Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Belantamab mafodotin Relapsed/Refractory Multiple Myeloma Maximum tolerated doses Overall response rate Overall survival Dose limiting toxicities
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 10
Healthy volunteers: no

Brief summary:
Evaluate the efficacy and safety of Belantamab Mafodotin, cyclophosphamide, and dexamethasone in patients with Relapsed/Refractory Multiple Myeloma

Detailed description:
This is a Phase I/II, open-label study to evaluate the efficacy and safety of Belantamab Mafodotin, cyclophosphamide, and dexamethasone.

In Phase I, the subjects will be assigned into two arms and there are two dose levels for Belantamab Mafodotin and there are two dose levels of cyclophosphamide in each arm.

In Phase II, once tolerability of the highest planned dose is established, the patients will be assessed for response rate. The arm with acceptable toxicity and best response will be further assessed in the expansion cohort.

Belantamab mafodotin was approved by the U.S. Food and Drug Administration (FDA) on Aug 5, 2020, for treating patients with relapsed/refractory multiple myeloma. Cyclophosphamide and dexamethasone are both approved by the FDA. But the combinations with these three drugs to treat people with relapsed/refractory multiple myeloma has not been approved by the FDA.

Arms:
arm 1: 1. Dose level 1: The subject will take 1.9 mg/kg of Belantamab Mafodotin, 300 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 3 weeks cycles.
2. Dose level 2: The subject will take 1.9 mg/kg of Belantamab Mafodotin, 500 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 each 3 weeks cycles. arm 2: 1. Dose level 1: The subject will take 2.5 mg/kg of Belantamab Mafodotin, 300 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 6 weeks cycles.
2. Dose level 2: The subject will take 2.5 mg/kg of Belantamab Mafodotin, 500 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 each 6 weeks cycles.

Interventions: intervention 1: Belantamab Mafodotin, Cyclophosphamide and Dexamethasone
Intervention descriptions: intervention 1: Study drug

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Page 1 of 58 
Version date: 09/12/2022 
 
Study Title Belantamab Mafodotin, Cyclophosphamide and Dexamethasone in 
Relapsed/Refractory Multiple Myeloma 
Sponsor: University of Maryland 
Principal Investigator: Ashraf Badros 
 
Sponsor Protocol Number: 2060GCCC 
Study Drug Name: Belantamab mafodotin (GSK2857916) 
Clinical Phase:  Phase I/II 
Number of Subjects: 58 
IND Number: 155858 
GCC Protocol Number:  2060GCCC 
EudraCT Number:  
Date of Original Protocol: June 11, 2020 
Date of Current Protocol: September 12, 2022  
Version:   
 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements including but 
not limited to Institutional Review Board/Ethics Committee (IRB/EC) approval. 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential. Any distribution, 
copying, or disclosure is strictly prohibited without prior written approval by the Sponsor. 
 
 


 
 
 
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LIST OF STUDY CONTACTS  
Sponsor 
University of Maryland 
22 South Greene Street 
Baltimore, MD 21201 
 
 
Principal Investigator 
Ashraf Badros, MB; ChB 
University of Maryland 
22 South Greene Street 
Baltimore, MD 21201 
  
abadros@UMM.edu 
Phone: (410) 328-1230 
Fax: (410) 328-1975 
 
Clinical Co-Investigators 
Aaron Rapoport, MD 
arapopo@umm.edu 
 
Djordje Atanackovic, MD.  
DAtanackovic@som.umaryland.edu 
 
Susan Ann Hodges, CRNP. 
shodges@umm.edu 
 
Mehmet Hakan Kocoglu, MD 
mkocoglu@umm.edu 
 
Elizabeth Krauss, CRNP, MSN, NP-C 
Elizabeth.Krauss@umm.edu 
Correlative Studies 
Xiaoxuan Fan, Ph.D. 
XiaoxuanFan@som.umaryland.edu 
Rena Lapidus, Ph.D. 
RLapidus@som.umaryland.edu 
 
 
Protocol Coordinator 
Sunita Philip 
University of Maryland 
22 South Greene Street 
Baltimore, MD 21201 
sphilip1@umm.edu 
Phone: (410) 328-8199 
Fax: (410) 328-8616 
 
Study Coordinator 
Thea NashThea.Nash@umm.edu 
 
Phone (410) 328-7680 
Fax: (410) 328-8616 
 
Ophthalmology Investigators 
Wuqaas Munir M.D., 
WMunir@som.umaryland.edu 
Sarah Brem Sunshine,MD 
ssunshine@som.umaryland.edu 
 
Statistical Analysis  
Farin Kamangar, MD, PhD 
Farin.kamangar@morgan.edu 
 
Research Funding 
GlaxoSmithKline Research & 
Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS. UK 
 


 
 
 
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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title:  
 
This study protocol was subjected to critical review and has been approved by the 
Sponsor. The information it contains is consistent with the current risk/benefit evaluation 
of the investigational product as well as with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and the guidelines on 
Good Clinical Practice. 
 
 
_____________________________________ _____________________ 
Ashraf Badros 
Date 
Professor of Medicine  
University of Maryland 


 
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Investigator 
 
Title: Study Principal Investigator 
I have read this study protocol, including all appendices.  By signing this protocol, I agree 
to conduct the clinical study, following approval by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), in accordance with the study protocol, the current 
International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP), and applicable regulatory requirements.  I will ensure that all personnel involved 
in the study under my direction will be informed about the contents of this study protocol 
and will receive all necessary instructions for performing the study according to the study 
protocol. 
 
