monitoring for infections, especially 
opportunistic infections will be performed. Subjects will 
receive immediate treatment according to standard practice. 
Potential for Other 
Laboratory 
abnormalities  
Belantamab mafodotin: An increased magnitude of AST relative to 
ALT consistent with increased skeletal troponin I was observed in the 
single dose monkey study. Increased skeletal troponin I and/or creatine 
kinase and aldolase was observed in the rat 3-week study.  
 
Cases of elevated aspartate aminotransferase (AST), lactic 
dehydrogenase (LDH) and creatine kinase (CK) alone or concomitant 
with no clear clinical correlate have been observed in clinical studies. 
 
Pembrolizumab: AST and ALT increase have been reported with 
pembrolizumab treatment. 
Laboratory parameters will be monitored as outlined in 
Section 7.  
 
Subjects with significant laboratory elevations (≥x3 ULN) 
should, where possible, have a sample sent to central 
testing of CK and LDH isoenzyme levels.  
 
Dose modifications for pembrolizumab ALT and AST 
elevations are provided in Table 5.   
Embryo-Fetal Toxicity 
Belantamab mafodotin: Nonclinical reproductive studies with 
belantamab mafodotin have not been conducted. Embryo-fetal toxicity is 
expected due to the cytotoxic component, cys-mcMMAF via nonspecific 
uptake and/or BCMA-mediated toxicity (due to reports of BCMA 
expression in human placental cells [Langat et al, 2008]). 
Use of belantamab mafodotin in pregnant women may cause fetal harm. 
 
Pembrolizumab: Animal reproduction studies have not been conducted 
with pembrolizumab; however, in murine models of pregnancy blockade 
of PD-L1 signaling has been shown to disrupt tolerance to the foetus 
and to result in an increased fetal loss. These results indicate a potential 
risk, based on its mechanism of action, that administration of 
pembrolizumab during pregnancy could cause fetal harm, including 
increased rates of abortion or stillbirth. 
See Contraception requirements in Section 6.11.1. 
 
Risks Related to Belantamab mafodotin not listed under potential overlapping toxicities 




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information, with additional changes based on agency feedback.   
19. Section 4.6.3. Overall Benefit:Risk Conclusion 
Although there is limited human experience with belantamab mafodotinGSK2857916, 
and no clinical experience with the combination of belantamab mafodotinGSK2857916 
with pembrolizumab, given the currently available safety data and the low likelihood of 
drug-drug interactions between belantamab mafodotinGSK2857916 and pembrolizumab, 
combination therapy may have an acceptable safety profile. Additionally, the 
combination , and may provide anti-tumor effect in subjects with MM; but this is 
unknown.   
Of note, excess deaths were noted with pembrolizumab in combination with lenalidomide 
and dexamethasone (Keynote-185) or in combination with pomalidomide and 
dexamethasone (Keynote-183) leading the FDA to suspend these phase 3 trials, in 
addition to other trials of anti-PD[L] therapies in combination with IMmiDs in myeloma 
or non- Hodgkin’s lymphoma were suspended . Please refer to Section 2.3.3 for 
additional information. This statement does not apply to patients taking KEYTRUDA 
(pembrolizumab) for an approved indication.  The safety and efficacy of using 
KEYTRUDA (pembrolizumab) for approved, on-label uses have been proven. 
(https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm). Considering the measures 
taken and, described in Section 7, to minimize risk to subjects, the potential risks 
associated with belantamab mafodotinGSK2857916 in combination with pembrolizumab 
noted in Section 4.6.1 are justified by the anticipated benefits that may be afforded to 
subjects with MM. 
Reason for change: Clarification of language. 
20. Section 5.1 Inclusion Criteria 
Note related to adequate organ function table:  
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria. In situations where laboratory results are outside the permitted range, 
the investigator may retest the subject and the subsequent within range screening result 
may be used to confirm eligibility. If laboratory results were obtained more than 72 hours 
before first dose, laboratory results must be redone within 72 hours prior to first dose to 
confirm eligibility. 
Reason for change: Clarification of requirement of safety laboratory samples.   
21. Section 5.4.1.6. Valvular Toxicity Stopping Criteria 
• If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
participant subject should permanently discontinue study treatment GSK2857916 and 
GSK3174998.  The valve should continue to be monitored via ECHO every 4 weeks 
for 16 weeks or until resolution. 


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22. Corneal Toxicity Stopping Criteria 
…If subject is allowed to continue on study, the dose of belantamab 
mafodotinGSK2857916 will be reduced by 1 dose level.at least 25%. ... 
Reason for change: Revised language for simplification of belantamab mafodotin dose 
reduction wording.  
23. Section 5.5.1. Subject completion 
For Part 1: A subject is considered to have completed the study if the subject is treated 
through the DLT determinative period or has a DLT during the DLT determinative 
period, i.e., a completed subject is one who is evaluable for the determination of DLT 
rate. 
For Part 1 and Part 2, a subject is considered to have completed the study if they received 
at least 1 cycle of combination study treatment, and:  
• 
The subject is followed until death, or  
• 
The subject is followed until the end of study 
 
Reason for change: Clarification of completer status to ensure one definition of 
completer.  
24. Section 6.1 Investigational Products 
Product name: 
Belantamab 
MafodotinGSK2857916 
Pembrolizumab 
Route of Administration  
Delivered as IV infusion over at 
least 30 minutes Infusions may be 
prolong in the event of an infusion 
reaction. If subjects experience 
clinically significant infusion 
reactions, the infusion rate may be 
slowed for all future administrations 
of study treatment(s) for each 
participant. Should a global change 
in infusion rate be required, it will be 
communicated to sites in writing. . 
Refer to SRM for details.  
 
Delivered as 30 min IV infusion 
Reason for change: Additions of administration language based on agency feedback.   
 
 


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25. Section 6.3.1.2. Pembrolizumab administration 
… All subjects are required to remain under observation at the study site for at least three 
hours post-infusion of the last study drug administered for the first two study treatment 
dosing visits. At subsequent study treatment dosing visits, for subjects who experience 
infusion-related reactions, the post-infusion observation time should remain as at least 
three hours; for subjects who do not experience infusion reactions, these subjects should 
remain under observation for a time period not shorter than one hour at least one hour (or 
longer as per the judgement of the investigator or as per institutional guidelines.) … 
Reason for change: Revision of observation timing  language. 
26. Section 6.5 Subject Specific Dose Adjustment Criteria 
Subjects should have their dose (including the first dose and subsequent doses) delayed 
or reduced for toxicities according to the recommendations as listed in Table 4. Dose 
reductions are only allowed for belantamab mafodotinGSK2857916. The rule of 25% or 
50% dose reduction always refers to the original assigned dose. 


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Table 4 
Dose Modification Guidelines for Belantamab MafodotinGSK2857916 Related Adverse Events 
Toxicity 
Grade 
Recommendations to belantamab mafodotinGSK2857916 
Recommendations to 
pembrolizumab 
Serum creatinine elevation or 
decrease in eGFR which cannot 
be explained by concomitant 
sepsis, TLS, other severe 
infection with fever or dehydration 
 If absolute serum 
creatinine increase 
from baseline of >0. 
5 mg/dL 
• Repeat serum creatinine within 48 hours  
• If confirmed: withhold therapy, institute treatment and monitoring 
as clinically indicated, and follow for resolution 
• Discuss any further dosing with Medical Monitora 
See Table 5 for guidance on 
pembrolizumab 
Serum creatinine>Grade 3 (acute 
kidney injury) 
 
>+4.0mg/dL  
 Or >3.0x baseline 
or hospitalization 
indicated>3.0mg/dL 
from baseline 
 Or 3.0-6.0xULN  
• 
Provide appropriate medical treatment. 
• Provide appropriate medical treatment. 
• Permanently discontinue treatment with belantamab mafodotin 
GSK2857916 
Resume treatment with 
pembrolizumab only if 
treatment with belantamab 
mafodotin GSK2857916 may 
be continued 
Spot urine (albumin / creatinine 
ratios) 
>2000 mg/g  
(or 224 mg/mmol) 
• Re-test (at least 7 days apart). 
• If not confirmed, continue belantamab mafodotin GSK2857916at 
current 100% dose 
• If confirmed on re-test and no clear evidence of disease 
progressionc 
o Interrupt treatment with belantamab mafodotin GSK2857916 
o Repeat testing within 4 weeks 
o If spot urine <2000 mg/g (224/mg/mmol) may restart 
belantamab mafodotin GSK2857916with one 25% 
dose level reduction 
o If spot urine remains >2000 mg/g (224/mg/mmol) 
after 4weeks; permanently discontinue belantamab 
mafodotin GSK2857916and discontinue withdraw 
subject from study treatment; provide treatment as 
clinically indicated and follow for resolution 
Resume treatment with 
pembrolizumab only if 
treatment with belantamab 
mafodotin GSK2857916 may 
be continued 
 


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Toxicity 
Grade 
Recommendations to belantamab mafodotinGSK2857916 
Recommendations to 
pembrolizumab 
Thrombocytopenia  
(on days of dosing)  
Thrombocytopenia 
(On days of dosing) 
3-4 
x
Withhold treatment until thrombocytopenia recovered to 
Grade 2 or less (≤G2). 
x
If Grade 3-4 thrombocytopenia is considered disease-related, 
treatment may be continued with dose reduction and more 
frequent hematology monitoring, until recovery to Grade 2 or 
less. 
x
Implement supportive treatment (e.g. transfusion) as clinically 
indicated and per local practice.No bleeding: continue 
treatment with 25% dose reduction. Consider reversing to 
previous dose once thrombocytopenia recovered to G2, or 
less. 
NoneDelay treatment until 
the next belantamab 
mafodotin dose 
x
With bleeding: withhold the dose, continue treatment after recovery 
with 25% dose reduction 
Delay treatment until the next 
GSK2857916 dose 
4 
x
Withhold the dose. Consider restarting with 25% dose reduction if 
recovered to dG3 only if there is no active bleeding at time of 
treatment re start 
Delay treatment until the next 
GSK2857916 dose 
x
If thrombocytopenia is considered disease related, is not 
accompanied by bleeding, and recovers with transfusion to >25 
x109/L continuing treatment at 25 50% dose reduction may be 
considered after discussion with the GSK Medical Monitor 
Delay treatment until the next 
GSK2857916 dose 
Febrile neutropenia 
3-4 
x
Withhold belantamab mafodotin GSK2857916 and pembrolizumab 
and hospitalize participantsubject with appropriate management, 
per local institutional guidance 
x
Consider additional supportive treatment per local guidance (e.g., 
Implement treatment with antibiotics, antivirals and antifungals, as 
clinically indicated, consider growth factors) 
x
Upon recovery, consider a dose reduction of belantamab 
mafodotin, if neutropenia was drug related 
x
Delay treatment until the 
next belantamab 
mafodotin dose 
CCI


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Toxicity 
Grade 
Recommendations to belantamab mafodotinGSK2857916 
Recommendations to 
pembrolizumab 
Neutropenia 
≥3 
 
 
x
If noted on Day 1 of any cycle, withhold belantamab mafodotin. 
Repeat hematology (CBC) as clinically indicated until recovery to 
Grade 2 or less.  
x
Resume belantamab mafodotin at pre-hold dose once neutropenia 
recovers to Grade ≤2 
 on Day 1 of the 
subsequent cycle. 
x
Implement supportive care as clinically indicated per local practice 
x
Delay treatment until the 
next belantamab 
mafodotin dose 
In case of 
recurrence of 
frequent episodes of 
neutropenia <1.0 × 
109 /L 
x
Consider dose reduction of belantamab mafodotin, if it was drug-
related. 
x
Delay treatment until the 
next belantamab 
mafodotin dose 
Belantamab 
mafodotinGSK2857916 
Treatment Related Corneal 
eventsb 
Corneal 
Management Care 
Regardless of Grade 
Steroid Eye Drops:  
x
If symptoms occur within the 7 day steroid eye drop prophylaxis window, increase the 
frequency to 1 drop every 2 4 hours (6 12 times daily) and continue until symptom resolution. 
x
If symptoms occur after the 7 day prophylaxis window is complete, re start ocular steroid 
drops at 4x daily until symptom resolution.   
Preservative-free artificial tears:   
x
Increase to 1 drop as frequently as every 2 hours, as needed 
Grade 1 per GSK 
Scale 
x
Continue treatment with current dose treatment with of belantamab 
mafodotin GSK2857916 
x
None 
Grade 2 per GSK 
Scale 
x
If Grade 2 finding (visual acuity and/or exam finding) and the 
participant is asymptomatic, continue dosing with belantamab 
mafodotin.  
x
If Grade 2 finding (visual acuity and/or exam findings) and the 
patient is symptomatic.  
o DOSE REDUCE and continue treatment.   
o If already on 1.92 mg/kg, participant may continue at current 
dose.   
x
Hold/Delay treatment 
until the next 
belantamab mafodotin 
GSK2857916 dose 
CCI
CCI


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Toxicity 
Grade 
Recommendations to belantamab mafodotinGSK2857916 
Recommendations to 
pembrolizumab 
o Upon improvement of either visual acuity or ophthalmic exam 
findings to ≤Grade 1 and improvement in symptoms, dose 
may be re-escalated to previous dose.  If either ophthalmic 
exam finding or visual acuity findings are Grade 1, continue 
dosing with GSK2857916 at current dose 
• 
If visual acuity and exam findings are both Grade 2, HOLD 
GSK2857916 
• 
Upon improvement of either visual acuity or ophthalmic exam 
findings to Grade 1 or baseline, resume with current dose 
Grade 3 per GSK 
Scale  
• 
If Grade 3 finding (exam finding) and the participant is 
asymptomatic: continue dosing with belantamab mafodotin. 
 
• 
If Grade 3 exam finding and the participant is symptomatic or 
Grade 3 visual acuity: 
o HOLD belantamab mafodotin . Upon improvement of either 
visual acuity or ophthalmic exam findings to ≤ Grade 2 and 
improvement in symptoms continue treatment with dose 
REDUCTION. 
o If already on 1.92 mg/kg participant may continue at current 
dose  
o If after event resolution eye symptoms are considered stable 
for at least 3 cycles consider re-escalation to previous 
dose.Hold GSK2857916 
• 
Upon improvement of either visual acuity or ophthalmic exam 
findings to Grade 1 or baseline, resume with 25% dose 
reduction (for subjects receive 1.92 mg/kg dose, continue at 
1.92 mg/kg) 
• 
In case of recurring ≥Grade 3 events, consult GSK Medical 
Monitor 
• 
Hold/Delay treatment 
until the next 
belantamab mafodotin 
GSK2857916 dose 


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Toxicity 
Grade 
Recommendations to belantamab mafodotinGSK2857916 
Recommendations to 
pembrolizumab 
Grade 4 per GSK 
Scale  
• 
Hold treatment with belantamab mafodotin. 
• 
Treatment re-start may be possible after discussion and 
agreement between the treating ophthalmologist*, treating 
physician, the GSK Medical Monitor  
• 
*or optometrist, if an ophthalmologist is not availableStop 
treatment with GSK2857916 
• 
Additional topical treatment may be prescribed, as recommended 
by ophthalmologist 
• 
Treatment re start may be possible after discussion and 
agreement between ophthalmologist (or optometrist if an 
ophthalmologist is not available), treating physician, GSK Medical 
Monitor and possibly a GSK ophthalmologist  
• 
Stop treatment with 
pembrolizumab.   
• 
Further treatment only 
possible if belantamab 
mafodotin 
GSK2857916is allowed 
to restart  
Infusion Reactionc 
2 
Stop the infusion, provide medical treatment and continue at slower 
pace after resolution to Grade 0-1 
See Table 6 for guidance on 
pembrolizumab 
 
 
3 
Further treatment with belantamab mafodotin GSK2857916needs to be 
discussed with Medical Monitor. Continuation only allowed after 
recovery to Grade 1 and with pre-medication, and extension of 
infusion time to 2-4 hours. Any future infusion needs to be pre-
medicated 
4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Continue when toxicity resolves to Grade 0-1 
See Table 5 for guidance on 
pembrolizumab  
Grade 3-4 
Permanently discontinue 
Permanently discontinue 
a. 
Medical Monitor may consult GSK's nephrotoxicity panel about plans to continue therapy 
b. 
Corneal toxicity should be graded according to GSK scale for belantamab mafodotinGSK2857916 treatment related Corneal Events (Appendix 9). 
c. 
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 
 


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AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-related response. 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 one 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 6. 
Table 5 
Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
General instructions: 
1. Severe and life-threatening irAEs, should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment 
should begin if the irAEs are not controlled by corticosteroids. 
2. Pembrolizumab must be permanently discontinued if AE does not resolve or the corticosteroid dose is ≤10 mg/day within 12 weeks of the 
last pembrolizumab treatment. 
3. The corticosteroid taper should begin when the  initiated upon irAE improving to is ≤Grade 1 and continue at least 4 weeks. or less and 
continue to taper over at least 4 weeks. 
4. If For situations where pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤Grade 1 after can be 
resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been taper. 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.  
5. 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. 
 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
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 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
• 
Monitor subjects for signs and symptoms of 
pneumonitis 
• 
Evaluate subjects with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic antibiotics for opportunistic 
infections 
Recurrent Grade 2, 
Grade 3 or 4, or 
recurrent grade 2 
Permanently 
discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor subjects 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). 
• 
Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis.  
• 
Subjects 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. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased Bilirubin 
Grade 21 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/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 32 or 43  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold4 
• Initiate insulin replacement therapy 
for subjects with T1DM  
• Administer anti-hyperglycemic in 
subjects with hyperglycemia  
 
• 
Monitor subjects 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 
discontinue4  
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, 3, 4 
Continue  
• Initiate thyroid replacement 
hormones (e.g. levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis; grading 
according to 
increased 
creatinine or acute 
kidney injury and 
renal dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or equivalent) 
followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
 
Grade 1 or 2 
Withhold  
• Based on severity of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Grade 3 or 4 
Permanently 
discontinue 
All Other immune-
related AEs 
Intolerable/ 
Persistent Grade 2 
Withhold 
• Based on severity of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event5.  Events that 
require 
discontinuation 
include and not 
limited to:  Gullain
Barre Syndrome, 
encephalitis 
Recurrent Grade 4 
or recurrent Grade 
4  
Permanently 
discontinue 
NOTES:  
1. 
AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0   5.0 x baseline, if baseline abnormal; bilirubin:>1.5   3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline 
abnormal  
2. 
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0   20.0 x baseline, if baseline abnormal; bilirubin:>3.0   10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if 
baseline abnormal 
3. 
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
4. 
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  If control achieved or For subjects with 
Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2, 
pembrolizumab may be resumed.   and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
5. 
Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 


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Table 6 
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NSAIDS 
Reason for change: Revision of language and Tables based on update to guidelines for 
belantamab mafodotin and Merck standard language.  
27. Section 6.7.2. Pembrolizumab 
Administration 
Pembrolizumab infusion solution should be intravenously administered over 30 minutes 
through an intravenous line containing a sterile, non-pryogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter. However, given the variability of infusion 
pumps from site to site, a window between -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes -5 min/+10 min). 
Reason for change: Revision of language for consistency with other pembrolizumab 
wording in protocol.   
28. Section 6.11.2 Subjects with Contact Lenses 
Contact lenses are prohibited while on the study treatment (from first dosing to the end of 
study treatment). Contact lens use may be restarted after the ophthalmologist (or an 
optometrist if an ophthalmologist is not available) confirms there are no other 
contraindications.  
Use of bandage contact lenses is permitted during study treatment as directed by the 
treating ophthalmologist (or optometrist if an ophthalmologist is not available). 
Reason for change: Elaboration of the timing and type of contact lens use.  
29. Section 6.12.3. Supportive Care Guidelines for Corneal Events 
Subjects will be assessed by ophthalmologists (or optometrist, if an ophthalmologist is 
not available) at baseline, and then every three weeks prior to each dose of belantamab 
mafodotin for the first 4 doses. After the 4th dose of belantamab mafodotin, Iif there are 
is no significant ocular symptoms or vision changes in vision and no corneal signs 
consistent with toxicity at time of the cycle 4 exam, subjects may have their the 
frequency of ophthalmologic exams may be decreased to once every 63 months until end 
of study treatment.  In case of persistent or newly developed ocular symptoms or vision 
changes, the If a participant subject subsequently develops a change in visual acuity or 
other ocular symptoms, the subject should be evaluated will have further ophthalmologic 


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method throughout the study as was done at baseline (i.e. if CT/PET scan was used as 
baseline, subject needs to be followed by CT/PET scans).  Selected target lesion needs to 
be measured and followed over time. For sites in Germany, only MRI is allowed as 
imaging modality 
14. 
FISH testing at least for: t(4;14), t(14;16), amp (1q), del(1p) and 17p13del. FISH 
results from samples taken within 60 days prior to first dose are acceptable. 
15. 
Samples from within 28 days prior to first dose are acceptable. . A portion of the 
aspirate collected for disease assessment will be used for biomarker research (BM 
aspirate clot is preferred for BCMA analysis), for FISH testing, and MRD testing. MRD 
testing will be performed by a central lab. 
16. 
Archival samples are acceptable; however, they should not replace fresh BM 
biopsies/aspirates … 
Table 8 Time and Events Table: Part 1 and Part 2 – On Study Assessments 
Completed Independent of Dosing 
Clinical chemistry (with corrected calcium)  
Urinalysise Dipstick 
BM aspirate for MRD testing bone marrow aspirate 
Footnotes: 
1. 
All assessments will apply to Part 1 and 2 unless stated otherwise. Assessments 
scheduled on days of dosing should be done prior to drug administration, unless 
otherwise specified.  Assessments for C1D8 can be performed up to +3 days of the 
scheduled date. All assessments from Cycle 2 can be performed +/-3 days prior to theof 
the scheduled date unless otherwise specified. 
3. 
AEs/SAEs will be collected assessed from first study dose up to 45 days post the 
last dose.  All related SAEs are to be collected from consent through OS follow-up. 
AEs/SAEs will be followed until the event is resolved, stabilized, otherwise explained or 
subject is lost to follow up. 
5. 
On-study ocular exams to be performed up to 5 days before scheduled study dose 
by an ophthalmologist (or an optometrist if an ophthalmologist is not available) every 
three weeks prior to each dose of belantamab mafodotin for the first 4 doses.  See Section 
7.3.5 for list of ophthalmic exam procedures. After the 4th dose of belantamab 
mafodotin, If there areis  no significant ocular symptoms or change in vision changes, the 
frequency of and no corneal signs consistent with toxicity at time of the cycle 4 exam, 
subjects may have their ophthalmologic exams may be decreased to once every 63 
months until end of study treatment. In case of persistent or newly developed ocular 
symptoms or vision changes, the Additional exams may be performed by the eye care 
professional, as clinically indicated.   If a subject subsequently develops a change in 






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SOI pembrolizumab dose, at EOI pembrolizumab, and at 2.5 h and 7 h post 
pembrolizumab SOI in addition to the time points listed above. 
 
9. 
Pre-dose belantamab mafodotin (within 30 min prior to SOI) at GSK2857916 C1 
Day1 (week 1), C2, C5 and every 3 cycles thereafter (i.e., C8, C11,..) until EOT for both 
belantamab mafodotin and pembrolizumab ADA samples. If belantamab mafodotin is 
administered but pembrolizumab is planned to be held during any of the above Cycle 
timepoints, pre-dose pembrolizumab ADA should still be collected. 
10. 
Serum sBCMA samples will be collected each cycle at pre-dose (within 30 
minutes prior to SOI),  and at each PK timepoint in Cycle 1.  at every time a PK sample is 
collected, as indicated in Section 7.4.1., and at every MRD assessment timepoint. 
11. 
Collect a cytokine/chemokine serum sample duringat C1D1 at pre-dose (within 30 
minutes prior to SOI belantamab mafodotin), EOI of pembrolizumab (within 30 minutes 
after EOI±5 min) (even when infusion is interrupted or halted), 4 h after belantamab 
mafodotinGSK2857916 SOI, 9 h OR 24 h after belantamab mafodotinGSK2857916 SOI 
(±1 h), according to the subject’s preference; and at C1D8 (+3 days, on same day as PK 
sample collection) and pre-dose belantamab mafodotin (within 30 min prior to SOI) at 
C2D1 and C5D1.   
12. 
Collect pre-dose belantamab mafodotin (within 30 min prior to SOI) at C1D1, at 
every 12 weeks thereafter (pre-dose belantamab mafodotin), and at every MRD 
assessment timepoint. 
13. 
Collect pre-dose belantamab mafodotin (within 30 min prior to SOI) at C1D1, 
C1D8 (+3 days, on same day as PK sample collection), and pre-dose belantamab 
mafodotin (within 30 min prior to SOI) at C2D1 and C5D1. 
14. 
Collect during C1D1 at pre-dose (within 30 minutes prior to SOI belantamab 
mafodotin), EOI of pembrolizumab (within 30 minutes after EOI) (even when infusion is 
interrupted or halted), 4 h after belantamab mafodotin SOI, 24 h after belantamab 
mafodotin SOI (±1 h); at C1D8 (+3 days, on same day as PK sample collection), and one 
pre-dose belantamab mafodotin (within 30 min prior to SOI) at C2D1 and C5D1. 
17. 
Corneal management information:  
- Prophylaxis with steroid eye drops (such as prednisolone phosphate 1% or 
dexamethasone 0.1%) 1 drop QID starting from 1 day prior to infusion and continuing for 
a total of 7 consecutive days.  If dosing delayed for a non corneal event, the prophylactic 
steroid drops can be stopped. 
-  Prophylactic preservative-free artificial tears must be administered in each eye at least 
4-8 times daily beginning on Cycle 1 Day 1 until end of treatment. 
-  At the start of each infusion, subjects may apply cooling eye masks to their eyes for 
approximately 1 hour as long as tolerated.   
 


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Abbreviations: 
PBMC = peripheral blood mononuclear cell 
Table 10 Time and Events Table: Part 1 and Part 2 – End of Treatment and Follow-
up Assessments 
Clinical chemistry (with corrected calcium)  
Urinalysis e Dipstick 
BM aspirate for MRD testing bone marrow aspirate  
Footnotes: 
5. 
AE/SAEs will be collectedassessed up to 45 days post the last dose. SAEs will be 
assessed up to 90 days post last dose, or 45 days post last dose if the subject initiates a 
new anticancer therapy (whichever is shorter), All related SAEs are to be collected from 
first dose through OS follow-up. AEs/SAEs will be followed until the event is resolved, 
stabilized, otherwise explained or subject is lost to follow up. 
9. 
Final pregnancy test (serum or urine) must be performed in women of 
childbearing potential 80 days (±7 days) after last study treatmen Final pregnancy test 
(serum or urine) must be performed in women of childbearing potential at the EOT Visit. 
Follow up pregnancy assessment by telephone (for WOCBP only) should be performed 9 
months after the last dose of belantamab mafodotin.  
22. 
MRD assessment to be performed by a central lab at the time of first achieving 
VGPR or CR, repeat testing at 6 and 12 months after achieving VGPR or CR (provided 
VGPR/CR is maintained). Additional samples to be collected for biomarker research are 
encouraged, as part of the same BM draw. .MRD testing will be performed by a central 
lab. 
24. 
Bone marrow aspirate sample to be collected at EOT. BM aspirate clot is 
preferred for BCMA analysis and immune cell characterization/profiling. 
26. 
Exit Interview should to be performed within approximately 21 days of last dose 
of study treatment end of treatment visit.  
Reason for change: Revision of assessments and/or footnotes for reasons which include 
revision, adding clarity, new assessments, and correction of errors in previous notes.   


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32. Section 7.1 Screening and Critical Baseline Assessments 
• … Imaging studies CT, MRI or PET-CT (for subjects with extramedullary diseasefor 
MM).. 
Reason for change: Clarify baseline imaging requirements.  
33. Section 7.3.1.1. Time Period and Frequency of Detecting AEs and SAEs 
… All SAEs will be collected from the time the first dose of study treatment is 
administered until 90 days following cessation of treatment, or 45 days following 
cessation of study treatment if the subject initiates new anticancer therapy, whichever is 
earlier. In addition, any SAE assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy), study treatment or 
GSK concomitant medication must be recorded from the time a subject consents to 
participate in the study up to and including any follow-up contact.  All SAEs will be 
reported to GSK within 24 hours, as indicated in Section 7.3.1.77.3.1.6. … 
Reason for change: Update of the GSK safety standard language.  
34. Section 7.3.2 Pregnancy (similar changes also apply to Section 12.8. Appendix 8:  
Contraceptive Guidance and Collection of Pregnancy Information Definitions) 
… Subjects with positive pregnancy test result must be excluded from the study.  
Subjects with negative pregnancy test result must agree to use an effective contraception 
method as described below during the study and for 9 monthsuntil 120 days following the 
last dose of study treatment. 
Details of all pregnancies in female participants will be collected after the start of study 
treatment and for 9 months following last dose of belantamab mafodotin. 
Details of all pregnancies for female partners of male participants will be collected after 
the start of study treatment and 6 months following last dose of belantamab mafodotin. 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until approximately 120 days. 
If a pregnancy is reported, the investigator must inform GSK within 24 hours of learning 
of the pregnancy and must follow the procedures outlined in Appendix 8. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at the end of relevant systemic exposure plus an additional 30 days (9 months after the 
last dose of belantamab mafodotin) and correspond with the time frame for female 
subject contraception in Section 5.1. … 
Reason for change: Update to the pregnancy language for belantamab mafodotin.  


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35. Section 7.3.5. Ocular Examinations and Procedures 
Study sites must establish a close collaboration with an ophthalmologist (or an 
optometrist if an ophthalmologist is not available) who will be responsible for assessing 
subjects while they are on study and managing subjects who develop treatment-related 
changes in vision associated with belantamab mafodotin. Management of subjects with 
treatment-related changes in vision must be performed in close communication with the 
GSK Medical Monitor and the coordinating ophthalmologist (or an optometrist if an 
ophthalmologist is not available). 
Subjects will be assessed by eye care specialist (ophthalmologist, or an optometrist if an 
ophthalmologist is not available) at screening/baseline.  
A full screening/baseline ophthalmic examination for all subjects must include for both 
eyes (OU): 
1. 
Best corrected visual acuity. 
2. 
Documentation of manifest refraction and the method used to obtain best 
corrected visual acuity. 
3. 
Current glasses prescription (if applicable). 
4. 
Selected anterior segment (slit lamp) examination with focus on the cornea and 
lens, including fluorescein staining of the cornea  
5. 
Intraocular pressure measurement.  
6. 
Dilated funduscopic exam 
 
The on treatment and follow-up ophthalmic exam should be performed for both eyes 
(OU) as described below and in the Time and Events Tables (Section 7):  
1. 
Best corrected visual acuity. 
2. 
Documentation of manifest refraction and the method used to obtain best 
corrected visual acuity. 
3. 
Selected anterior segment (slit lamp) examination with focus on the cornea and 
lens, including fluorescein staining of the cornea and lens. 
4. 
Intraocular pressure measurement (if clinically indicated) 
5. 
Dilated funduscopic exam (if clinically indicated) 
 
A full screening/baseline ophthalmic examination for all subjects must include for both 
eyes (OU): 
1. 
Best corrected visual acuity 
2. 
Documentation of manifest refraction used to obtain best corrected visual acuity 
3. 
Current glasses prescription (if applicable) 
4. 
Pupillary light reflex 
Extraocular muscle movements (graded from one to four with (+) sign indicating over 
action, ( ) sign indicating under action and 0 representing normal movements 
5. 
Intraocular pressure measurement & time checked 
6. 
Full anterior segment (slit lamp) examination including fluorescein staining of the 
cornea. : 
• 
Anterior segment exam (slit lamp) includes: orbit/lids/adnexa, conjunctiva, sclera, 
cornea,  anterior chamber, iris, lens and anterior vitreous,  
7. 
Anterior segment photography of a fluorescein stained cornea 


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8. 
Dilated funduscopic exam: fundus photography with interpretation 
The on treatment and follow up ophthalmic exam should be performed for both eyes 
(OU) must include everything except: dilated funduscopic/ fundus photography, anterior 
segment photography, and extraocular muscle movements (all of which must be 
performed as clinically indicated) and current glasses prescription (if applicable).  The 
last follow up visit should also include anterior segment photography of a fluorescein 
stained cornea. Representative images will be collected and stored centrally. 
Reason for change: Upon review of 205678 (DREAMM 2) clinical trial ocular data, it 
was determined that ocular changes in patients treated with belantamab mafodotin are 
largely limited to the corneal epithelium and therefore data collection in clinical trial will 
be focused on corneal changes.   
36. Section 7.3.7. Vital Signs 
Removal of the following statement from both First and Subsequent Infusion:  
Subjects may be discharged after the infusion has been completed if considered clinically 
stable and all other study procedures have been completed.   
Reason for change: Statements contradicted another location which provided more 
detailed post infusion observation time frames.  
37. Section 7.3.8. Electrocardiogram 
… For triplicate ECGs, 3 individual ECG tracings should be obtained as closely as 
possible in succession, but no more than 2 minutes apart. The full set of triplicate ECGs 
should be completed in 4 minutes or less. 
Reason for change: Removal of requirement to provide more flexibility in completion of 
triplicate ECGs.  
38. Section 7.3.10. Clinical Safety Laboratory Assessments 
… Asymptomatic elevations of lactate dehydrogenase (LDH) and creatine kinase (CK) 
and AST have been observed in study BMA117159. Subjects with significant elevations 
(≥x3 ULN) should, where possible, have a sample sent for central testing of CK and LDH 
isoenzyme levels… 
Table 11 List of Clinical Laboratory Tests 
… Corrected calcium with albumin … 
…LDH and CK isoenzymes4… with footnote: Subjects with significant elevations (≥x3 
ULN) and performed by central laboratory 
… Reticulocyte Count 


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Added peripheral blood mononuclear cell and whole blood RNA samples 
Reason for change: One assessment deleted based on study team decision, and others 
added for additional efficacy and safety assessments.   
 