Investigator 
 
 
_____________________________________ _____________________ 
Ashraf Badros 
Date 
Professor of Medicine 
University of Maryland 
 
 
 
 
 


 
 
 
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Table of Contents 
 
 
 
 
Page 
1.0 Synopsis 
Schedule of activities 
  7 
14 
2.0 Introduction 
2.1 Background of Investigational Product 
2.2 Study rationale 
2.3 Risk Assessment and Management of Belantamab Mafodotin 
17 
17 
18 
19 
3.0 Objective and Endpoints 
3.1 Primary Objectives 
3.2 Primary Endpoints 
3.3 Secondary Endpoints 
3.4 Exploratory Endpoints 
19 
19 
19 
19 
19 
4.0 Study Design 
4.1 Treatment Schedule 
4.2 Number of Participants and Duration of Therapy 
20 
20 
20 
5.0 Study Population 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria  
5.3 Screen Failures 
21 
21 
22 
24 
6.0 Treatment  
6.1 Belantamab Mafodotin 
6.1.1 Belantamab Dose Modification 
6.1.2 Belantamab Mafodotin (GSK2857916) Dose Reductions 
6.1.3 Corneal Supportive Care Guidelines 
6.1.4 Dose Modification for Belantamab-Related Adverse Events 
6.1.5 Dose Modification Guidelines for Corneal-Related Adverse Events 
Associated with Belantamab Mafodotin 
6.2 Cyclophosphamide 
6.2.1 Dose Modification for Cyclophosphamide Related Adverse Events 
6.3 Dexamethasone 
6.3.1 Dose Modification for Dexamethasone Related Adverse Events 
6.4 Guidelines for Therapy-Related Adverse Events Not Otherwise Specified 
6.4.1 Liver Chemistry Stopping Criteria 
6.5 Treatment Compliance 
6.6 Concomitant Therapy 
6.7 Discontinuation of Study Treatment                                                
24 
24 
24 
24 
25 
26 
27 
 
27 
28 
28 
28 
29 
29 
30 
30 
30 
7.0 Correlative Studies 
7.1 Tear Film Collection Procedure for Cytokine Assessment 
7.2 Peripheral Blood Collection for Immune Profile  
30 
30 
31 
8.0 Study Procedures 
8.1 List of Clinical Laboratory Tests 
8.2 Disease Assessment 
8.3 Ocular Examination and Procedures 
8.4 PFS Follow-up 
8.5 Overall Survival Follow-up 
8.6 Reporting Adverse Events 
32 
31 
32 
32 
33 
33 
33 


 
 
 
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8.6.1 Definitions 
8.6.2 Adverse Event of Special Interest (AESI) for Belantamab Mafodotin 
8.6.3 Assessment of Adverse Events 
8.6.3.1 Severity Assessment 
8.6.3.2 Relationship to Study Drug 
8.6.4 Reporting of Adverse Events 
8.6.5 Reporting of Serious Adverse Events 
8.6.6 Reporting to GSK 
8.6.6.1 Quarterly AE/SAE Reporting to GSK 
8.6.7 Collection of Pregnancy Information 
8.6.8 Reporting Product Complaints for Belantamab Mafodotin 
33 
35 
3 
34 
35 
35 
35 
36 
36 
36 
37 
9.0 Statistical Analysis 
9.1 Study Objectives 
9.2 Sample Size 
9.3 Statistical Analysis 
9.3.1 Phase I 
9.3.2 Phase II 
9.3.3 Planned Analyses  
38 
38 
38 
39 
39 
39 
39 
10.0 Study Oversight & Data Reporting/Regulatory Requirements 
10.1 Data Quality Assurance 
10.2 SAE and Reporting Definitions 
10.3 MedWatch 3500A Reporting Guidelines 
10.4 Assessing Causality 
10.5 Safety Reporting Requirements for IND Holders 
10.6 Calendar-Day Telephone or Fax Report 
10.7 Calendar-Day Written Report 
10.8 Study Initiation 
10.9 Institutional Review Board Approval 
10.10 Informed Consent 
10.11 Study Monitoring Requirements 
10.12 Data Collection 
10.13 Study Medication Accountability 
10.14 Disclosure of Data 
10.15 Retention of Records 
10.16 Study Completion 
40 
40 
40 
40 
41 
41 
41 
42 
42 
42 
43 
43 
43 
43 
43 
44 
44 
11.0 References                                                                                                                45 
Appendix  
A. Ocular Grading scale 
B. ECOG performance status  
C. IMWG response criteria 
D. Study Monitoring and SAE reporting 
E. Permitted and prohibited medications 
F. Liver Safety  
G. Ocular Monitoring 
H. Contraceptive Guidelines 
I. Human PBMC Staining Protocol 
 
46 
47 
48 
49 
50 
51 
53 
56 
57 


 
 
 
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1. 
SYNOPSIS 
Study Title: Belantamab Mafodotin, Cyclophosphamide and Dexamethasone in Relapsed/Refractory 
Multiple Myeloma 
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 US in 2016.  Despite 
significant advances in treatment options, including hematopoietic stem cell transplant (HSCT), and novel 
therapies like second- and third-generation proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), 
and the recent addition of monoclonal antibodies (mAbs), most MM patients will ultimately develop 
resistance to existing therapies.  
Belantamab mafodotin is a humanized (IgG1) antibody-drug conjugate (ADC) which binds to BCMA, a 
target widely expressed on malignant plasma cells in MM.  The parent anti-BCMA antibody is conjugated 
to the microtubule inhibitor, MMAF, which is released inside the malignant cell after binding and 
internalization of the antibody.  The normal function of BCMA is to promote cell survival by transduction 
of signals from two known ligands: B-cell activating factor from the tumor necrosis factor (TNF) family 
(BAFF/BLyS), and APRIL, a proliferation-inducing ligand.  In DREAMM-1 study, belantamab mafodotin 
(3.4-mg/kg every 3 weeks) demonstrated promising single-agent activity inducing rapid and durable 
responses [overall response rate (ORR) of 60% with a median progression free survival (PFS) of 12 
months]. In DREAMM-2 study, patients received (2.5-mg/kg or 3.4-mg/kg) with an ORR of 31%-34% and 
a median progression-free survival of 2.9-4.9 months, for 2.5-mg/kg and 3.4-mg/kg, respectively. The most 
common adverse events in both studies were eye complications (70% irrespective of the dose) and 
thrombocytopenia (21% and 44%, which was dose dependent). 
Cyclophosphamide was shown to synergistically enhance the therapeutic activities of several 
antibodies in B cell malignances; for e.g. cyclophosphamide, enhanced rituximab induced B cell 
toxicity by increasing acute secretory activation phenotype (affecting tumor necrosis factor α, 
interferon γ as well as interleukin (IL)-6, IL-10, and IL-12.). In addition, cyclophosphamide alters 
overall immune regulatory cells leading to stimulation of the cytotoxic functions of T lymphocytes 
(CD-44 lymphocytes), inhibition of regulatory T cells (CD-4/CD-25) and increasing the 
macrophage induced phagocytosis. In MM, cyclophosphamide has limited activity especially in 
the relapsed and refractory setting; however, in combination with other agents such as 
Daratumumab, pomalidomide and carfilzomib it led to enhanced efficacy. It would be very 
interesting to investigate the impact of the immune modulatory properties of cyclophosphamide 
on the ophthalmology effects of belantamab. We hypothesize that immune-modulatory properties 
of cyclophosphamide in combination with Belantamab mafodotin can improve ORR in 
relapsed/refractory (RR) MM by combining direct tumor kill, with enhanced cytokine profile, 
cellular toxicity and phagocytosis with no increased toxicities.  
Objectives and Endpoints 
 
Primary Objectives: 
(1) 
To characterize the safety and tolerability of chemotherapeutic regimen belantamab mafodotin, 
cyclophosphamide, and dexamethasone in patients with relapsed/refractory multiple myeloma. 
 (2)        Identifying the maximum tolerated dose and recommended Phase 2 dose. 


 
 
 
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Primary Endpoints  
(1) Incidence of RLTs  
(2) Treatment emergent adverse events 
(3) Treatment-related adverse events. 
Secondary Endpoints 
(1) 
The overall response rate of the better tolerated regimen in an expansion cohort. 
(2) 
The percentage of patients with confirmed partial (or better) response 
(3) 
Duration of response 
(4) 
Time to response 
(5) 
Time to progression 
(6) 
Progression-free survival (PFS) 
(7) 
Overall survival (OS) 
Exploratory Endpoints 
Obtain exploratory data on cytokine profile in the eye and T cell subsets in the peripheral blood before and 
after initiation of therapy (cycle 2 day 1). 
 
Overall Study Design: This is a Phase I/II, open-label study to evaluate the efficacy and safety of 
Belantamab Mafodotin, cyclophosphamide and dexamethasone.  
Treatment schedule 
Phase I 
 
 
Belantamab Mafodotin  
   Cyclophosphamide       Dexamethasone 
pts # 
Arm A (cycles repeated every 3 weeks) 
 
 
 
Day 1   
 
           Day 1  
 
           Day 1 
 
Dose level 1 
 
1.9 mg/kg 
 
         300 mg 
 
          40 mg 
 
3-6 
Dose level 2 
 
1.9 mg/kg 
 
         500 mg 
         
          40 mg 
 
3-6 
 
Arm B (cycles repeated every 6 weeks) 
Day 1  
 
           Day 1 
 
           Day 1 
Dose level 1 
 
2.5 mg/kg 
 
         300 mg 
 
          40 mg                   3-6 
Dose level 2 
 
2.5 mg/kg 
 
         500 mg 
 
          40 mg 
 
3-6 
 
 
- 
Patients will be assigned to Arm A and B sequentially (one patient to arm A and the next to Arm B); there is no 
randomization and no stratification.  


 
 
 
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Version date: 09/12/2022 
- 
3 patients will be treated at each dose level. Patients will be assessed for RLT defined as:  
- 
Any non-hematological toxicity Grade ≥ 3, except: 
• 
Alopecia 
• 
Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic and other 
supportive care 
• 
Grade 3 fatigue for less than 1 week 
• 
Grade 3 or higher isolated electrolyte abnormalities that last up to 72 hours, are not clinically 
complicated, and resolve spontaneously or respond to conventional medical interventions 
• 
Grade 3 or higher amylase or lipase elevation that is not associated with symptoms or clinical 
manifestations of pancreatitis 
• 
Grade 3 tumor lysis syndrome (TLS) that lasts up to 72 hours, is not clinically complicated, and resolves 
spontaneously or responds to conventional medical interventions 
- 
Grade 4 neutropenia lasting more than 5 days 
- 
Febrile neutropenia of any duration (ANC <1.0 x 109/L, fever ≥ 38.4°C or ≥ 38° C for 1 hour) 
- 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically significant bleeding  
- 
Grade 4 anemia, unexplained by underlying disease 
- 
Grade 5 event from any cause. 
- 
If 1 of 3 patients within a dose level developed RLT, 3 more will be treated at the same dose level, if no additional 
toxicity occurs. Proceed to the next dose level if </=1 out of 6 patients experience RLT.  
- 
There is no planned dose escalation for MTD.  
- 
Three patients can be simultaneously enrolled on each arm. Subsequent dose escalation can occur after 
observation of one cycle in each cohort. 
- 
All concomitant meds will be recorded on each visit.  
- 
All patients will be provided a daily symptom log for reporting side effects. 
- 
Response will be assessed using revised IMWG criteria. 
Phase II 
Expansion Cohort 
- 
Once tolerability of the highest planned dose is established, patients will be assessed for response rate. 
The arm with acceptable toxicity and best response will be further assessed in the expansion cohort. 
Number of Participants:  
- 
Phase 1; for arm A and B 12-24 patients 
- 
Phase II: 40 patients will be enrolled. If 21 responses are seen, the treatment would be recommended 
for further study.  
 