 
39. Section 7.4.1. Blood Sample collection for Pharmacokinetics 
Blood samples for pharmacokinetic (PK) analysis of belantamab mafodotinGSK2857916 
(ADC and total monoclonal antibody [mAb]), cys-mcMMAF and corresponding blood 
samples for sBCMA as well as and pembrolizumab will be collected at the time points 
indicated in Table 12.Time and Events Table (Table 9 and Table 10). The actual date and 
time of each blood sample collection will be recorded.  The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring and need to be accompanied by a corresponding sBCMA sample. Note 
that sBCMA samples will also be collected independent from PK samples, as described 
in the Time and Events table. Samples for pembrolizumab will be collected and stored. 
Pembrolizumab PK samples will only be analysed if clinical observations warrant it (e.g. 
to rule out or confirm suspicion of DDI). 
Blood samples for pharmacokinetic (PK) analysis of belantamab mafodotinGSK2857916 
(ADC and total mAb), cys mcMMAF, and for potential PK analysis for pembrolizumab 
will be collected at the time points indicated in the Time and Events Table (Table 9).  
Each PK sample should be collected as close as possible to the planned time relative to 
the dose (i.e., time zero) administered to the subject on PK days.  The actual date and 
time of each blood sample collection will be recorded. 
Table 1219 
Pharmacokinetic and sBCMA blood sampling times 
Cycle Day 
Sampling Times 
Belantamab 
Mafodotin 
sBCMA 
Pembrolizumab 
Sampling window 
C1D1 
Pre-dose 
belantamab 
mafodotin 
X 
X 
 
Within 30 minutes 
prior to start of 
infusion 
EOI belantamab 
mafodotin  
X 
X 
 
Within 30 min after 
EOI 
Pre-dose 
Pembrolizumab1 
 
 
P 
Within 30 minutes 
prior to start of 
infusion 
EOI Pembrolizumab1 
 
 
P 
Within 30 min after 
EOI 
2 hr SOI 
belantamab 
mafodotin 
X 
X 
 
15 min 
24 hr SOI 
belantamab 
mafodotin 
X 
X 
 
1 hr 
C1D4 
Any time 
X 
X 
 
1 day 


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C1D8 
Any time 
X 
X 
 
+3 days 
C2D1 & C5D1 
Pre-dose 
belantamab 
mafodotin 
X 
X 
 
Within 30 minutes 
prior to start of 
infusion 
EOI belantamab 
mafodotin 
X 
X 
 
Within 30 min after 
EOI 
Pre-dose 
Pembrolizumab1 
 
 
P 
Within 30 minutes 
prior to start of 
infusion 
EOI Pembrolizumab1 
 
 
P 
Within 30 min after 
EOI 
C8D1 & 
C11D1 
Pre-dose 
belantamab 
mafodotin 
X 
X 
X 
Within 30 minutes 
prior to start of 
infusion 
EOI belantamab 
mafodotin 
X 
X 
 
Within 30 min after 
EOI 
C14D1 and 
every 3 cycles 
thereafter 
(i.e., C17, 20, 
until EOT) 
Pre-dose 
belantamab 
mafodotin 
X 
X 
X 
Within 30 minutes 
prior to start of 
infusion 
End of 
Treatment 
 
X 
X 
X 
 
EOI = end of the infusion; SOI = start of the infusion, EOT = end of treatment;  
X = time relative to belantamab mafodotin dose; P = time relative to pembrolizumab dose 
1. 
To be obtained pre- and post- first dose of pembrolizumab irrespective of any dose delay 
Reason for change: Introduced a table for collection of PK and sBCMA samples based 
on feedback to provide clarity.  
40. Section 7.5.1. sBCMA Analysis 
To measure any changes in the levels of soluble BCMA (sBCMA) concentration during 
the study, serum will be collected to measure concentrations of sBCMA at the time points 
specified in the Time and Events Tables (refer to Table 9 and Table 10) and per PK Table 
12. 
Reason for change: Revised wording and linked sampling information to PK Table due 
to collection of sBCMA samples at all PK timepoints.   
41. Section 7.5.3., Subject Stratification/Predictive Biomarkers 
… Though the majority of MM subjects express BCMA, the intensity of expression 
varies. To evaluate whether BCMA expression has utility in patient stratification, BCMA 
protein expression will be measured by IHC in malignant plasma cells at baseline, and 
other timepoints if available, will be measured for BCMA expression by IHC and will be 
correlated with clinical outcomes and potentially other biomarker or disease assessments. 
Because BCMA can also be detected in circulation, the soluble form (sBCMA) has the 
potential to serve as a surrogate markerfor of BCMA at the cell surface.BCMA marker. 
This study will correlate subjects sBCMA levels with BCMA cell surface expression and 
clinical response…. 


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… The timing of the collections may be adjusted on the basis of emerging data from this 
study or other new information, in order to ensure optimal evaluation of the 
pharmacodynamic and/or biomarker endpoints.  Novel or emerging candidate biomarkers 
associated and subsequently discovered biomarkers ofwith the biological response 
associated withto advanced multiple myeloma, hematological malignancies and/or 
medically related conditions, as well as the biological and clinical responses to 
belantamab mafodotinGSK2857916 in combination with pembrolizumab, may also be 
evaluated.  These analyses may include but are not be limited to: 
• 
Tumor/bone marrow BCMA receptor expression by IHC and/or by RNA 
analyses.     
• 
Soluble factors, including circulating cfDNA, bloodanalysis and derivatives 
including cytokine/chemokine analysis of serum 
• 
Immune cell characterization and/or profiling of peripheral blood and/or bone 
marrow aspirate samples by protein and/or RNA analyses 
• 
Additional soluble marker measurements tothat include serum levels of sBCMA  
• 
RNA/DNA/gene and/or protein analysis of tumor tissue/bone marrow aspirates or 
samples in circulation 
 
Reason for change: Revised based on additions and changes related to immune cell 
characterization/profiling plans. 
42. Section 7.5.4., Tumor Biomarker Analysis 
… BCMA expression in the plasma cells offrom bone marrow aspirates or trephines will 
be evaluated at baseline, and other timepoints if available, by IHCfor tumor cell 
expression of BCMA. Analysis of the immune context (immune cell characterization) of 
the bone marrow aspirate samples may also be performed to analyse the tumor 
microenvironment…. 
Reason for change: Revisions based on update to biomarker sampling plan.  
43. Section 7.7.3. Exit Interview 
…. The Exit Interview shouldwill be scheduled to be completed within approximately 21 
days of the last dose of study treatment end of treatment visitfor all available subjects.   
Reason for change: Provide flexibility.  
44. Section 9.4.1. Analysis Populations 
… DLT Evaluable Population: will consist of subjects fulfilling the ‘All Treated’ 
population criteria during part 1 (Dose Escalation) and are followed up for a 21-day 
period or withdrawn within 21 days due to an AE meeting the definition of a DLT as 
defined in Section 4.2.3.1. … 
Reason for change: Addition of new population to be analyzed.  
45. Section 10.6. Study and Site Closure 


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…GSK may also close study sites which fail to recruit subjects within a predefined 
timeframe, as defined within the SRM. 
Reason for change: Alignment with updated GSK protocol template.   
46. Appendix 9: Belantamab mafodotin associated Corneal Event Severity Grading 
and Mitigation Strategy 
In order to minimize the corneal toxicity, subjects must receive steroid eye drops as 
prophylaxis (such as: prednisolone phosphate 1%, or dexamethasone 0.1%) 1 drop QID 
starting 1 day prior to each GSK2857916 infusion, and continuing for a total of 
consecutive 7 days.  Other equivalent eye drops may be considered after confirming with 
GSK.  Omission or discontinuation of prophylactic steroid eye drops may be allowed 
under certain circumstances (e.g., in the setting of intolerability, contraindication, or 
toxicity secondary to steroid eye drops) upon discussion with the Medical Monitor. … 
… An ophthalmology (or optometrist, if an ophthalmologist is not available) consult is 
required for all subjects who develop signs or symptoms of corneal toxicity.. or require 
steroid eye drops for more than 7 days. … 
Prophylactic 
Measurea 
Dose and Administration 
Timing 
Steroid eye dropsb 
Prednisolone phosphate 1%, or 
dexamethasone 0.1%, or 
equivalent, 1 drop QID  
Begin 1 day prior to each dose of 
belantamab mafodotinGSK2857916 
infusion, and continuing for a total of 
consecutive 7 days 
Preservative-free 
artificial tears 
Administer in each eye at least 
4-8 times daily 
Administer daily beginning on Cycle 1 
Day 1 until EOT.  Allow 5 10 minutes 
between administration of artificial tears 
and steroid eye drops 
b. 
Omission or discontinuation of prophylactic steroid eye drops may be allowed 
under certain circumstances (e.g., in the setting of intolerability, contraindication, or 
toxicity secondary to steroid eye drops) upon discussion with the Medical Monitor 
Reason for change: After review of data from the primary analyses in study 205678 
(DREAMM 2), there is no evidence that steroid eye drops were beneficial in preventing 
or mitigating corneal events. As a result, corticosteroid eye drops are no longer required 
in belantamab mafodotin clinical trials but can be used if clinically indicated per 
discretion of an eye-care specialist.   
 


Signature Page for  205207 TMF-14344600 v2.0
Signature Page for TMF-14344600 v2.0
Reason for signing: Approved
Name: Timothy Crossman
Role: Approver
Date of signature: 21-Feb-2022 17:46:12 GMT+0000

SAP_001.pdf: 


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CONFIDENTIAL 
 
 
205207 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
1.1. 
RAP Amendments ........................................................................................ 8 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ................................................ 10 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan .......................... 10 
2.2. 
Study Objective(s) and Endpoint(s)............................................................. 10 
2.3. 
Study Design .............................................................................................. 13 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 14 
2.4.1. 
Part 1: Dose Escalation Phase .................................................... 14 
2.4.2. 
Part 2: Expansion Cohort ............................................................. 14 
3. 
PLANNED ANALYSES .......................................................................................... 15 
3.1. 
Interim Analyses ......................................................................................... 15 
3.1.1. 
Part 1: Dose Escalation Phase .................................................... 15 
3.1.2. 
Part 2 Dose Expansion Phase ..................................................... 16 
3.2. 
Primary and Final Analyses ........................................................................ 19 
4. 
ANALYSIS POPULATIONS ................................................................................... 19 
4.1. 
Protocol Deviations ..................................................................................... 20 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 21 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 21 
5.2. 
Baseline Definitions .................................................................................... 22 
5.3. 
Examination of Covariates, Other Strata and Subgroups ............................ 22 
5.3.1. 
Examination of Subgroups ........................................................... 22 
5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 23 
6. 
STUDY POPULATION ANALYSES ....................................................................... 24 
6.1. 
Overview of Planned Study Population Analyses ........................................ 24 
6.2. 
Disposition of Subjects ................................................................................ 24 
6.3. 
Demographic and Baseline Characteristics ................................................. 25 
6.4. 
Treatment Compliance ................................................................................ 25 
6.4.1. 
Extent of Exposure ...................................................................... 25 
6.5. 
Concomitant Medications ............................................................................ 26 
6.6. 
Subsequent Anti-Cancer Therapies ............................................................ 27 
7. 
EFFICACY ANALYSES .......................................................................................... 28 
7.1. 
Part 1: Dose Escalation .............................................................................. 28 
7.1.1. 
Secondary Efficacy Analyses ....................................................... 28 
7.1.2. 
Exploratory Efficacy Analyses ...................................................... 33 
7.2. 
Part 2: Dose Expansion .............................................................................. 34 
7.2.1. 
Primary Efficacy Analyses ........................................................... 34 
7.2.2. 
Secondary Efficacy Analyses ....................................................... 35 
7.2.3. 
Exploratory Efficacy Analyses ...................................................... 42 
7.3. 
Other Efficacy Analyses .............................................................................. 43 
7.3.1. 
Endpoint / Variables ..................................................................... 43 


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7.3.2. 
Summary Measure ...................................................................... 43 
7.3.3. 
Population of Interest ................................................................... 43 
8. 
SAFETY ANALYSES ............................................................................................. 44 
8.1. 
Adverse Events Analyses ........................................................................... 44 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 45 
8.2.1. 
Belantamab Mafodotin ................................................................. 45 
8.2.2. 
Pembrolizumab ............................................................................ 47 
8.3. 
Deaths and Serious Adverse Events ........................................................... 47 
8.4. 
Adverse Events Leading to Discontinuation of Study Treatments 
and Other Significant Adverse Events ......................................................... 48 
8.4.1. 
Immune-Related Adverse Events Leading to 
Discontinuation of Study Treatments and Other Significant 
Adverse Events............................................................................ 48 
8.5. 
Ocular Findings from Ophthalmic Exam (Part 2) ......................................... 49 
8.6. 
Pregnancies ................................................................................................ 50 
8.7. 
Clinical Laboratory Analyses ....................................................................... 50 
8.7.1. 
Analyses of Liver Function Tests ................................................. 51 
8.8. 
Other Safety Analyses ................................................................................ 52 
8.8.1. 
Performance Status ..................................................................... 52 
8.8.2. 
ECG ............................................................................................. 52 
8.8.3. 
LVEF ........................................................................................... 53 
8.8.4. 
Immunogenicity Analyses ............................................................ 53 
8.8.5. 
Profile Plot ................................................................................... 54 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 55 
9.1. 
Drug Concentration Measures .................................................................... 55 
9.2. 
Derived Pharmacokinetic Parameters ......................................................... 55 
9.3. 
Summary Measure ..................................................................................... 56 
9.4. 
Population of Interest .................................................................................. 56 
9.5. 
Statistical Analyses / Methods .................................................................... 56 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 57 
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 58 
12. BIOMARKER ANALYSES ...................................................................................... 59 
12.1. 
Data processing .......................................................................................... 59 
12.2. 
Visualization and Tables ............................................................................. 59 
12.2.1. 
Exploratory Objective: To evaluate PD markers in MM 
after treatment with belantamab mafodotin in combination 
with pembrolizumab. .................................................................... 59 
13. PATIENT REPORTED OUTCOMES ANALYSES .................................................. 61 
13.1. 
Patient-Reported Outcome Version of the Common Term Criteria 
for Adverse Events (PRO-CTCAE) ............................................................. 61 
13.2. 
Visual Function Questionnaires .................................................................. 62 
13.2.1. 
National Eye Institute Visual Function Questionnaire-25 
(NEI-VFQ-25) .............................................................................. 62 
13.2.2. 
Ocular Surface Disease Index ..................................................... 62 
13.3. 
Value Evidence and Outcome (Part 2 only) ................................................ 63 