Treatment Groups and Duration:  
The enrolled patients will be treated with belantamab mafodotin. until any of the following: 
• 
Occurrence of an AE which makes discontinuation from treatment necessary due to protocol-
specified safety criteria or desirable in the investigator’s and/or the subject´s opinion 
• 
Investigator’s decision that a change of therapy is in the subject´s best interest 
• 
Investigator’s decision that a subject does not benefit from treatment anymore, e.g., non-
response or development of progressive disease  
• 
Intercurrent medical condition, which in the opinion of the investigator or the subject precludes 
further treatment of the subject  
• 
Withdrawal of subject’s consent to further study treatment 
• 
Death 
• 
Lost to follow-up 
 


 
 
 
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Inclusion Criteria:  
1. 
Histologically confirmed diagnosis of Refractory MM; 
Has  received at least 3 prior classes of anti-myeloma drugs, including an anti-CD38 antibody (e.g., 
daratumumab) alone or in combination, and is refractory to an IMiD (i.e., lenalidomide or 
pomalidomide), and to a proteasome inhibitor (e.g., bortezomib, ixazomib or carfilzomib).  (Refractory 
myeloma is defined as disease that is nonresponsive while on primary or salvage therapy or progresses 
within 60 days of last therapy.  Nonresponsive disease is defined as either failure to achieve at least 
minimal response or development of progressive disease (PD) while on therapy).  
2. 
Has measurable disease with at least 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 and an abnormal ratio (<0.26 or >1.65) 
d. Non secretory myeloma patients can be enrolled if: 
Bone marrow shows > 20% plasma cells 
PET/CT scan is positive for myeloma 
3. 
Provide signed written informed consent 
4. 
18 years or older (at the time consent is obtained)  
5. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
6. 
Participants with a history of autologous stem cell transplant or prior BCMA targeted therapy (e.g. 
CAR-T cells, BiTes) can enroll on the study provided that: 
a. Therapy was >100 days prior to study enrolment 
b. No active infection(s) 
7. 
Adequate organ system function  
System 
Laboratory Values 
Hematologic 
Absolute neutrophil count (ANC) 
1.0 X 109/L 
Hemoglobin 
8.0 g/dL 
Platelets 
50 X 109/L 
Hepatic 
 
Total bilirubin 
≤1.5X ULN  
Except in patients with congenital 
bilirubinemia, such as Gilbert syndrome, 
direct bilirubin ≤1.5 x ULN 
ALT 
2.5 X ULN 
Renal eGFR 
30 mL/min/1.73 m2  
 
Urine Dipstick  
 
Or 
 
Albumin/creatinine ratio (from spot urine) 
Negative/trace (if ≥ 1+ only eligible if confirmed 
≤500 mg/g by albumin/creatinine ratio (spot 
urine) 
 
500 mg/g (56 mg/mmol) 
 
8. 
Female participants: Contraceptive use for those participating in clinical studies (men or women) 
should be consistent with local regulations   
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 
one of the following conditions applies:  


 
 
 
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a. Is not a woman of childbearing potential (WOCBP) 
OR 
b. 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, during the intervention period and for at 
least 12 months 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. 
- 
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.  
- 
We will review the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a woman with a new undetected pregnancy. 
Non childbearing potential is defined as follows (by other than medical reasons): 
- 
≥45 years of age and has not had menses for >1 year 
- 
Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and 
oophorectomy must have a follicle stimulating hormone value in the postmenopausal range 
upon screening evaluation 
- 
Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical 
records of the actual procedure. 
9. 
Male participants: contraceptive use should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.   
Male participants are eligible to participate if they agree to the following during the intervention 
period and for 6 months after the last dose of study treatment to allow for clearance of any altered 
sperm: 
a. 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 and 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 when having sexual intercourse 
with a woman of childbearing potential  
 
10. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE), version 5.0) must be ≤ Grade 1 at the time of enrollment except 
for alopecia and Grade 2 peripheral neuropathy. 
 
 
 
 


 
 
 
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Exclusion Criteria:  
1. 
Systemic anti-myeloma therapy within ≤14 days or 5 half-lives, whichever is shorter, or 
plasmapheresis within 7 days prior to the first dose of study drug 
2. 
Systemic treatment with high dose steroids (equivalent to >60 mg prednisone daily for ≥4 days) within 
the past 14 days if administered to treat MM or non- MM disease 
3. 
Prior allogeneic transplant (SCT). NOTE – Participants who have undergone syngeneic transplant may 
be allowed, if no history of GvHD 
4. 
Current corneal epithelial disease except mild punctate keratopathy  
5. 
Evidence of active bleeding 
6. 
Any major surgery within the last four weeks 
7. 
Presence of active renal condition (infection, requirement for dialysis or any other condition that could 
affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, 
provided participants fulfil entry criteria (as defined by inclusion criteria #7) 
8. 
Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including 
lab abnormalities) that could interfere participants’ safety, obtaining informed consent or compliance 
with study procedures.  
9. 
Current unstable liver disease per Investigator assessment defined by the presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, 
or cirrhosis. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or 
asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.  
10. Other malignancies are excluded, except for malignancy from which the patients have been disease-
free for more than 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, prostate cancer or in situ cervical cancer that has undergone potentially curative 
therapy. 
11. Evidence of cardiovascular disease including any of the following: 
a) Evidence of current clinically significant untreated arrhythmias, including clinically significant 
ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) 
block. 
b) History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary 
angioplasty, or stenting or bypass grafting within 3 months of screening. 
c) Class III or IV heart failure as defined by the New York Heart Association functional classification 
system.  
d) Uncontrolled hypertension. 
12. 
Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically 
related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any other 
components of the study treatment. 
13. Active infection requiring treatment. 
14. Known HIV infection. 
15. 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.  Note:  presence of Hep B surface antibody 
(HBsAb) indicating previous vaccination will not exclude a participant. 