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13.3.1. 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 30-item Core module 
(EORTC QLQ-C30) ..................................................................... 63 
13.3.2. 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 20-item Multiple 
Myeloma module (EORTC QLQ-MY20) ....................................... 64 
13.4. 
Compliance of OSDI, EORTC QLQ-C30, and EORTC-QLQ-MY20............. 64 
14. ADDITIONAL ANALYSES DUE TO THE COVID-19 PANDEMIC ........................... 65 
14.1. 
Study Population ......................................................................................... 65 
14.1.1. 
Subject Disposition ...................................................................... 65 
14.1.2. 
Protocol Deviations ...................................................................... 65 
14.1.3. 
Additional Displays for Participants with a COVID-19 
Infection ....................................................................................... 65 
14.2. 
Safety ......................................................................................................... 66 
14.2.1. 
Assessment of COVID-19 AEs .................................................... 66 
15. REFERENCES ....................................................................................................... 67 
16. APPENDICES ........................................................................................................ 69 
16.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 69 
16.2. 
Appendix 2: Schedule of Activities .............................................................. 70 
16.2.1. 
Protocol Defined Schedule of Events ........................................... 70 
16.3. 
Appendix 3: Assessment Windows ............................................................. 71 
16.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 72 
16.4.1. 
Study Phases .............................................................................. 72 
16.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 73 
16.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 74 
16.5.1. 
Reporting Process ....................................................................... 74 
16.5.2. 
Reporting Standards .................................................................... 74 
16.5.3. 
Reporting Standards for Pharmacokinetic .................................... 75 
16.6. 
Appendix 6: Derived and Transformed Data ............................................... 76 
16.6.1. 
General ........................................................................................ 76 
16.6.2. 
Study Population .......................................................................... 77 
16.6.3. 
Efficacy ........................................................................................ 78 
16.6.4. 
Safety .......................................................................................... 78 
16.6.5. 
Patient Reported Outcomes ......................................................... 79 
16.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 86 
16.7.1. 
Premature Withdrawals ................................................................ 86 
16.7.2. 
Handling of Missing Data ............................................................. 86 
16.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 90 
16.8.1. 
ECG Parameters and Vital Signs ................................................. 90 
16.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 91 
16.9.1. 
Population Pharmacokinetic (PopPK) Methodology ..................... 91 
16.10. Appendix 10: Abbreviations & Trade Marks ................................................ 93 
16.10.1. Abbreviations ............................................................................... 93 
16.10.2. Trademarks ................................................................................. 96 
16.11. Appendix 11: List of Data Displays.............................................................. 97 
16.11.1. Data Display Numbering .............................................................. 97 
16.11.2. Mock Example Shell Referencing ................................................ 97 


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16.11.3. Deliverables ................................................................................. 97 
16.11.4. Study Population Tables .............................................................. 98 
16.11.5. Efficacy Tables .......................................................................... 112 
16.11.6. Efficacy Figures ......................................................................... 117 
16.11.7. Safety Tables ............................................................................. 119 
16.11.8. Safety Figures ........................................................................... 161 
16.11.9. Pharmacokinetic Tables ............................................................. 164 
16.11.10. Pharmacokinetic Figures ........................................................... 168 
16.11.11. Biomarker Figures ..................................................................... 169 
16.11.12. Health Outcomes Tables ........................................................... 171 
16.11.13. Health Outcomes Figures .......................................................... 176 
16.11.14. ICH Listings ............................................................................... 183 
16.11.15. Non-ICH Listings ........................................................................ 192 
16.12. Appendix 12: Example Mock Shells for Data Displays .............................. 199 
 


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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 205207.  
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology. 
Revision Chronology: 
2016N273410_00 
11-MAY-2017 
Original 
2016N273410_01 
26-SEP-2018 
Amendment 01 
 
The protocol had been amended to address feedback from 
regulatory agencies. The lowest dose level (1.92 mg/kg) in 
dose escalation phase is removed. To accommodate these 
changes, the statistical model in dose escalation is revised 
from Bayesian Logistic Regression Model to modified mTPI 
and the overall sample size and related analytical methods 
have been changed. Part 2 stopping criteria has been added 
for continuous safety monitoring.  
2016N273410_02 
26-FEB-2020 
Amendment 02 
 
The protocol had been amended to address feedback from 
regulatory agencies, inclusions of items noted in protocol 
clarification letters, revisions due to discrepancies, revision of 
study drug related language and other clarifications. DLT 
evaluable population is included to analysis population to 
further define Part 1 population.  
TMF-12902367 
27-AUG-2021 
Amendment 03 
 
The protocol had been amended to update pembrolizumab 
safety, ECI-overdose language, and standard text based on 
latest IB update for pembrolizumab (2021) and belantamab 
mafodotin (2021). Addition of the primary analysis at 
approximately 15 months follow-up from LSLV. Update on 
planned derived PK parameters and PK/PD analyses, update 
to data monitoring language, medical monitoring information, 
and SAE reporting. 
TMF-14344600 
21-FEB-2022 
Amendment 04 
 
The protocol has been amended to provide updates including 
the addition of the end of study definition Section and 
continued access to study intervention after the end of the 
study Section (Post Analysis Continued Treatment [PACT]). 
Additional contents for risk assessment and mitigation 
strategy and updated PK and PD Section. 
















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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
3.1.1. 
Part 1: Dose Escalation Phase 
During dose escalation, no formal interim analysis will be performed. Data will be 
reviewed through data visualization tool to inform dose escalation decisions. The mTPI 
(modified Toxicity Probability Interval) design will be utilized to guide dose 
escalation/de-escalation decisions which is described in Section 3.1.1.1. 
After the last cohort of patients in Part 1 complete the DLT observation period (21 days), 
a formal interim analysis will be performed to support the RP2D decision, except for 
scenarios where RP2D is clearly defined by the toxicity profile. Data considered to 
support RP2D decision will include but not limited to safety, available PK profile and 
observed signs of clinical activity. Details of the planned displays for RP2D are provided 
in a separate RAP. 
3.1.1.1. 
Description of the Modified Toxicity Probability Interval 
The mTPI design assumes the true underlying toxicity rate for maximum tolerated dose 
(MTD) of belantamab mafodotin falls within the range from 25% to 35% and centered at 
30%.  The monitoring rules for guiding dose escalations are provided in Table 1.  
Columns provide the numbers of subjects treated at the current dose level, and rows 
provide the corresponding numbers of subjects experiencing toxicity.  The entries of the 
table are dose-finding decisions (i.e., E, S, and D) representing escalating the dose, 
staying at the same dose, and de-escalating the dose.  In addition, decision U means that 
the current dose level is unacceptable because of high toxicity; the current dose level and 
any higher dose level should be excluded from the trial.  For example, when one of three 
subject’s experiences toxicity, the decision can be located at row 1 and column 3, which 
is S – to stay at the current dose level.  Consequently, the next cohort of subjects will be 
treated at the same dose level currently being used.  If 0 of 3 subjects experiences 
toxicity, the decision is at row 0 and column 3, which is E – to escalate.  Thus, the next 
cohort of subjects will be treated at the next-higher dose level.  If three of three subjects 
experiences toxicity, the decision is DU – to de-escalate to the next-lower dose level, and 
exclude the current dose and any higher dose from the trial, because the high toxicity 
level is unacceptable. In dose escalation (E)/de-escalation (D), no dose skipping is 
allowed. 
Table 1 
Dose-Escalation Monitoring Rules for Part 1 Using the mTPI Method 
Number of TDLTs 
Number of Patients treated at current dose 
1 
2 
3 
4 
5 
6 
0 
E 
E 
E 
E 
E 
E 
1 
D 
S 
S 
S 
S 
E 
2 
DU 
D 
S 
S 
S 
3 
DU 
DU 
D 
S 
4 
 
 
 
DU 
DU 
DU 
5 
DU 
DU 
6 
DU 


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The Table was generated based on a beta/binomial model and precalculated before trial initiation.  
The letters in different colors are computed based on the decision rules under the mTPI method 
and represent different dose-finding actions.  In addition to actions de-escalate the dose (D), stay 
at the same dose (S), and escalate the dose (E), the Table includes action unacceptable toxicity 
(DU), which is defined as the execution of the dose-exclusion rule in mTPI.  Excerpted from Ji et 
al [Ji, 2010] 
3.1.1.2. 
Displays To Be Created For Dose Escalation Review By Request 
Review of preliminary data will be performed after completion of each dosing cohort in 
Part 1. Preliminary safety and study population data may include, if requested, a 
demographic characteristics summary, exposure of study drugs summary, adverse event 
(AE) summary by systems organ class (SOC) and preferred term (PT) and maximum 
grade, AE related to study treatment summary by maximum grade, AEs leading to dose 
modification by PT summary, serious adverse events (SAE) summary by SOC and PT, 
and listing of laboratory assessments with NCI-CTCAE Grade 3 and 4. Spreadsheets 
containing study data will be supplied by the study data manager. 
Dose escalation/de-escalation decisions will take into account all available 
safety and tolerability data. The decisions will be informed by the mTPI approach and 
will occur following review of these data and joint discussion by the GSK Study Team 
and investigators. The details of the planned displays, if requested, are provided in 
Appendix 11: List of Data Displays. 
3.1.2. 
Part 2 Dose Expansion Phase 
Continuous safety monitoring will be conducted for the expansion cohort starting from 
when 5 subjects are dosed. The observed number of treatment-related Grade 4 or higher 
AEs will be compared against the safety stopping rule in Table 2 . Enrollment may stop if 
the safety stopping rule is met based on totality of safety data. For example, if there are 3 
events out of 5 dosed subjects, enrollment may stop after review of all safety data; if 
there is 2 or fewer events out of 5 dosed subjects, enrollment will continue. Operating 
characteristics for the safety stopping rule are provided in Figure 1. The iSRC will review 
and may implement Part 2 safety stopping rules, if pre-specified criteria are met. Details 
of the planned analyses for the iSRC data review meetings, including subject 
demographic, subject disposition, AE and SAE data, are documented in a separate RAP. 
Table 2 
Safety Stopping Rules for the Expansion Cohort 
Number of dosed subjects 
Stop if treatment related Grade 4 or higher 
AEs larger or equal to this this number 
5 
3 
6-10 
4 
11-14 
5 
15-19 
6 
20-25 
7 
26-28 
8 


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Figure 1 
Operating Characteristics of Safety Stopping Rule for Expansion 
Cohort 
 
Interim analyses for ORR will start when at least 10 subjects are evaluable as defined in 
Section 4. Subjects who initially received RP2D in Part 1 may also be included. The 
observed number of subjects with unconfirmed response of PR or better will be compared 
with the stopping boundary in Table 3. Enrolment may stop if the stopping rule is met. 
Final decision will be based on the totality of data. For example, if there are 2 
unconfirmed responses out of 10 evaluable subjects, enrolment may stop after review of 
all available data; if there are 3 or more unconfirmed responses out of 10 evaluable 
subjects, enrolment will continue. More details of the operating characteristics for futility 
analysis are provided in Section 3.1.2.1. 
3.1.2.1. 
Operating Characteristics of the Stopping Rules for Futility 
The futility stopping rule in Table 3 is based on the methodology of Lee et al. [Lee, 
2008]. The optimal design has a maximum sample size of 28 and a type I error rate of 
0.10 and power of 80.6%. The expansion cohort may be stopped early for futility if the 
predicted probability of success is less than 1.5%. Under the null hypothesis, if the true 
ORR is 40%, the expected sample size of the design is 20 subjects and probability of 
early termination is 86.1%. Under the alternative hypothesis, if the true ORR is 60%, the 
expected sample size is 28 and the probability of early termination is 15.6%. 


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Table 3 
Decision Making Criteria for Futility Analysis 
Number of 
Evaluable 
Subjects 
This Number of 
Responses to Stop 
Early for Futility 
Probability of 
continuing enrolling 
when ORR=0.4 
Probability of 
continuing enrolling 
when ORR=0.6 
10 
2 
83.3% 
98.8% 
11 
2 
83.3% 
98.8% 
12 
3 
75.5% 
98.1% 
13 
3 
75.5% 
98.1% 
14 
4 
68.6% 
97.5% 
15 
4 
68.6% 
97.5% 
16 
5 
62.3% 
96.9% 
17 
6 
52.9% 
95.7% 
18 
6 
52.9% 
95.7% 
19 
7 
46.7% 
94.9% 
20 
7 
46.7% 
94.9% 
21 
8 
41.6% 
94.2% 
22 
9 
34.6% 
92.8% 
23 
9 
34.6% 
92.8% 
24 
10 
30.2% 
91.9% 
25 
11 
24.4% 
90.2% 
26 
12 
18.8% 
87.7% 
27 
13 
13.9% 
84.5% 
28 
14 
0.0% 
0.0% 
 
 














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6.3. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and 
baseline body weight and baseline BMI) will be summarized. Age, height, weight and 
BMI will be summarized using the mean, standard deviation, minimum, median, and 
maximum. The count and percentage will be computed for sex and ethnicity. 
Race and racial combinations will be summarized. 
Disease history and characteristics (e.g. time since initial diagnosis in years, date of initial 
diagnosis) at initial diagnosis and screening will be listed. Separate summaries of disease 
characteristics at initial diagnosis and screening will be provided. Disease characteristics 
at screening, including stage, type of multiple myeloma, myeloma light chain and 
myeloma immunoglobulin, extramedullary disease, lytic bone lesion, renal impairment 
per eGFR, and genetic characteristics (including high cytogenetic risk) will be 
summarized and listed. 
Medical conditions collected at screening will be summarized by past and current 
separately. 
Substance use, including smoking history and alcohol use will be summarized. Smoking 
Pack Years which is calculated as (number of cigarettes smoked per day/20) x number of 
years smoked will be provided. 
Prior anti-cancer therapy will be coded using GSK Drug coding dictionary, then 
summarized by type of therapy and listed. A listing of prior anti-cancer therapy will show 
the relationship between ATC Level 1, Ingredient, and verbatim text. A summary of the 
number of prior anti-cancer therapy regimens will also be produced. 
Prior anti-cancer therapy for multiple myeloma subjects will also be summarized by type 
of therapy, and drug class. A summary of multiple myeloma subjects’ refractory to prior 
anti-cancer therapy by drug class will be provided. 
Anti-cancer radiotherapy will be listed. Prior cancer and non-cancer related surgeries will 
be summarized. Prior and on treatment cancer and non-cancer related surgeries will be 
listed. 
6.4. 
Treatment Compliance 
Summaries of study treatment exposure and dose modifications (e.g., number of dose 
reductions, number of dose interruptions) will further characterize compliance. These 
analyses are described in Section 6.4.1 ‘Extent of Exposure’. 
6.4.1. 
Extent of Exposure 
Extent of exposure to belantamab mafodotin and pembrolizumab will be summarized and 
listed separately for each component. 


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The number of cycles administered to study treatment will be summarised with mean, 
median, standard deviation, minimum, and maximum.  
Dose delivered per cycle (mg/kg/cycle) will be summarized using mean, median, 
standard deviation, minimum, and maximum by cycle and overall.  
• the dose intensity for belantamab mafodotin (mg/kg/3 weeks) which is calculated 
as the actual cumulative dose (mg/kg) divided by expected duration of exposure 
in 3 weeks (last infusion date– first infusion date + 21)/21 
• the dose intensity for pembrolizumab (mg/3 weeks), which is calculated as the 
actual cumulative dose (mg) divided by expected duration of exposure in 3 weeks 
(last infusion date– first infusion date + 21)/21 
A by subject summary listing of data on exposure to all study treatments will be 
produced. 
Dose reductions will be summarised by number of reductions and reasons for reductions. 
Infusion interruptions will be summarised by number of interruptions and reasons for 
interruptions. Dose delays will be summarised by number of delays and delay duration 
(days). The number and percentage of the delays for intervals of 1-21, 22-42 and >42 
days will be computed. Primary reasons for dose reductions and infusion interruptions 
will also be summarized by cycle. 
Duration of delays is defined as period from the expected start date of dose to actual start 
date of current dose. Calculation: (actual start date of current dose - expected start date of 
dose). Expected start date of dose = actual start date of previous dose + 21. Because the 
protocol allows a window of  3 days for administration of study treatment after Cycle 1, 
a dose will only be considered delayed if it is 4 or more days after the scheduled dose 
date. 
The summaries of dose modifications will be provided. A plot showing the number and 
percentage of subjects treated at different dose levels over time will be provided. 
The duration of exposure to study treatment (from first day to last day of treatment) will 
be calculated and summarized using mean, median, standard deviation, minimum, and 
maximum. A horizontal bar graph of duration of treatment will be produced that displays 
duration of treatment in months for each subject. 
6.5. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary and 
summarized. The summary of concomitant medications will show the number and 
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient 
products will be summarized by their separate ingredients rather than as a combination of 
ingredients. Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body 
System) information will be included in the dataset created but will not appear on the 
summary. 


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In the summary of concomitant medications, each subject is counted once within each 
unique ingredient. For example, if a subject takes Amoxycillin on two separate occasions, 
the subject is counted only once under the ingredient “Amoxycillin”. In the summary of 
concomitant medications, the ingredients will be summarized by the base only, using 
CMBASECD and CMBASE. Note: In order to be considered a concomitant medication, 
the concomitant medication must have been taken at some point during the on-treatment 
window. 
Blood products or blood supportive care products with onset date within the on-therapy 
window will be included in the summary Tables. The frequency and percentage of 
subjects using blood products and blood supportive care products after the start of study 
medication will be provided. Supporting listings will also be provided. 
6.6. 
Subsequent Anti-Cancer Therapies 
The number and percentage of subjects that received chemotherapy, immunotherapy, 
hormonal therapy, biologic therapy, radioactive therapy, small molecule targeted therapy, 
as post study treatment anti-cancer therapy will be summarized. Time from study 
treatment discontinuation to the first post study treatment anti-cancer therapy will also be 
included in this summary Table, if available. 
Follow-up anti-cancer therapy will be coded using GSK Drug coding dictionary, then 
summarized by ingredient. A listing of the type of follow-up anti-cancer therapy received 
(chemotherapy, immunotherapy, hormonal therapy, biologic therapy, radioactive therapy, 
and small molecule targeted therapy for each subject will be provided). 


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7. 
EFFICACY ANALYSES 
7.1. 
Part 1: Dose Escalation 
7.1.1. 
Secondary Efficacy Analyses 
7.1.1.1. 
Endpoint / Variables 
BOR 
Best Overall Response (BOR) is defined as the best confirmed response (stringent 
Complete Response [sCR] > Complete Response [CR] > Very Good Partial Response 
[VGPR] > Partial Response [PR] > Minimal Response [MR] > Stable Disease [SD] > 
Progressive Disease [PD] > Not Evaluable [NE]) from treatment start date until disease 
progression or initiation of new anti-cancer therapy, whichever is earlier, as assessed by 
the investigator per IMWG (2016). Details on derivation of confirmed response are 
provided in Table 4.  
ORR 
Overall Response Rate (ORR), defined as the percentage of participants with a confirmed 
PR or better as the BOR (i.e., Partial Response [PR], Very Good Partial Response 
[VGPR], Complete Response [CR], and stringent Complete Response [sCR]), as assessed 
by the investigator per IMWG (2016).  
ORR at interim analysis will be analysed based on confirmed responses, if available. 
However, in case a participant has achieved a response of PR or better at data cut, which 
was not confirmed due to the time constraints (too short timeframe for the next 
assessment), but with a potential to be confirmed through subsequent assessments after 
interim, the participant will also be considered as a responder; if the participant dies or 
discontinues study or starts other anti-cancer therapy prior to confirming the response, the 
participant will not be considered as a responder at IA. 
Only the assessments from the start of treatment up to the earlier of confirmed disease 
progression or the start of new anti-cancer therapy will be considered. Only new systemic 
anti-cancer drugs taken are considered as anti-cancer therapy (radiotherapy and surgeries 
are not considered as systemic anti-cancer therapy for the purpose of this analysis). 
Subjects with only assessments of Not Evaluable or missing response will be treated as 
non-responders; i.e. they will be included in the denominator when calculating the 
percentage. 
Details on derivation of confirmed response are provided in Table 4. 


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Table 4 
Derivation of Confirmed Response  
 
Response at the First Time Point 
Response at Subsequent Time Point1 
Confirmed Response at the First Time 
Point 
1 
sCR 
sCR 
sCR 
2 
sCR 
CR 
CR 
3 
CR 
sCR/CR 
4 
sCR/CR 
VGPR 
VGPR 
5 
VGPR 
sCR/CR/VGPR 
6 
sCR/CR/VGPR 
PR 
PR 
7 
PR 
sCR/CR/VGPR/PR 
8 
sCR/CR/VGPR/PR 
MR 
MR 
9 
MR 
sCR/CR/VGPR/PR/MR 
10 
sCR/CR/VGPR/PR/MR 
SD 
SD 
11 
sCR/CR/VGPR/PR/MR 
PD (any reason)  
 
OR 
 
No subsequent disease assessment: subject died or 
discontinued study or started new anti-cancer 
therapy before further adequate disease assessment 
SD 
12 
sCR/CR/VGPR/PR/MR/PD 
(due to reasons other than imaging, i.e., 
plasmacytoma or bone lesion) 
No subsequent disease assessment: subject has not died, 
discontinued from study or (except for PD) started new 
anti-cancer therapy; but as yet has no further adequate 
disease assessments 
Unconfirmed sCR/CR/VGPR/PR/MR/PD 
 
Will be categorized as NE 
for ORR analysis. 
 
For ORR analysis in IA, the UC response 
(PR or better) will be counted as 
responder. 
13 
PD (due to reasons other than imaging, 
i.e., plasmacytoma or bone lesion) 
PD (any reason) including PD after initiation of new 
anti-cancer therapy 
 
OR 
PD 


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Response at the First Time Point 
Response at Subsequent Time Point1 
Confirmed Response at the First Time 
Point 
 
No subsequent disease assessment: subject died due 
to PD before further adequate disease assessment 
(including death due to PD after initiation 
of new anti-cancer therapy) 
14 
PD (due to reasons other than imaging, 
i.e., plasmacytoma or bone lesion) 
sCR/CR/VGPR/PR/MR/SD 
 
OR 
 
No subsequent disease assessment: subject died due to 
reasons other than PD before further adequate disease 
assessment  
 
OR 
 
No subsequent disease assessment: subject 
discontinued study before further adequate disease 
assessment 
NE 
15 
SD 
Any 
 
OR 
No subsequent disease assessment 
SD 
16 
PD due to  
imaging (plasmacytoma or bone lesion) 
Any 
 
OR 
No subsequent disease assessment 
PD 
17 
NE or missing 
Any 
 
OR 
No subsequent disease assessment 
NE 


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1 Subsequent disease assessment is defined as the next adequate (not missing or NE) disease assessment following the first timepoint before (or on the same date of) 
start of new anti-cancer therapy except for confirmation of PD, for which PD or death due to PD after new anti-cancer therapy are considered for confirmation of PD. 
No minimal time interval is required for the subsequent disease assessment but a different sample is required for confirmation. 
2 SD does not need to be confirmed. 
3 PD due to imaging (i.e., plasmacytoma or bone lesion) does not need to be confirmed. 
Where criteria are not mutually exclusive, take the first that applies. 
 


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7.1.1.2. 
Summary Measure 
ORR  
The number and percentage of participants with the BOR in the following response 
categories at timepoint will be summarized: sCR, CR, VGPR, PR, overall response 
(sCR+CR+VGPR+PR), minimal response (MR), stable disease (SD), progressive disease 
(PD), and not evaluable (NE). The corresponding exact 95% CI for ORR will also be 
provided. Participants with unknown or missing responses will be treated as non-
responders, i.e., these participants will be included in the denominator when calculating 
percentages of response. A list of investigator-assessed response at each visit will be 
listed. 
A waterfall plot showing the maximum percent reduction from baseline in Serum M 
protein, or Urine M-protein, or difference between two types Serum FLC [Kappa light 
chain (Kappa LC) and Lambda light chain (Lambda LC)] for each subject will be 
produced using by dose level. The plot will be color-coded for M-protein types and 
Serum FLC, etc. Indication of the best overall response will be provided below the plot. 
Only the assessments from the start of treatment up to the start of new anti-cancer therapy 
will be considered. Only new systemic anti-cancer drugs taken are considered as anti-
cancer cancer therapy (radiotherapy and surgeries are not considered as systemic anti-
cancer therapy for the purpose of this analysis). 
The maximum percent reduction will be plotted in the following hierarchical 
order: 
[1] Plot Serum M-protein maximum percent reduction from baseline if data is   
available; 
[2] If [1] is not feasible, plot Urine M-protein maximum percent reduction from 
baseline if data is available; 
[3] If both [1] and [2] are not feasible, plot maximum percent reduction from 
baseline for difference between two types of Serum FLC if data is available; 
Difference between two types of Serum FLC 
The percent change from baseline for difference between two types of Serum FLC is 
defined as: 
(post-baseline difference-baseline difference) / baseline difference *100% 
To calculate the difference, the “involved” and “non-involved” light chains must be 
determined at first based on the ratio of non-missing values for Serum Kappa LC protein 
and Serum Lambda LC protein at baseline. 
The detailed algorithm is provided as below: 


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• If the baseline ratio of (Kappa LC/Lambda LC)>1.65, then Kappa LC is defined 
as involved FLC, and Lambda LC is defined as non-involved FLC. Then 
o Difference between involved and uninvolved = Kappa LC-Lambda LC 
• If the baseline ratio of (kappa/lambda) <0.26, then Lambda light chain is defined 
as involved FLC, and Kappa light chain is defined as non-involved FLC 
o Difference between involved and uninvolved = Lambda LC-Kappa LC 
• If the baseline ratio of (Kappa LC/Lambda LC) ≤1.65 and ≥0.26, then “involved” 
and “non-involved” FLC can not be determined (ratio is normal), and maximum 
percent reduction from baseline for difference between two types of Serum FLC 
won’t be available. 
7.1.1.3. 
Population of Interest  
The secondary efficacy analysis of ORR will be based on the All Treated population, 
unless otherwise specified. 
7.1.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.  
7.1.2. 
Exploratory Efficacy Analyses 
7.1.2.1. 
Endpoint / Variables 
MRD Negativity Rate 
Minimal Residual Disease (MRD) negativity rate, defined as the percentage of 
participants who are MRD negative (with threshold 10-5) and achieve confirmed VGPR 
or CR from treatment start date until disease progression or initiation of new anti-cancer 
therapy, whichever is earlier, as assessed by next generation sequencing (NGS) per 
IMWG (2016). 
For analysis purposes, subjects in the All Treated population without MRD assessment 
will be considered as having positive MRD. 
7.1.2.2. 
Summary Measure 
MRD Negativity Rate  
MRD negativity rate at any timepoint will be summarized. the number and percentage of 
participants who have achieved MRD negativity will be summarized by dose level. The 
corresponding 95% exact CI will be provided. Information of MRD will be included in 
the listing of response. For analysis purposes, subjects in the All Treated population 
without MRD assessment will be considered as having positive MRD. 


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7.1.2.3. 
Population of Interest  
The MRD negative rate analyses will be based on the All Treated population, unless 
otherwise specified. 
7.1.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Display, based 
on GSK data standards. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.2. 
Part 2: Dose Expansion 
7.2.1. 
Primary Efficacy Analyses 
7.2.1.1. 
Endpoint / Variables 
BOR 
The definition of BOR is provided in Section 7.1.1.1. Details on derivation of confirmed 
response are provided in Table 4.  
ORR 
The definition of ORR is provided in Section 7.1.1.1. Details on derivation of confirmed 
response are provided in Table 4. 
7.2.1.2. 
Summary Measure 
ORR  
The summary measure of ORR is provided in Section 7.1.1.2. 
7.2.1.3. 
Population of Interest  
At futility interim, the primary efficacy analysis of ORR will be based on the All 
Evaluable population. 
Otherwise, the primary efficacy analysis of ORR will be based on the All Treated 
population, unless otherwise specified. 
7.2.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles. 


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Unless otherwise specified, endpoints / variables defined in Section 7.2.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.2.2. 
Secondary Efficacy Analyses 
7.2.2.1. 
Endpoint / Variables 
CBR 
Clinical Benefit Rate (CBR), defined as the percentage of participants with a confirmed 
MR or better (i.e., MR, PR, VGPR, CR and sCR) as the BOR assessed by the investigator 
per IMWG (2016). 
DOR 
Duration of response (DoR), defined as the interval of time (in months) from first 
documented evidence of confirmed PR or better to the time when disease progression is 
documented assessed by the investigator per IMWG (2016), or death due to PD among 
participants with a confirmed PR or better as the BOR. Responders without confirmed 
PD will be censored at the censoring time point for time to progression as specified in 
Table 6.  
TTR 
Time to response (TTR), defined as the interval of time (in months) between the date of 
first dose and the first documented evidence of response (PR or better) among 
participants with a confirmed PR or better as the BOR assessed by the investigator per 
IMWG (2016). 
TTBR 
Time to best response (TTBR), defined as the interval of time (in months) between the 
date of first dose and the earliest date of achieving BOR among participants with a 
confirmed PR or better as the BOR assessed by investigator per IMWG (2016). 
PFS  
Progression-free survival (PFS), defined as the interval of time (in months) from first 
dose until the earlier date of disease progression per IMWG (2016), or the date of death 
due to any cause. Determination of dates of PFS events and dates for censoring are 
described in Table 5. 
TTP 
Time to disease progression (TTP), defined as the interval of time (in months) from first 
dose until the earlier date of PD per IMWG (2016), or the date of death due to PD. 
Determination of dates of TTP events and dates for censoring are described in Table 6. 
OS  
Overall Survival (OS), defined as the interval of time (in months) from first dose to the 
date of death due to any cause. Participants who withdraw consent from the study or are 
lost to follow-up will be censored at the time of withdrawal or lost to follow-up. 
Participants who do not have a death record at the clinical cut-off date for the analysis 
will be censored at the last known alive date. The last contact date will be determined by 


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the maximum collection/assessment date from among selected data domains within the 
clinical database. 


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Table 5 
Assignments of Progression and Censoring Dates for PFS Analysis 
Situation 
Date of Event (Progression/Death) or Censored1  
Event 
(Progression/Death) 
Or Censored 
No adequate baseline assessments4 and the subject has 
not died (if the subject has died follow the rules for death 
indicted at the bottom of the Table) 
First dose 
 
Censored 
No post-baseline assessments and the subject has not 
died (if the subject has died follow the rules for death 
indicted at the bottom of the Table) 
First dose 
Censored 
Progression documented between scheduled visits 
Date of assessment of progression 
Event 
With post-baseline assessment but no progression (or 
death)  
Date of last ‘adequate’ assessment of response2   
Censored 
No adequate post-baseline assessment before start of new 
anticancer therapy 
First dose 
Censored 
With adequate post-baseline assessment and new 
anticancer treatment started (prior to documented disease 
progression).3 
Date of last ‘adequate’ assessment of response2 (on or prior to 
starting anti-cancer therapy)  
Censored 
Death before first scheduled assessment (or Death at 
baseline or without any adequate assessments) 
Date of death 
Event 
Death between adequate assessment visits  
Date of death 
Event 
Death or progression after more than three missed 
scheduled assessment 
Date of last ‘adequate’ assessment of response2 (prior to missed 
assessments): If the disease assessment is every 3 weeks, a 
window of 66 days (9 weeks + 3  day window) will be used to 
determine whether there is extended time without adequate 
assessment. If the time difference between PD/death and last 
adequate disease assessment is more than 66 days, PFS will be 
censored at the last adequate disease assessment prior to 
PD/death. 
Censored 


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1 Event or censored are based on confirmed responses. 
2 An adequate assessment is defined as an unconfirmed assessment where the investigator assessed response is sCR, CR, PR, VGPR, MR, or SD. 
3 If PD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is progression and the date is the date of the 
assessment of progression). 
4 Adequate baseline assessment is defined as at baseline, a patient has at least one of the following measurements: a. Serum M-protein ≥0.5 g/dL (≥5 g/L) or b. Urine 
M-protein ≥200 mg/24h or c. Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65). 
 


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Table 6 
Assignments for Progression and Censoring Dates for TTP Analysis 
Situation 
Date of Event (Progression/Death due to PD) or Censored1  
Event 
(Progression/Death 
due to PD) 
Or Censored 
No adequate baseline assessments4 and the subject has not 
died (if the subject has died due to PD follow the rules for 
death indicted at the bottom of the Table) 
First dose 
 
Censored 
No post-baseline assessments and the subject has not died (if 
the subject has died due to PD follow the rules for death due 
to PD indicted at the bottom of the Table)  
First dose 
Censored 
Progression documented between scheduled visits 
Date of assessment of progression 
Event 
With post-baseline assessment but no progression (or death 
due to PD)  
Date of last ‘adequate’ assessment of response2 
Censored 
No adequate post-baseline assessment before start of new 
anticancer therapy 
First dose 
Censored 
With adequate post-baseline assessment and new anticancer 
treatment started (prior to documented disease progression).3 
Date of last ‘adequate’ assessment of response2 (on or prior 
to starting anti-cancer therapy)  
Censored 
Death due to PD before first scheduled assessment (or Death 
at baseline or without any adequate assessments) 
Date of death 
Event 
Death due to PD between adequate assessment visits  
Date of death 
Event 
Death from causes other than PD before first scheduled 
assessment (or Death at baseline or without any adequate 
assessments) 
Date of death 
Censored 
Death from causes other than PD between adequate 
assessment visits  
Date of death 
Censored 
Death due to PD or progression after more than three missed 
scheduled assessment 
Date of last ‘adequate’ assessment of response2 (prior to 
missed assessments): If the disease assessment is every 3 
weeks, a window of 66 days (9 weeks + 3 day window) will 
be used to determine whether there is extended time without 
adequate assessment. If the time difference between 
PD/death due to PD and last adequate disease assessment is 
Censored 


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Situation 
Date of Event (Progression/Death due to PD) or Censored1  
Event 
(Progression/Death 
due to PD) 
Or Censored 
more than 66 days, PFS will be censored at the last adequate 
disease assessment prior to PD/death due to PD.  
1 Event or censored are based on confirmed responses. 
2 An adequate assessment is defined as an assessment where the investigator assessed response is sCR, CR, PR, VGPR, MR, or SD . 
3 If PD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is progression and the date is the date of the 
assessment of progression). 
4 Adequate baseline assessment is defined as at baseline, a patient has at least one of the following measurements: a. Serum M-protein ≥0.5 g/dL (≥5 g/L) or b. Urine 
M-protein ≥200 mg/24h or c. Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65).  
 