 
 
 
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16. 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: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, 
only if a confirmatory negative Hepatitis C RNA test is obtained. Hepatitis RNA testing is optional and 
participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA 
testing. 
17. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of 
screening. 
18. Pregnant or lactating female 
19. Concomitant administration of strong P-glycoprotein inhibitors and inhibitors of OATP. 


 
 
 
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Schedule of Activities (SOA) 
Arm A; 3-week (21 Day) cycle14 
 
Study Assessments8 
Screen
1 
 
Cycle 1-6; 
day 1 
>Cycle 6 
day 1 
Once ≥ 
VGPR 
End of 
Treatment 
30 day 
Follow-Up  
PFS 
Follow-
up 5 
OS 
Follow
-up6 
Window 
30 
days 
± 3 days 
± 3 days 
 
±14 days 
± 3 days 
± 7 
days 
± 14 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
 
Q3M 
 
Concomitant Meds 
X 
X 
X 
X 
X 
 
 
 
Adverse Events10 
 
X 
X 
X 
X 
X 
 
 
Ocular Exam7 
X 
Every cycle and as clinically 
indicated 
X 
 
Q3M 7 
 
ECOG  
X 
X 
X 
X 
X 
 
 
 
Vitals4 (BP, HR, 
Temp) 
X 
X 
X 
X 
X 
 
 
 
Weight and Height13 
X 
X 
X 
 
X 
 
 
 
CBC with diff  
X 
X 
X 
X 
X 
 
 
 
Chemistry Panel 
X 
X 
X 
X 
X 
 
 
 
eGFR 
X 
X 
X 
 
X 
 
 
 
Urinalysis (dipstick) 
OR Spot Urine 
(albumin/creatinine 
ratio)11 
X 
X 
X 
 
X 
 
 
 
HBsAg, HBcAb, hep 
C Ab 
X 
 
 
 
X 
 
 
 
Pregnancy Test9  
X 
X 
X 
X 
X 
 
 
 
Beta2 microglobulin 
X 
 
 
X 
X 
 
 
 
Skeletal survey2 
X 
To Confirm  ≥ VGPR 
X 
 
 
 
Imaging for 
Extramedullary3 
X 
To Confirm  ≥ VGPR 
 
 
 
 
UPEP/IFE (24 hr. 
urine) 
X 
X 
X 
X 
X 
 
Q3M 
 
SPEP/IFE 
X 
X 
X 
X 
X 
 
Q3M 
 
C-reactive protein 
X 
 
 
 
 
 
 
 
Serum FLC levels 
and ratio 
X 
X 
X 
X 
X 
 
Q3M 
 
IgG, IgM, IgA 
X 
X 
X 
X 
X 
 
Q3M 
 
BM for FISH  
X 
To Confirm  ≥ VGPR 
X 
 
 
 
BM aspirate for 
BCMA IHC 
X 
X 
 
 
 
BM for MRD testing 
 
 
 
 
 
BM for disease 
assessment 
X 
X 
 
 
 
Correlative studies12 
X 
C2D1 
 
 
 
 
 
 
Treatment 
administration  
 
X 
X 
X 
 
 
 
 


 
 
 
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Schedule of Activities (SOA) 
Arm B;  6-week (42 day) cycle 
 
Study 
Assessments8 
Screen1 
Cycle 1-6; 
day 1 & 22 
>Cycle 6 
day 1 
Once ≥ 
VGPR 
End of 
Treatment  
30 day 
Follow-
Up 
PFS 
Follow-
up5 
OS 
Follow
-up6 
Window 
30 days 
± 3 days 
± 3 days 
 
±14 days 
± 3 days 
± 7 
days 
± 14 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
Physical Exam 
X 
DAY 1 
X 
X 
X 
 
Q3M 
 
Concomitant Meds 
X 
X 
X 
X 
X 
 
 
 
Adverse Events10  
 
X 
X 
X 
X 
X 
 
 
Ocular Exam7 
X 
Day 1 of Every Cycle and as clinically 
indicated 
X 
 
Q3M7 
 
ECOG  
X 
DAY 1 
X 
X 
X 
 
 
 
Vitals4 (BP, HR, 
Temp) 
X 
Day 1  
X 
X 
X 
 
 
 
Weight and Height13 
X 
X 
X 
 
X 
 
 
 
CBC with diff  
X 
X 
X 
X 
X 
 
 
 
Chemistry Panel 
X 
X 
X 
X 
X 
 
 
 
eGFR 
X 
X 
X 
 
X 
 
 
 
Urinalysis (dipstick) 
OR Spot Urine 
(albumin/creatinine 
ratio)11 
X 
DAY 1 
X 
 
X 
 
 
 
HBsAg, HBcAb, 
hep C Ab 
X 
 
 
 
X 
 
 
 
Pregnancy Test9  
X 
DAY 1 
X 
X 
X 
 
 
 
Beta2 microglobulin 
X 
 
 
X 
X 
 
 
 
Skeletal survey2 
X 
To Confirm  ≥ VGPR 
X 
 
 
 
Imaging for 
Extramedullary3 
X 
To Confirm  ≥ VGPR 
 
 
 
 
UPEP/IFE (24 hr. 
urine) 
X 
DAY 1 
X 
X 
X 
 
Q3M 
 
SPEP/IFE 
X 
DAY 1 
X 
X 
X 
 
Q3M 
 
C-reactive protein 
X 
 
 
 
 
 
 
 
Serum FLC levels 
and ratio 
X 
DAY 1 
X 
X 
X 
 
Q3M 
 
IgG, IgM, IgA 
X 
DAY 1 
X 
X 
X 
 
Q3M 
 
BM for FISH  
X 
To Confirm  ≥ VGPR 
X 
 
 
 
BM aspirate for 
BCMA IHC 
X 
X 
 
 
 
BM for MRD 
testing 
 
 
 
 
 
BM for disease 
assessment 
X 
X 
 
 
 
Correlative studies12 
X 
C2D1 
 
 
 
 
 
 
Treatment 
administration  
 
DAY1 
X 
X 
 
 
 
 
BM = bone marrow; BP = blood pressure; C1D1 = Cycle 1 Day 1, etc.  CRP = C-reactive protein; FISH = fluorescence in situ 
hybridization; FLC = free light chain; HR= heart rate; Ig = immunoglobulin. 
 
 


 
 
 
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Footnotes for Schedule of Activities 
1. All screening assessments must be performed within 30 days prior to first dose.  
2. Skeletal Survey should include imaging of bones for lytic lesions by X-ray, CT, or MRI as clinically indicated.  .   
3. PET/CT is indicated for all patients with possible extramedullary disease (symptoms or high LDH [ULN])   
4. At the first dose of belantamab mafodotin, vital signs must be assessed within 30 min prior to Start of Infusion 
(SOI), 15 mins after SOI, (±10 min), within 15 min after End of Infusion (EOI), and at 1 h (±10 min) after EOI. 
On subsequent doses of belantamab mafodotin, vital signs must be assessed within 30 minutes prior to SOI and 
within 15 min after EOI.  
5. Progression-Free Survival (PFS) Follow-up Every 3 months (+/- 7 days) for 9 months 
6. Overall Survival (OS) Follow-up Every 3 months (+/- 14 days) for 9 months 
7. C1D1 ocular exam does not need to be repeated if within 21 days of screening exam. On treatment ocular exams 
to be performed Q3W (Arm A),Q 6W (Arm B) prior to each dose. Ocular exam may be performed up to 5 days 
prior to second dose onwards for belantamab mafodotin.   Participants in PFS follow up or OS follow up will 
only have ocular exams if they had signs or symptoms at EOT. See Section 6.1.3. 
8. All laboratory tests with values considered clinically significantly or abnormal during participation in the study 
or within 70 days after the last dose of study treatment should be repeated weekly until the values return to normal 
or baseline. 
9. Perform only on women of childbearing potential (WOCBP). A serum pregnancy test must be performed at 
screening; if the test is completed within 72 hours prior to the first dose of belantamab mafodotin, this assessment 
does not have to be repeated on C1D1. For questionable cases, follicle-stimulating hormone (FSH) and estradiol 
(as needed in WOCBP) should be performed at local lab to determine childbearing potential. WOCBP must have 
a negative highly sensitive serum pregnancy test within 72 hours of dosing on C1D1. Subsequent pregnancy tests 
on dosing days may be either serum or urine. Final pregnancy test (serum or urine) must be performed in WOCBP 
at the EOT Visit. Follow up pregnancy assessment by telephone (for WOCBP only) should be performed 4 months 
after the last dose of belantamab mafodotin. 
10. AE/SAEs will be collected from the start of study treatment until at least 70 days following EOT, regardless of 
initiation of new cancer therapy. 
11. Urine dipstick may be used to assess for presence of urine protein. Albumin/creatinine ratio needs to be done in 
any participant with urine dipstick result of >1+ at Screening or >2+ on treatment, or with positive protein if 
urine dipstick protein quantification is not available.  
12. Correlative studies include obtaining tear drops for cytokine assessment and 5 ml peripheral blood for assessment 
of T cell profile at Screening, C2D1, and per clinician’s discretion. 
13. Height measure is required only at screening, Arm A and Arm B 
14. Arm A subject will follow Arm B Schedule of Activities if dosing schedule is changed to Q6W  
 
 


 
 
 
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2.0 INTRODUCTION 
Multiple myeloma (MM) is an incurable malignancy and accounts for 1% of all cancers and for 10% of all 
hematologic malignancies.  Approximately 33,000 new cases are diagnosed annually, and 13,000 deaths 
will occur in the US.  There have been significant advances in treatment for MM, including therapies like 
second and third -generation proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and 
monoclonal antibodies (mAbs).  Those advances have contributed to incremental gains in PFS and OS, but 
most MM patients still relapse and ultimately develop resistance to existing therapies highlighting the need 
for new drugs with novel targets. 
B-cell maturation antigen (BCMA) 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 promotes B-cell survival and proliferation.  BCMA is expressed on 
malignant plasma cells in all MM patients.  Chimeric Antigen Receptor T-Cells (CAR-T) based therapies 
targeting BCMA have also demonstrated powerful activity against MM, with substantial albeit reversible 
risks.  Other approaches utilizing bispecific antibodies (BiTe) have also entered development.   
2.1 Background of Investigational Product 
Belantamab mafodotin (GSK2857916) is a dual acting Antibody-Drug Conjugate (ADC), comprised of an 
anti-B-Cell Maturation Antigen (BCMA) afucosylated humanized immunoglobulin G1 (IgG1) conjugated 
with the tubulin polymerization disrupting agent monomethyl auristatin F (MMAF).  
The normal function of BCMA is to promote cell survival by transduction of signals from two known 
ligands: B cell activating factor from the tumor necrosis factor (TNF) family (BAFF/BLys) and a 
proliferation inducing ligand (APRIL). BCMA expression is restricted to B cells at later stages of 
differentiation, with expression on germinal center B cells in tonsil, blood plasma blasts, and long-lived 
plasma cells. BCMA is expressed in various B cell malignancies, including multiple myeloma (MM), 
diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), chronic lymphocytic leukemia 
(CLL) and Waldenstrom’s macroglobulinemia (WM) at varying frequencies. Belantamab mafodotin binds 
to BCMA, is internalized, and releases free cys-mcMMAF, which disrupts the microtubule network, leading 
to cell cycle arrest and apoptosis. Belantamab mafodotin also mediates antibody-dependent cell-mediated 
cytotoxicity (ADCC) effector function directed towards BCMA-expressing cells. The mechanisms of action 
of belantamab mafodotin are designed to enable anti-tumor activity of cells by ADCC activity (non-
dividing), as well as ADC activity (dividing cells). Moreover, ADC-induced apoptosis by belantamab 
mafodotin was recently shown to be potentially immunogenic as measured by cell surface externalization 
of calreticulin (CRT) and secretion of high mobility group box 1 (HMGB1) and adenosine triphosphate 
(ATP). 
Clinical and non-clinical data for belantamab mafodotin are discussed in detail in the Investigators Brochure 
(IB).  
 