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7.2.2.2. 
Summary Measure 
CBR 
The number and percentage of participants with the BOR in the following response 
categories will be summarized by dose level: sCR, CR, VGPR, PR, MR, clinical benefit 
response (sCR+CR+VGPR+PR+MR), SD, PD, and NE. The corresponding exact 95% CI 
for CBR will also be provided. Participants with unknown or missing responses will be 
treated as non-responders, i.e., these participants will be included in the denominator 
when calculating percentages of response. 
DOR 
If there are sufficient number of responders who subsequently progress or die due to PD, 
distribution of DOR will be summarized using the Kaplan-Meier method. The median, 
25th and 75th percentiles of DOR will be estimated and corresponding 95% confidence 
intervals will be estimated using the Brookmeyer-Crowley method (1982). A Figure and 
listing of DoR time will also be provided. 
TTR 
If there are sufficient number of responses by dose level, time to response at will be 
summarized descriptively using median(s) and quartiles in the subset of subjects with a 
confirmed response of PR or better as the BOR and corresponding 95% confidence 
intervals will be estimated using the Brookmeyer-Crowley method (1982). A Figure and 
listing of TTR time will also be provided. 
TTBR 
If there are sufficient number of responses by dose level, time to best response at will be 
summarized descriptively using median(s) and quartiles in the subset of subjects with a 
confirmed response of PR or better as the BOR and corresponding 95% confidence 
intervals will be estimated using the Brookmeyer-Crowley method (1982). A Figure and 
listing of TTBR time will also be provided. 
PFS  
The distribution of PFS for each dose level will be estimated using the Kaplan-Meier 
method. If there is a sufficient number of progressions or death due to PD, the median, 
25th and 75th percentiles of PFS will be estimated and corresponding 95% confidence 
intervals will be estimated using the Brookmeyer-Crowley method (1982). PFS rate at 6, 
9, 12, 15, and 18 months and corresponding 95% CI will also be estimated from the 
Kaplan-Meier analysis. A Figure and listing of PFS time will also be provided. 
OS  
The distribution of OS for each dose level will be estimated using the Kaplan-Meier 
method. If there are a sufficient number of deaths, then the median, 25th and 75th 
percentiles of OS will be estimated and corresponding 95% confidence intervals will be 


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estimated using the Brookmeyer-Crowley method (1982). A graph of survival curves and 
a listing of survival times will also be provided. In addition, pending on maturity of data, 
the survival probability at 6, 9, 12, 15, and 18 months with 95% CI will be estimated 
using Kaplan-Meier method. 
TTP  
The distribution of TTP will be estimated using the Kaplan-Meier method. The median, 
25th and 75th percentiles of TTP will be estimated and corresponding 95% confidence 
intervals will be estimated using the Brookmeyer-Crowley method (1982). A Figure and 
listing of TTP time will also be provided. 
7.2.2.3. 
Population of Interest  
The secondary efficacy analyses will be based on the All Treated population, unless 
otherwise specified. 
7.2.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.2.3. 
Exploratory Efficacy Analyses 
7.2.3.1. 
Endpoint / Variables 
MRD Negativity Rate 
MRD negativity rate is defined in Section 7.1.2.1. 
7.2.3.2. 
Summary Measure 
MRD Negativity Rate  
The summary measure of MRD negativity rate is provided at Section 7.1.2.2. 
7.2.3.3. 
Population of Interest  
The MRD negative rate analyses will be based on the All Treated population, unless 
otherwise specified. 
7.2.3.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Display, based 
on GSK data standards. 


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Unless otherwise specified, endpoints / variables defined in Section 7.1.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.3. 
Other Efficacy Analyses  
7.3.1. 
Endpoint / Variables 
Time to Next Treatment  
Time to next treatment (TTNT) is defined as the time from the date of first dose of study 
treatment to the date of next subsequent treatment for relapse refractory multiple 
myeloma due to any reasons. Subjects who have not started the next subsequent anti-
cancer treatment will be censored at the date of last contact or at death. Subjects who do 
not have a documented start date of first dose of study treatment will be excluded from 
this analysis. 
Rate of VGPR or Better  
Rate of VGPR or better, defined as the percentage of participants with a confirmed 
VGPR or better as the BOR (i.e., VGPR, CR and sCR), per IMWG (2016). 
7.3.2. 
Summary Measure 
Time to Next Treatment 
If there are sufficient number of responders who started new anti-cancer treatment due to 
any reasons by dose level, time to next treatment will be summarized descriptively using 
median(s) and quartiles.  
Rate of VGPR or Better  
The number and percentage of participants with the BOR in the following response 
categories will be summarized: sCR, CR, and VGPR. The corresponding exact 95% CI 
for rate of VGPR or better will also be provided. Participants with unknown or missing 
responses will be treated as non-responders, i.e., these participants will be included in the 
denominator when calculating percentages of response.  
7.3.3. 
Population of Interest  
Time to next treatment and rate of VGPR or better analyses will be based on the All 
Treated population, unless otherwise specified. 
 
 


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8. 
SAFETY ANALYSES 
The safety analyses will be based on the All Treated population, unless otherwise 
specified.  
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs), 
ir (immune-related) AEs associated with pembrolizumab, and other significant AEs and 
serious and other significant irAEs will be based on GSK Core Data Standards. Details 
on treatment emergent AEs are provided in Section 16.4.1.2. Dose modifications (dose 
interruptions, dose reduction, and dose delays) and dose limiting toxicity (DLT) will also 
be summarized and listed according to GSK Oncology Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays. 
A summary of non-serious adverse events that occurred in strictly 5% of the subjects or 
above will be provided (no rounding for the percentage will be used in terms of 5% 
threshold, e.g., event with 4.99% incidence rate should not be included in this Table). The 
summary will be displayed by SOC and PT. 
Adverse events (AEs) and immune-related adverse events (irAEs) will be graded by the 
investigator according to the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), Version 4.03 [NCI, 2010]. Adverse events will be coded 
using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary) and grouped 
by system organ class (SOC). Immune-related adverse events will be coded using the 
Medical Dictionary for Regulatory Affairs (MedDRA dictionary) and grouped by 
preferred terms (PT). In addition, corneal findings will also be graded using the GSK 
scale for corneal events. 
A summary of number and percentage of subjects with any adverse events and immune-
related adverse events by maximum grade will be produced. AEs and irAEs will be 
sorted by Preferred term (PT) in descending order of total incidence. The summary will 
use the following algorithms for counting the subject (this applies also for subjects with 
irAEs): 
• 
Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade. 
• 
Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 
In addition, the frequency and percentage of AEs (all grades) and irAEs (all grades) will 
be summarized and displayed in two ways: 1) in descending order of total incidence by 
PT only and 2) in descending order of total incidence by System Organ Classes (SOC) 
and PT and Maximum Grade for AEs and irAEs. In the SOC row, the number of subjects 
with multiple events under the same system organ class will be counted once. Otherwise, 
if AEs and irAEs are not listed in the NCI-CTCAE (version 4.03, [NCI, 2010]), then the 
AEs and irAEs will be summarized by maximum intensity.  


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A separate summary will be provided for study treatment-related AEs. A study treatment-
related AE is defined as an AE for which the investigator classifies the relationship to 
study treatment as “Yes”. A worst-case scenario approach will be taken to handle missing 
relatedness data, i.e. the summary Table will include events with the relationship to study 
treatment as ‘Yes’ or missing. The summary Table will be displayed in descending order 
of total incidence by SOC and PT and Maximum Grade for AEs. 
All AEs and irAEs will be listed. Additionally, a listing of subject IDs for each individual 
AE and a listing of subject IDs for each individual irAE will be produced.  
A summary of the number of patients experiencing DLTs will be provided. Grade 3 or 
above corneal events based on the GSK scale for corneal events associated with 
belantamab mafodotin should be used for evaluation of DLT. 
8.2. 
Adverse Events of Special Interest Analyses 
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following 
AEs of special interest and identified risk for belantamab mafodotin and AEs of special 
interest for pembrolizumab will be summarized separately:  
• Belantamab Mafodotin (AESIs) 
o Corneal events (GSK Scale)  
o Eye Disorders (CTCAE) 
o Thrombocytopenia 
o Infusion related reactions 
• Belantamab Mafodotin (Identified Risk) 
o Neutropenia 
• Pembrolizumab (AESIs) 
o Overdose 
8.2.1. 
Belantamab Mafodotin  
8.2.1.1. 
Eye Disorders, Thrombocytopenia, and Infusion Related Reactions 
The severity of all AESI will be graded utilizing the National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE) v.4.03 [NCI, 2010]. For 
thrombocytopenia, in addition to events identified and collected in eCRF, a 
comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. For infusion 
related reactions (IRR), events are only considered IRR if the preferred term = “Infusion 
related reaction” or event was reported on an infusion day after the start of infusion or 
within 24 hours following end of infusion and led to a temporary interruption or 
prolongation of infusion time or treatment withdrawal. For keratopathy events (CTCAE) 
under eye disorders, events are considered keratopathy events if the synonym = 


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“keratopathy/keratitis”. The details of the planned displays are provided in Appendix 11: 
List of Data Displays. 
Summaries of the number and percentage of subjects with these events will be provided 
for each type of events separately by preferred term and maximum grade. The time of 
onset and duration of first occurrence of each type of events will be summarized using 
summary statistics mean, standard deviation, median, minimum value, and maximum. 
The number and percentage of subjects who have time of onset of first occurrence and 
the number and percentage of subjects who have duration of first occurrence will be 
reported in the following: 
Thrombocytopenia and Eye Disorders: 
• Time of first occurrence: 1-21, 22-42, 43-63, >63 days 
• Duration of first occurrence: 1-21, 22-42, >42 days 
Infusion Related Reactions: 
• Time of first occurrence: 0-6, >6-12, >12-18, >18-24 hours 
• Duration of first occurrence: 0-12, >12-24, >24 hours 
The summary of event characteristics will also be provided, including number of subjects 
with any event, number of events, number of subjects with any event that is serious, 
number of subjects with any event that is related to study treatment, number of 
occurrences (One, Two, Three or more), maximum grade and the action taken for the 
event. Distinct occurrences require at least one day (or hour for IRR) gap between the 
resolution of all events from first course to the onset of second course. Overlapping 
occurrences of events are treated as the same occurrence. The percentage will be 
calculated in two ways, one with number of subjects with event as the denominator and 
the other with total number of subjects as the denominator.  The worst-case approach will 
be applied at subject level for the maximum grade, i.e. a subject will only be counted 
once as the worst case from all the events experienced by the subject. For action taken to 
an event, subject will be counted once under each action, e.g. if a subject has an event 
leading to both study treatment discontinuation and dose reduction, the subject will be 
counted once under both actions.  
8.2.1.2. 
Corneal Events (GSK Scale)  
After discussions with regulatory agencies, GSK developed a grading scale to capture 
both corneal examination findings and visual acuity changes in participants treated with 
belantamab mafodotin. This GSK scale differs from the CTCAE criteria for eye disorders 
which relies mainly on patient’s symptoms and patient’s ability to attend to ‘activities of 
daily living’ for grading of events. 
Severity of belantamab mafodotin treatment related corneal events will also be graded 
using the GSK scale for corneal events and should be used for evaluation of DLT.  
Summaries of the number and percentage of subjects with these events will be provided 
for each type of grade separately by visit. The time of onset and duration of first 


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occurrence of grade 2 or above events, and the event characteristics will be summarized 
similarly as the AESIs for belantamab mafodotin provided in Section 8.2.1.1.  
In addition to the listing, the following outputs will be provided for corneal events graded 
using the GSK scale:  
1. Overview for corneal event (GSK scale)  
2. Summary of actions taken with study treatment (e.g. dose reduction/delay/study 
treatment withdrawn) 
The details of the planned displays are provided in Appendix 11: List of Data Displays. 
 
8.2.1.3. 
Identified Risks: Neutropenia 
Characteristics (e.g., number of occurrences, action taken, grade, etc.) of the important 
identified risk, neutropenia, will be summarized separately. The severity of neutropenia 
will be graded utilizing the NCI-CTCAE v.4.03 [NCI, 2010]. 
A comprehensive list of MedDRA preferred terms for neutropenia based on clinical 
review will be used to identify each type of event similarly as the AESIs for belantamab 
mafodotin provided in Section 8.2.1.1. The details of the planned displays are provided in 
Appendix 11: List of Data Displays. 
Summaries of the number and percentage of subjects with these events will be provided 
for each type of events separately by preferred term and maximum grade. The time of 
onset and duration of first occurrence of each type of events in days, and the event 
characteristics will be summarized similarly as the AESI for belantamab mafodotin 
provided in Section 8.2.1.1. 
8.2.2. 
Pembrolizumab 
8.2.2.1. 
Overdose 
For pembrolizumab, an overdose as defined in Section 6.10 of protocol that is not 
associated with clinical symptoms or abnormal laboratory results is an AESI. 
A comprehensive list of MedDRA preferred terms for overdose based on clinical review 
will be used to identify each type of event similarly as the AESIs for belantamab 
mafodotin provided in Section 8.2.1.1. The details of the planned displays are provided in 
Appendix 11: List of Data Displays. 
8.3. 
Deaths and Serious Adverse Events 
All deaths will be summarised based on the number and percentage of subjects. This 
summary will classify subjects by time of death relative to the last dose of medication 
(>30 days or 30 days) and primary cause of death (disease under study, SAE related to 


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study treatment, or other). A supportive listing will be generated to provide subject-
specific details on subjects who died and have fatal SAEs and fatal serious irAEs.  
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. Separate summaries will also be provided for study treatment-
related SAEs. The summary Tables will be displayed in descending order of total 
incidence by SOC and PT.  
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment as “Yes”. A worst-case scenario approach will be 
taken to handle missing data, i.e. the summary Table will include events with the 
relationship to study treatment as ‘Yes’ or missing.  
SAEs are included in the listing of all adverse events and immune-related adverse events. 
Separate supportive listings with subject-level details will be generated for 
• 
Non-Fatal SAEs. 
• 
Non-Fatal serious irAEs 
8.4. 
Adverse Events Leading to Discontinuation of Study 
Treatments and Other Significant Adverse Events 
The following categories of AEs will be summarized for separately in descending order 
of total incidence by SOC and PT and separate supportive listings will be generated with 
subject level details for those subjects: 
• 
AEs Leading to Permanent Discontinuation of Study Treatment (belantamab 
mafodotin and pembrolizumab) 
• 
AEs Leading to Dose Interruptions (belantamab mafodotin and pembrolizumab) 
• 
AEs Leadings to Dose Reductions (belantamab mafodotin) 
• 
All Treatment-related Serious Adverse Events (belantamab mafodotin and 
pembrolizumab) 
8.4.1. 
Immune-Related Adverse Events Leading to Discontinuation of 
Study Treatments and Other Significant Adverse Events 
The following categories of irAEs will be summarized for separately in descending order 
of total incidence by SOC and PT and separate supportive listings will be generated with 
subject level details for those subjects: 
• 
irAEs Leading to Dose Interruptions (Pembrolizumab) 


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8.5. 
Ocular Findings from Ophthalmic Exam (Part 2) 
As outlined in study protocol (GSK Document Number.: TMF-14344600) Schedule of 
Activities (Table 7- Table 10 of Section 7), ophthalmic exams are scheduled at screening, 
during the study, end of treatment, and follow-up period. The ocular findings from 
ophthalmic exams will be analysed as described below. 
1. From baseline to last follow-up, the following analysis will be performed: 
 
a. Visual Acuity: 
i. 
The best corrected visual acuity (BCVA) summary will be based on the 
Logarithm of the Minimum Angle of Resolution (logMAR score), where: 
logMAR score = -log10(Snellen Acuity Score) 
The following categories of logMAR score changes from baseline are 
defined:  
▪ No change/improved vision is defined as a change from baseline 
<0.12;  
▪ A possible worsened vision is defined as a change from baseline 
>=0.12 to <0.3; 
▪ a definite worsened vision is defined as a change from baseline 
>=0.3 logMAR score. 
ii. 
A summary of characteristics of definite worsen vision as defined above 
by subject will be provided, including time to onset of first occurrence; 
outcome and duration of first occurrence; number of occurrences based on 
subjects with definite worsen vision; outcome post treatment exposure; 
time to resolution post-treatment exposure 
iii. 
In addition, a summary of worst change from baseline (based on the eye 
with worst change) in BCVA score (logMAR score) will be provided for 
the following categories: 
• Increase >=0.12 to < 0.3 
• Increase >=0.3 to < 0.6 
• Increase >= 0.6 
iv. 
Number (%) of subjects with a decline in BCVA to ‘light perception’ (LP) 
or ‘no light perception’ (NLP) anytime post-baseline will also be 
provided. 
 