 
 
 


 
 
 
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2.2 Study Rationale 
Patients with MM who relapse after IMiDS, SCT, PI and daratumumab therapy, have few treatment options 
available and could benefit from treatment with a novel drug such as Belantamab mafodotin.  Belantamab 
mafodotin is a first in class, ADCC enhanced, humanized immunoglobulin G1 (IgG1) antibody-drug 
conjugate (ADC) that binds specifically to B-cell maturation antigen (BCMA), a target present on mature 
B cells and on tumor cells in patients with MM.  The antibody is conjugated to the microtubule inhibitor 
monomethyl auristatin-F (MMAF) and is produced as an afucosylated form that generates an enhanced 
antibody-dependent cellular cytotoxicity (ADCC) response.  This novel mechanism of action can be 
reasonably expected to overcome cross resistance to existing therapies. Single agent Belantamab mafodotin 
pharmacokinetics were linear over the range of doses tested, with exposure of all analytes increasing 
proportionately with increasing dose. In DREAMM-1 study, single agent belantamab mafodotin (3.4-mg/kg 
every 3 weeks) demonstrated promising single-agent activity inducing rapid and durable responses [overall 
response rate (ORR) of 60% with a median progression free survival (PFS) of 12 months]. In DREAMM-
2 study, patients received (2.5-mg/kg or 3.4-mg/kg) with an ORR of 31%-34% and a median progression-
free survival of 2.9-4.9 months, for 2.5-mg/kg and 3.4-mg/kg, respectively. The most common adverse 
events in both studies were eye complications (70% irrespective of the dose) and thrombocytopenia (21% 
and 44%, which was dose dependent).  
Cyclophosphamide synergistically enhanced many therapeutic antibodies in several models of B cell 
malignances; for e.g. cyclophosphamide, enhanced rituximab induced B cell toxicity by increasing acute 
secretory activation phenotype (affecting tumor necrosis factor α, interferon γ as well as interleukin (IL)-6, 
IL-10, and IL-12.). In addition, cyclophosphamide alters overall immune regulatory cells leading to 
stimulation of the cytotoxic functions of T lymphocytes (CD-44 lymphocytes), inhibition of regulatory T 
cells (CD-4/CD-25) and increasing the macrophage induced phagocytosis. In MM, cyclophosphamide has 
limited activity especially in the relapsed and refractory setting; however, in combination with other agents 
such as Daratumumab, pomalidomide and carfilzomib it led to enhanced activity. It would be very 
interesting to investigate the impact of the immune modulatory properties of cyclophosphamide on the 
ophthalmology effects of belantamab.  
We hypothesize that immune-modulatory properties of cyclophosphamide in combination with Belantamab 
mafodotin can improve ORR in relapsed/refractory (RR) MM by combining direct tumor kill, with 
enhanced cytokine profile, cellular toxicity and phagocytosis with no increased toxicities.  
2.3 Study Risk  
 
Corneal AEs have been observed with various ADC drugs and represent the most commonly reported types 
of AEs associated with Belantamab.  As there is no single term which appropriately captures these events, 
the term ‘corneal events’ includes reported preferred terms (from Eye Disorders System Organ Class) 
describing events associated with the corneal events related to Belantamab.  The most commonly reported 
corneal events included vision blurred, dry eye, photophobia, and lacrimation increased.  More severe cases 
included keratitis. In most cases the vision returned to baseline after stopping therapy.  Interestingly, 90% 
of participants 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 participants experiencing these clinical findings. Additional information about the known and 
expected benefits and risks, detailed information of nonclinical and clinical findings information regarding 
warnings, precautions, contraindications, adverse events, and other pertinent information on Belantamab 
that may impact participant eligibility is provided in the Investigator’s Brochure.  


 
 
 
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Cyclophosphamide is a known cancer drug with known side effects that include bone marrow suppression, 
nausea, vomiting reversible alopecia. The combination with Belantamab has not been studied and will be 
carefully assessed in the current study.  
2.3 Risk Assessment and Management of Belantamab Mafodotin 
Please refer to section 6 of the current Investigator brochure for the comprehensive and updated 
list of adverse events. 
 All risks will be considered against the potential benefit to patients who have no other therapeutic 
options. Patients will be closely monitored on the study; they will continue therapy if the risk/ benefit 
ratio is favorable and reasonable.  
3.0 Objectives and Endpoints 
3.1 Primary Objectives: 
(1) 
To characterize the safety and tolerability of chemotherapeutic regimen belantamab mafodotin, 
cyclophosphamide, and dexamethasone in patients with relapsed/refractory multiple myeloma. 
 (2)        Identifying the maximum tolerated dose and recommended Phase 2 dose. 
3.2 Primary Endpoints  
(1) Incidence of RLTs  
(2) Treatment emergent adverse events 
(3) Treatment-related adverse events. 
3.3 Secondary Endpoints 
(1) 
The overall response rate of the better tolerated regimen in an expansion cohort. 
(2) 
The percentage of patients with confirmed partial (or better) response 
(3) 
Duration of response 
(4) 
Time to response 
(5) 
Time to progression 
(6) 
Progression-free survival (PFS) 
(7) 
Overall survival (OS) 
 
3.4. Exploratory Endpoints 
Obtain exploratory data on cytokine profile in the eye and T cell subsets in the peripheral blood before and 
after initiation of therapy (cycle 2 day 1). 
 