b. Corneal Exam 
i. 
Shift table from baseline to worst post-baseline by eye (R/L) and subject 
(worse eye, defined as the eye with the maximum worsening change from 
baseline) for corneal epithelium findings: 
• Corneal epithelium (Normal to Abnormal), Corneal ulcer (No to 
Yes), Epithelial microcystic edema (No to Yes), Subepithelial haze 
(No to Yes), Corneal neovascularization (No to Yes), and 
Microcysts without edema (No to Yes) 


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ii. 
For punctate keratopathy, summary Table of worst grade post-baseline and 
most frequent grade post-baseline across ocular exams by eye (R/L) and 
subject (worse eye) 
 
 
 
c. Lens 
i. 
Shift Table from baseline to worst post-baseline by eye (R/L) and subject 
(worse eye, defined as the eye with the maximum worsening changes from 
baseline) for lens findings: 
•  Lens: Clear (No to Yes), Pseudophakia (No to Yes); and Types of 
cataract (Nuclear Sclerosis, Cortical Cataract, Posterior 
Subcapsular Cataract). 
The details of the planned displays are provided in Appendix 11: List of Data Displays. 
8.6. 
Pregnancies  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If subjects and subjects’ partner become 
pregnant while on the study, the information will be included in the narratives and no 
separate Table or listing will be produced. 
8.7. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays. 
Summary of change from baseline by scheduled visits using mean, median, standard 
deviation, minimum and maximum will be provided. 
Summaries of worst case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by CTCAE v4.03. These summaries will display the number 
and percentage of subjects with a maximum post-baseline grade increasing from their 
baseline grade. Any increase in grade from baseline will be summarized along with any 
increase to a maximum grade of 3 and any increase to a maximum grade of 4. The ‘Any 
Grade Increase’ column will include all cases where the worst-case grade is 1 or higher 
and the baseline grade is missing. Likewise the Increase to Grade X (where X=3 or 4) 
will include cases that are worst-case grade X and the baseline grade is missing. Missing 
baseline grade will be assumed as grade 0. For laboratory tests that are graded for both 
low and high values, summaries will be done separately and labelled by direction, e.g., 
sodium will be summarized as hyponatremia and hypernatremia. 
For lab tests that are not gradable by CTCAE v4.03, summaries of worst case changes 
from baseline with respect to normal range will be generated. Decreases to low, changes 
to normal or no changes from baseline, and increases to high will be summarized for the 
worst case post-baseline. If a subject has a decrease to low and an increase to high during 


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the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories.  
For urinalysis laboratory tests results, occult blood, proteins, ketones, and glucose 
dipstick tests will be summarized. If the subject has a discrete value greater than 0 or a 
character value that is positive, then the subject is counted in the “Presence” category. 
Otherwise, the subject is counted in the “Absence” category.  
The number of subjects with worst case urinalysis laboratory tests results will be 
summarized by the combination of specimen, method, test, and category. Subjects with a 
missing baseline value are to be assumed to have a negative baseline value. 
• If the subject with “Presence” or “Absence” category at baseline does not change 
post-baseline, then the subject is counted in the “No Change” category.  
• If the subject with “Presence” category at baseline changed to “Absence” 
category post-baseline, then the subject is counted in the “Decreased” category.    
• If the subject with “Absence” category at baseline changed to “Presence” 
category post-baseline, then the subject is counted in the “Any Increase” category 
Separate summary tables for hematology, chemistry, urinalysis, and hepatobiliary 
laboratory tests will be produced. Liver function laboratory tests will be included with 
hepatobiliary laboratory tests. 
A supporting listing of laboratory data for subjects with abnormalities of potential clinical 
concern will be provided. A separate listing of laboratory data with character values will 
also be provided. For lab test values that can be graded, values of grade 1 or above are 
defined as values of potential clinical concern. For lab test values that can not be graded, 
values out of the normal range are defined as values of potential clinical concern. 
Detailed derivation of baseline assessment is specified in Section 5.2. 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
8.7.1. 
Analyses of Liver Function Tests 
A summary of Liver Monitoring/Stopping Event Reporting will be provided. A Liver 
event profile which includes medical conditions data for subjects with liver stopping 
events, substance use data for subjects with liver stopping events, liver biopsy results for 
subjects and recorded outcomes of liver imaging assessments for subjects will be listed. 
Summaries of hepatobiliary laboratory abnormalities including possible Hy’s law cases 
will be provided. A summary of liver restart/re-challenge timings will be provided. 
Plots of maximum total bilirubin versus maximum ALT, maximum ALT versus baseline 
ALT, maximum AST versus maximum LDH, maximum AST versus maximum 
Creatinine Kinase, and maximum LDH versus maximum Creatinine Kinase will be 
generated. A plot of maximum albumin/creatinine ratio (greater than 2000 mg/g) versus 


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8.8.3. 
LVEF 
Absolute change from baseline in LVEF will be summarized in the worst case post-
baseline only. Only the post-baseline assessments that used the same method (ECHO or 
MUGA) as the baseline assessments will be used to derive the change from baseline. The 
change from baseline will be categorized as follows: 
• 
No change or any increase 
• 
Any decrease 
o >0-<10 decrease 
o 10-19 decrease 
o >=20 decrease 
o >=10 decrease and >= LLN 
o >=10 decrease and < LLN 
o >=20 decrease and >= LLN 
o >=20 decrease and < LLN 
8.8.4. 
Immunogenicity Analyses 
For each subject, the results and titers of anti-belantamab mafodotin binding antibodies 
and neutralizing antibody assay results will be listed for each assessment time point, 
along with ADC and total antibody concentration. The frequency and percentage of 
subjects with positive and negative anti-drug antibody and neutralizing antibody assay 
results will be summarized for each assessment time and overall for each subject by dose 
cohort.  
The number and percentage of subjects with baseline anti-drug antibody results, overall 
and split by negative and positive samples in each treatment group will be provided. A 
further summary of subjects with post-baseline anti-drug antibody and neutralizing 
antibody results, anti-drug antibody negative (overall and for treatment-unaffected only), 
and treatment-emergent anti-drug antibody results (overall and split by treatment-induced 
and treatment-boosted) in each treatment group will be presented. Treatment-emergent 
anti-drug antibody is the sum of treatment-induced anti-drug antibody subjects and 
treatment-boosted anti-drug antibody positive subjects. Treatment unaffected anti-drug 
antibody is defined as a subject with an ADA-positive sample at baseline, in which post-
baseline sample titer results are less than or equal to a four-fold increase in titer values 
relative to the baseline titer value (titer ≤ 4x baseline titer) or was ADA negative anytime 
post baseline. 
For treatment-induced and treatment-boosted subjects, a summary of all their titer values 
will be presented. Treatment-induced anti-drug antibody is defined as a subject with at 
least one post-baseline anti-drug antibody positive sample and an anti-drug antibody 
negative or missing baseline sample. Treatment-boosted anti-drug antibody is defined as 
a subject with an anti-drug antibody positive baseline sample in which at least one post-
baseline sample titer value is four-fold greater than the baseline titer value (titer > 4x 


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baseline titer) or if titer result is missing at baseline or missing at all post-baseline 
assessments. 
8.8.5. 
Profile Plot 
A profile plot for subjects will be produced. This plot will display the duration of study 
treatment in days for each subject, along with an indication of each subject’s actual dose 
over time, investigator assessed confirmed response, highlighting responders versus non-
responders, and those ongoing on belantamab mafodotin study treatment.  


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9. 
PHARMACOKINETIC ANALYSES 
Concentration-time data collected in Cycle 1 will be analyzed using standard non-
compartmental methods; some parameters will be determined for all participants and 
cycles, as data permit.  The concentration-time data for belantamab mafodotin, total 
mAb, and/or cys-mcMMAF may be combined with data from other studies and analyzed 
in a population approach using nonlinear mixed effects modeling.  
9.1. 
Drug Concentration Measures  
Linear and semi-logarithmic individual concentration-time profiles will be plotted for 
belantamab mafodotin, total mAb, cys-mcMMAF, and pembrolizumab (if tested) in Part 
1 and Part 2. Mean and median profiles (when applicable) will be plotted for each analyte 
by study part and belantamab dose cohort. Plasma concentrations of belantamab 
mafodotin, total mAb, cys-mcMMAF, and pembrolizumab (if tested) will be listed for 
each subject and summarized (when appropriate) by study part, belantamab mafodotin 
dose cohort, and planned time point. Refer to Appendix 5: Data Display Standards & 
Handling Conventions (Section 16.5.3 Reporting Standards for Pharmacokinetic) 
9.2. 
Derived Pharmacokinetic Parameters 
Concentration-time data for belantamab mafodotin, total mAb, cys-mcMMAF, and 
pembrolizumab (if measured) will be used. 
The following pharmacokinetic parameters will be determined separately for each 
analyte, as data permit: 
• 
Belantamab mafodotin and total mAb: Cmax, C-EOI, tmax, Ctrough, tlast, and 
AUC(0-) 
• 
cys-mcMMAF: Cmax, C-EOI, tmax, tlast, and AUC(0-168) 
• 
Pembrolizumab (if measured):  Cmax, tmax, AUC(0-) 
The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin, version 
6.3 or later, as data permit, or by population pharmacokinetic analysis (Section 10). 
Calculations of pharmacokinetic parameter values will be based on the actual sampling 
times recorded during the study. 
The pharmacokinetic parameters C-EOI and Ctrough will be determined directly from the 
concentration-time dataset. Notes:  For the dosing occasions with only predose and end of 
infusion samples, the end of infusion sample will not be identified as Cmax.  
 
 
 




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10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Belantamab mafodotin, total mAb, and/or cys-mcMMAF concentration-time data may be 
analysed using a population pharmacokinetic approach. The planned population PK 
analysis will use the then-current population pharmacokinetic model(s) to generate post 
hoc pharmacokinetic parameter estimates (e.g., CL, Vss, t½, AUC(0-)) for the individual 
participants in this study on certain dosing occasions, data permitting. These parameter 
values will be listed and summarized as described in Section 9.5. 
Based on the individual post hoc parameter values, dosing information, and sample 
collection times, drug concentrations at the time of sample collection will be predicted for 
each participant. Model evaluation will consist of comparison of model-predicted and 
observed concentrations. If necessary, model estimation will be performed.  
Results of this analysis may be provided in a separate report. 
To support this analysis, a population PK dataset will be generated. Detailed population 
PK methodology is also presented in Appendix 9: Population Pharmacokinetic (PopPK) 
Analyses. 
 


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11. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
If deemed appropriate and if data permit, exposure-response relationships between 
belantamab mafodotin exposure (e.g., concentration, Cmax, or AUC) and clinical activity 
and/or toxicity (e.g., response, AESIs) may be explored using population methods. If data 
permit, the effects of covariates may be explored.   
If done, the analysis will be performed by, or under the direct auspices of, Clinical 
Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline, using the currently 
supported versions of all software packages. These analyses will be performed using R 
(The R Foundation for Statistical Computing), NONMEM (ICON Solutions) with PsN 
(Perl Speaks NONMEM), or another software platform deemed appropriate.  
The results of this analysis may be provided in a separate report. 


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12. 
BIOMARKER ANALYSES 
Description of exploratory biomarker data is intended for hypothesis generation in 
relation to the pharmacodynamics of belantamab mafodotin and/or combinations, for 
potential prognostic or predictive biomarker evaluation and/or for patient monitoring. 
Different shapes, colors, symbols and split plots will be used as appropriate to denote 
patient cohort, response group, dose group or other characteristics. On-treatment 
measurements may be visualized as percent or fold changes from baseline or as absolute 
values, as appropriate. Subjects may be plotted individually or in groups, as appropriate. 
Linear, semi-logarithmic, or logarithmic scales will be used for data visualization where 
appropriate. Linear interpolation will be used to visually connect measurements from 
individual subjects to aid interpretations, where appropriate. 
If deemed appropriate and if data permit, relationships between biomarkers and/or 
pharmacodynamic markers and clinical activity and/or toxicity (e.g., response, AESIs) 
may be explored. If data permit, the effects of covariates may be explored.  Details of 
these analyses will be reported either within the main clinical study report (CSR) or in a 
separate report.  
Data measured from the following samples will be assessed in this RAP: 
• Serum samples collected at pre- and post-belantamab mafodotin infusion and/or 
on-treatment to determine soluble BCMA (sBCMA) concentration by an 
electrochemiluminescent (ECL)-based MesoScale Discovery (MSD) 
immunoassays designed to detect GSK2857916 bound and free sBCMA. 
12.1. 
Data processing 
• Any out of range values defined by BISTRESC = BLQ or ALQ will be imputed 
respectively as LLOQ/3 or ULOQ and marked as out of range using distinct 
colors, shapes, or similar demarcation. 
• Duplicate measurements for collections (same collection date/time) will be 
averaged across the duplicate measurements, when applicable. 
• In cases where there are multiple pre-infusion collections (i.e. different collection 
date/time), the most recent measurement will be used as the baseline 
measurement. 
12.2. 
Visualization and Tables  
12.2.1. 
Exploratory Objective: To evaluate PD markers in MM after 
treatment with belantamab mafodotin in combination with 
pembrolizumab.  
Endpoint: sBCMA concentration at baseline and on-treatment in subjects with MM and 
in relationship to clinical response. 


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12.2.1.1. 
Population of Interest 
The biomarker/pharmacodynamic analyses will be based on the pharmacodynamic 
population in the All treated population, unless otherwise specified. 
12.2.1.2. 
sBCMA 
• 
Box plot showing absolute free sBCMA serum concentrations (log scale) 
measured at baseline in all participants, marked or separated by dose level and 
categorized by responders (participants with a best confirmed response (partial 
response (PR) or better)), non-responders (participants with best confirmed 
response (minimal response (MR), stable disease (SD) or progressive disease 
(PD)), and participants with best confirmed response of not evaluable (NE). Plots 
will illustrate the data gathered in Part 1 and Part 2 of this study. 
• 
Spider plot showing absolute free sBCMA serum concentrations (log scale) 
measured at baseline and while on treatment versus the corresponding treatment 
cycle number or timepoint in all participants, marked or separated by dose level 
and categorized by responders (participants with a best confirmed response 
(partial response (PR) or better)), non-responders (participants with best 
confirmed response (minimal response (MR), stable disease (SD) or progressive 
disease (PD)), and participants with best confirmed response of not evaluable 
(NE).  Plots will illustrate the data gathered in Part 1 and Part 2 of this study. 
• 
Spider plot showing fold and/or percentage (%) change from baseline in free 
sBCMA serum concentrations (log scale) while on treatment versus the 
corresponding treatment cycle number or timepoint in all participants, marked or 
separated by dose level and categorized by responders (participants with a best 
confirmed response (partial response (PR) or better)), non-responders 
(participants with best confirmed response (minimal response (MR), stable 
disease (SD) or progressive disease (PD)), and participants with best confirmed 
response of not evaluable (NE). Plots will illustrate the data gathered in Part 1 and 
Part 2 of this study. 
• 
Box plot showing absolute free sBCMA serum concentrations in relation to other 
disease burden markers, including but not limited to 2 microglobulin, 
kappa/lambda free light chain, M-protein, etc. (log scale), measured at baseline in 
all participants, marked or separated by dose level and categorized by responders 
(participants with a best confirmed response (partial response (PR) or better)), 
non-responders (participants with best confirmed response (minimal response 
(MR), stable disease (SD) or progressive disease (PD)), and participants with best 
confirmed response of not evaluable (NE), and extramedullary disease. Plots will 
illustrate the data gathered in Part 1 and Part 2 of this study. 
Table 8 below provides an overview of all the planned interim exploratory biomarker 
analyses in this RAP. Pre-defined assay parameters (e.g., dynamic range) will be used to 
identify and exclude from further analysis invalid biomarker data. Other biomarker 
variables may be examined in relation to other clinical variables, laboratory values, 
biomarkers, or safety endpoints, as deemed necessary.  




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The total OSDI score = ([sum of scores for all questions answered × 100]/[total number 
of questions answered ×4]). Subscale scores are computed similarly with only the 
questions from each subscale used to generate its own score. Subscale scores are 
computed similarly with only the questions from each subscale used to generate its own 
score. A score of 100 corresponds to complete disability (a response of “all of the time” 
to all questions answered), while a score of 0 corresponds to no disability (a response of 
“none of the time” to all questions answered). Therefore, decrease in score from baseline 
means improvement.  
For each of the three sub-scales, the descriptive summary of the actual value and change 
from baseline at selected time points will be provided. For the Vision-Related 
Functioning domain, the number and percentage of participants with post-baseline score 
worsening of ≥ 12.5 from baseline score will be summarized at selected time points. 
Additionally, a time to event analysis of time to meaningful worsening based on the ≥ 
12.5 threshold will be summarized with frequency of number of patients with event (N, 
%).  Time to first event and duration of event will also be calculated (median days, 
range). Additionally, recovery from first event defined as ≥ 12.5 decrease from the first 
worst score will be summarized.  
Plots of mean change from baseline (including baseline) and 95% confidence interval 
over time by visit, and at end of study treatment, last follow-up, and worst case post-
baseline for individual domains will also be provided. The overall total score and sub-
scale scores will be listed. 
13.3. 
Value Evidence and Outcome (Part 2 only) 
13.3.1. 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core module (EORTC QLQ-
C30) 
The EORTC QLQ-C30 is a 30-item questionnaire containing both single- and multi-item 
measures [Aaronson, 1993].  These include five functional scales (Physical, Role, 
Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and 
Nausea/Vomiting), a Global Health Status/QoL scale, and six single items (Constipation, 
Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). Scores for each 
scale and single-item measure are averaged and transformed linearly to a score ranging 
from 0–100. Details of deriving domain scores (9 scales and 6 single items) and summary 
score can be found in Section 16.6.5.1. 
A high score for functional scales and for Global Health Status/QoL represent better 
functioning ability or Health-Related Qualify of Life (HRQoL), (higher score indicates 
improvement) whereas a high score for symptom scales and single items represents 
significant symptomatology [Proskorovsky 2014]. (lower score indicates improvement) 
Descriptive summaries (mean, SD, median, min and max) of the actual value and change 
from baseline at selected time points will be provided for EORTC QLQ-C30 summary 
score and each domain score.  


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Plots of mean change from baseline (including baseline) and 95% confidence interval 
over time by visit, and at end of study treatment, last follow-up, and worst case post-
baseline for individual domains will also be provided. The overall summary score and 11-
sub-scale scores will be listed. 
13.3.2. 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 20-item Multiple Myeloma module 
(EORTC QLQ-MY20) 
The EORTC QLQ-MY20 is a supplement to the QLQ-C30 instrument used in patients 
with multiple myeloma [Aaronson, 1993; Cocks, 2007]. The module comprises 20 
questions that address four myeloma-specific HRQoL domains: Disease Symptoms, Side 
Effects of Treatment, Future Perspective, and Body Image. Three of the four QLQ-MY20 
domains are multi-item scales: Disease Symptoms (includes bone aches or pain, back 
pain, hip pain, arm or shoulder pain, chest pain, and pain increasing with activity); Side 
Effects of Treatment (includes drowsiness, thirst, feeling ill, dry mouth, hair loss, upset 
by hair loss, tingling hands or feet, restlessness/agitation, acid indigestion/heartburn, and 
burning or sore eyes); and Future Perspective (includes worry about death and health in 
the future, and thinking about illness).  The Body Image scale is a single-item scale that 
addresses physical attractiveness. Details of deriving domain scores can be found in 
Section 16.6.5.2.  
For each of four domain scores, a descriptive summary of the actual value and change 
from baseline by visit will be provided: 
Plots of mean change from baseline (including baseline) and 95% confidence interval 
over time by visit, and at end of study treatment, last follow-up, and worst case post-
baseline for individual domains will also be provided. The 4-domain scores will be listed. 
13.4. 
Compliance of OSDI, EORTC QLQ-C30, and EORTC-QLQ-
MY20 
Tables to summarize the compliance of OSDI (Part 1 and Part 2) and EORTC QLQ-C30 
and EORTC-QLQ-MY20 (Part 2 only) by visit will be provided. The Tables will include 
number of subjects remaining in study, number and percentage of participants with OSDI 
summary score, QLQ-C30 summary score, and QLQ-MY20 summary score. The 
percentage is calculated using number of participants remaining in the study at given 
timepoint as denominator. 


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14. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
14.1. 
Study Population 
14.1.1. 
Subject Disposition 
A summary of recruitment by country and site, relative to COVID-19 Pandemic measures 
will be produced. For the definition of the phases of the COVID-19 pandemic measures 
see Section 16.4.1.4. 
A country level listing of the dates of the COVID-19 Pandemic measures, will be 
produced. The ‘Summary of Subject Status and Reason for Study Withdrawal’ and the 
‘Summary of Treatment Status and Reasons for Discontinuation of Study Treatment’ will 
be repeated, with the reason for withdrawal/discontinuation categorised as due to the 
COVID-19 pandemic, or non-due to the COVID-19 pandemic based on information 
collected on the COVID-19 Pandemic Study Impact form. The summaries will be based 
on GSK Core Data Standards, and details are provided in Appendix 11: List of Data 
Displays. 
 
14.1.2. 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced of important protocol deviations related to COVID-19, and non-
important protocol deviations related to COVID-19. A listing of important protocol 
deviations related to COVID-19 will also be produced.  
The summaries will be based on GSK Core Data Standards, and details are provided in 
Appendix 11: List of Data Displays. 
 
14.1.3. 
Additional Displays for Participants with a COVID-19 Infection 
A participant is defined as having a suspected, probable or confirmed COVID-19 
infection during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF. 
Summaries and listings of the numbers of participants with a suspected, probable or 
confirmed COVID-19 infection, and of COVID-19 test results will be based on GSK 
Core Data Standards. The details of the planned displays are provided in Appendix 11: 
List of Data Displays. 
Additionally, if greater than 5 participants have a suspected, probable of confirmed 
COVID-19 infection, the following data displays will be produced: 
• Summary of COVID-19 Assessments for Subjects with Suspected, Probable or 
Confirmed COVID-19 Case Diagnosis  


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• Summary of COVID-19 Symptoms for Subjects with Suspected, Probable or 
Confirmed COVID-19 Case Diagnosis 
All of the above displays will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays. 
14.2. 
Safety 
14.2.1. 
Assessment of COVID-19 AEs 
A Standardised MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
The incidence of AEs of COVID-19, and COVID-19 AEs leading to study drug 
discontinuation will be obtained from standard AE summaries.  
If >5% participants report ≥1 COVID-19 AEs, then the following data displays will be 
produced: 
• Summary of COVID-19-Related Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade  
• Summary of COVID-19 Adverse Events Leading to Permanent Discontinuation 
of Study Treatment by Overall Frequency 
• Listing of COVID-19 Adverse Events 
• Listing of COVID-19 Assessments and Symptom Assessments for Subjects with 
COVID-19 Adverse Events 
 
All of the above displays will be based on All of the above displays will be GSK Core 
Data Standards. The details of the planned displays are provided in Appendix 11: List of 
Data Displays. 


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15. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life 
instrument for use in international clinical trials in oncology. J Natl Cancer Institute. 
1993 Mar 3;85(5):365-76. 
Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, et al. 
Development of the National Cancer Institute patient-reported outcomes version of the 
common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 
2014;106:1-11. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
Cocks K, Cohen D, Wisløff F, Sezer O, Lee S, Hippe E, et al. An international field study 
of the reliability and validity of a disease-specific questionnaire module (the QLQ-
MY20) in assessing the quality of life of patients with multiple myeloma. European 
Journal of Cancer. 2007 Jul 31;43(11):1670-8. 
Fayers et. al., The EORTC QLQ-C30 Scoring Manual (3rd Edition) 2001 
GlaxoSmithKline Document Number TMF-14344600 Study ID 205207. DREAMM-4: A 
Phase I/II Single Arm Open-Label Study to Explore Safety and Clinical Activity of 
GSK2857916 Administered in Combination with Pembrolizumab in Subjects with 
Relapsed/Refractory Multiple Myeloma (DREAMM 4). Report Date 21-FEB-2022. 
Ji Y, Li Y, Bekele BN. Dose-finding in phase I clinical trials based on toxicity probability 
intervals. Clin Trials. 2007;4:235–44. 
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-
finding trials. Clin Trials. 2010; 7(6): 653-663. 
Kastritis Efstathios, et al. Evaluation of the Revised International Staging System in an 
independent cohort of unselected patients with multiple myeloma. Haematologica. 2017; 
102(3):593–599. 
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International 
Myeloma Working Group consensus criteria for response and minimal residual disease 
assessment in multiple myeloma. The Lancet Oncology. 2016;17: e328-46. 
Lee J, Liu D. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 2008;5:93-106.  
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Richardson PG. Targeting 
CD38 with daratumumab monotherapy in multiple myeloma. N Eng J Med. 
2015;373:1207-19.  
Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. for the National 
Eye Institute Visual Function Questionnaire Field Test Investigator, "Development of the 
25-item National Eye Institute Visual Function Questionnaire". Arch Ophthalmol. 
2001;119:1050-1058.  
National Cancer Institute (NCI). CTCAE. National Cancer Institute (NCI), 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03; 2010. CTCAE Version 4.03.  


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Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes 
in health-related quality-of-life scores. J Clin Oncol. 1998 Jan;16(1):139-44 
Proskorovsky I., P. Lewis, C. D. Williams, K. Jordan, C. Kyriakou, J. Ishak, et al.  
Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple 
myeloma. Health Qual Life Outcomes. 2014 Mar 11;12:35. 
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. 
International Myeloma Working Group updated criteria for the diagnosis of multiple 
myeloma. The Lancet Oncology. 2014;15: e538-e548. 
Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and 
validity of the ocular surface disease index. Arch Ophthalmol. 2000;118:615-621.  
 


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16. 
APPENDICES 
16.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
This study does not have per protocol population. 
 
 


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16.2. 
Appendix 2: Schedule of Activities 
16.2.1. 
Protocol Defined Schedule of Events 
Refer to Section 7 of Protocol (Version: GSK Document Number TMF-14344600). 


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16.3. 
Appendix 3: Assessment Windows 
No assessment windows will be applied.  
 
 


















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Scoring of the QLQ-C30 Summary Score 
The EORTC QLQ-C30 Summary Score is calculated from the mean of 13 of the 15 
QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact scale are not 
included). Prior to calculating the mean, the symptom scales need to be reversed to obtain 
a uniform direction of all scales. The summary score should only be calculated if all of 
the required 13 scale scores are available. 
QLQ-C30 Summary Score = [Physical Functioning+ Role Functioning+ Social 
Functioning+ Emotional Functioning+ Cognitive Functioning+ (100 - Fatigue) + (100 - 
Pain) + (100 -Nausea_Vomiting) + (100 - Dyspnoea) + (100 - Sleeping Disturbances) + 
(100 - Appetite Loss) + (100 - Constipation) + (100 - Diarrhoea)]/13. 
Handling of missing items 
Single-item measures: if the item is missing, the score S will be set to missing.  
Scales requiring multiple items: if at least half of the items from the scale are available, 
the score S will be calculated based on available items. If more than half of the items 
from the scale are missing, the score S will be set to missing (Fayers et. al., The EORTC 
QLQ-C30 Scoring Manual (3rd Edition) 2001). 
Minimal Important Difference (MID) 
In a sample of patients who received chemotherapy for either breast cancer or small-cell 
lung cancer (n=246, n=80 respectively), the mean change in EORTC QLQ-C30 score 




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Functional scales:    S = 
  
Symptom scales:   S = 
  
A high score for Disease Symptoms and Side Effects of Treatment represents a high level 
of symptomatology or problems, whereas a high score for Future Perspective and Body 
Image represents better outcomes [Proskorovsky, 2014]. 
Missing items can be handled similarly to EORTC QLQ-C30 as described in Section 
16.6.5.1. 
16.6.5.3. 
NEI-VFQ-25 
The NEI-VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 
vision-related constructs, plus an additional single-item general health rating question 
[Mangione, 2001]. The NEIVFQ-25 generates the following 11 vision-targeted sub-
scales: global vision rating, difficulty with near vision activities; difficulty with distance 
vision activities; limitations in social functioning due to vision; role limitations due to 
vision; dependency on others due to vision; mental health symptoms due to vision; 
driving difficulties; limitations with peripheral vision, limitations with color vision; and 
corneal pain. 
The following two Tables (from the NEI-VFQ-25 User Manuals) provide the details of 
converting the original response category to the recorded values, and items of which 
recorded values need to be averaged to generate the VFQ-25 sub-scales. Items that are 
left blank (missing data) are not taken into account when calculating the scale scores. 
Hence scores represent the average for all items in the sub-scale that the respondent 
answered. Sub-scales with at least one item answered can be used to generate a sub-scale 
score. To calculate an overall composite score for the VFQ-25, simply average the 11 
vision-targeted sub-scale scores.  
 














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16.8. 
Appendix 8: Values of Potential Clinical Importance 
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern. The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings. 
 
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) will be used to 
assign grades for relevant laboratory parameters. NCI-CTCAE v4.03 can be found at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
For laboratory data which are not listed in the NCI CTCAE v4.03, a summary of values 
outside the normal range will be provided. 
 
16.8.1. 
ECG Parameters and Vital Signs 
For ECG and vital signs, outputs per the most updated IDSL standard up to the RAP 
effective date will be provided.  
 


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16.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
16.9.1. 
Population Pharmacokinetic (PopPK) Methodology 
Belantamab mafodotin, total mAb, and/or cys-mcMMAF plasma concentration-time data 
may be analyzed by population PK methods using a nonlinear mixed-effects modelling 
approach. 
The key objective of this analysis is to: 
• 
Predict individual pharmacokinetic parameter values for belantamab mafodotin, total 
mAb, and/or cys-mcMMAF  
16.9.1.1. 
Systems 
The population PK analysis will be performed using NONMEM (ICON Solutions) and 
PsN (Perl Speaks NONMEM) or another software platform deemed appropriate. 
Graphical displays and data summary will be produced using R (The R Foundation for 
Statistical Computing). The analysis will be performed by, or under the direct auspices 
of, Clinical Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline using 
the currently supported versions of all software packages. 
16.9.1.2. 
Data Assembly 
Participant data will be collected in the electronic CRF and will be transmitted into a 
validated database by GSK data management. Derived/processed variables will be 
provided by or under the guidance of Clinical Programming. Plasma samples will be 
analyzed using approved analytical methodology. Data will be transferred electronically 
to data managers to be processed and stored in the GSK database. GSK or a designated 
third party will generate the NONMEM input dataset. 
Previously combined belantamab mafodotin, total mAb, and/or cys-mcMMAF PK data 
may be merged with the PK data in Study 205207 in order to provide a pooled 
NONMEM data set. 
16.9.1.3. 
Model Development 
The analysis will use the then-current population pharmacokinetic model for each 
compound analyzed. 
Initially, empirical Bayes estimates will be derived applying the current population PK 
model to the Study 205207 dataset with the MAXEVAL=0 option. If the corresponding 
model diagnostics indicate that this population PK model is appropriate to represent the 
belantamab mafodotin, total mAb, and/or cys-mcMMAF data from Study 205207, then 
individual PK parameter estimates will be based on the current population PK parameter 
values. 
If the parameter set of the current population PK model applied to the Study 205207 
dataset results in substantial bias or if a further exploration of the covariate effect in the 
Study 205207 population is deemed necessary, the parameters of the current population 


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PK model will be re-estimated for the Study 205207 PK data alone and/or for a pooled 
dataset before generating the individual PK parameter estimates. Certain parameter 
values may be fixed to the value in the current population PK model, if they cannot be 
estimated with sufficient precision within the Study 205207 PK population. Covariates 
not available for the Study 205207 PK population but present in the current population 
PK model may be removed from the Study 205207 population PK model. Lastly, a model 
refinement step, if needed, will include, but may not be limited to, a qualification and 
possible modification of the model’s random effect structure. 
16.9.1.4. 
Model Qualification 
Any model development will be supported and the final model will be qualified using the 
following criteria where appropriate: 
• 
Scientific plausibility of parameter estimates 
• 
Goodness of fit plots 
• 
Relative standard errors (RSE) of the parameter estimates 
• 
Objective function value 
• 
Distribution and shrinkage of random effects; 
• 
Successful minimization and execution of covariance step 
• 
Condition number (ratio of the largest and smallest eigenvalue of the covariance 
matrix 
• 
Visual predictive check 
• 
Bootstrap (if deemed necessary/feasible) 






















































































































































































































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16.12. 
Appendix 12: Example Mock Shells for Data Displays 
All data displays are available upon request. 
 


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