 
 
 
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4.0 Study Design; This is a Phase I/II, open-label study to evaluate the efficacy and safety of Belantamab 
Mafodotin, cyclophosphamide and dexamethasone.  
 
4.1 Treatment schedule 
Phase I 
 
 
Belantamab Mafodotin  
   Cyclophosphamide       Dexamethasone 
pts # 
Arm A (cycles repeated every 3 weeks) 
 
 
 
Day 1   
 
             Day 1   
           Day 1 
 
Dose level 1 
 
1.9 mg/kg 
 
             300 mg  
           40 mg 
 
3-6 
Dose level 2 
 
1.9 mg/kg 
 
             500 mg  
           40 mg 
 
3-6 
 
Arm B (cycles repeated every 6 weeks) 
Day 1  
 
             Day 1  
           Day 1 
Dose level 1 
 
2.5 mg/kg 
 
             300 mg  
           40 mg 
 
3-6 
Dose level 2 
 
2.5 mg/kg 
 
             500 mg  
           40 mg 
 
3-6 
 
 
- 
Patients will be assigned to Arm A and B sequentially (one patient to arm A and the next to Arm B); there is no 
randomization and no stratification.  
- 
3 patients will be treated at each dose level. Patients will be assessed for RLT (defined as grade 3-4 
nonhematologic toxicity that fails to recover to grade 1 in 7 days; 7 days delay due to toxicity; treatment related 
death). If 1 of 3 developed RLT, 3 more will be treated at the dose level, if no additional toxicity 1 out of 6 RLT 
will proceed to next dose level.  
- 
There is no planned dose escalation for MTD.  
- 
Three patients can be simultaneously enrolled on each arm. Subsequent dose escalation can occur after 
observation of one cycle in each cohort. 
- 
All concomitant meds will be recorded on each visit.  
- 
All patients will provide a diary symptom log for reporting side effects.  
- 
Response will be assessed using revised IMWG criteria. 
- 
RLT assessment duration will be 3 weeks for arm A and 6 weeks for arm B.  
- 
If ≥2/6 RLT occurs in the lowest dose, the protocol will be placed on hold for unacceptable toxicity until further 
negotiation/discussion with regulatory bodies (e.g. IRB, FDA) occur. 
 
Phase II; Expansion Cohort 
Once tolerability of the highest planned dose is established, patients will be assessed for response rate. The 
arm with acceptable toxicity and best response will be further assessed in the expansion cohort. 
 
4.2 Number of Participants and duration of therapy:  
- 
Phase 1: for arm A and B 12-24 patients 
- 
Phase II: 40 patients will be enrolled. If 21 responses are seen, the treatment would be recommended 
for further study.  
- 
Patients will be treated until disease progression or until unacceptable toxicity. For patients who 
discontinue study treatment for reasons other than PD, disease evaluations will continue to be 


 
 
 
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Version date: 09/12/2022 
performed at monthly intervals until confirmed PD, death, start of a new anticancer treatment, 
withdrawal of consent, or end of the study whichever occurs first.   
 
5.0 Study Population 
5.1 Inclusion Criteria:  
1. Histologically confirmed diagnosis of Refractory MM  
a. Has received at least 3 prior classes of anti-myeloma drugs, including an anti-CD38 antibody 
(e.g., daratumumab) alone or in combination, and is refractory to an IMiD (i.e., lenalidomide 
or pomalidomide), and to a proteasome inhibitor (e.g., bortezomib, ixazomib or carfilzomib). 
(Refractory myeloma is defined as disease that is nonresponsive while on primary or salvage 
therapy or progresses within 60 days of last therapy.  Nonresponsive disease is defined as 
either failure to achieve at least minimal response or development of progressive disease (PD) 
while on therapy). 
2. Has measurable disease with at least 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 and an abnormal ratio (<0.26 or >1.65) 
d. Non secretory myeloma patients can be enrolled if: 
Bone marrow shows > 20% plasma cells 
PET/CT scan is positive for myeloma 
3. Provide signed written informed consent 
4. 18 years or older (at the time consent is obtained)  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
6. Participants with a history of autologous stem cell transplant or prior BCMA targeted therapy (e.g. 
CAR-T cells, BiTes) can enroll on the study provided that: 
a. Therapy was >100 days prior to study enrolment 
b. No active infection(s) 
7. Adequate organ system function: 


 
 
 
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System 
Laboratory Values 
Hematologic 
Absolute neutrophil count (ANC) 
1.0 X 109/L 
Hemoglobin 
8.0 g/dL 
Platelets 
50 X 109/L 
Hepatic 
 
Total bilirubin 
≤1.5X ULN  
Except in patients with congenital bilirubinemia, such 
as Gilbert syndrome, direct bilirubin ≤1.5 x ULN 
ALT 
2.5 X ULN 
Renal eGFR 
30 mL/min  
Urine Dipstick  
 
Or 
 
Albumin/creatinine ratio (from spot urine) 
Negative/trace (if ≥ 1+ only eligible if confirmed 
≤500 mg/g by albumin/creatinine ratio (spot 
urine) 
 
500 mg/g (56 mg/mmol) 
 
8. Female participants: Contraceptive use for those participating in clinical studies (men or women) 
should be consistent with local regulations   
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 
one of the following conditions applies:  
a. Is not a woman of childbearing potential (WOCBP) 
OR 
b. 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), during the intervention period and for at 
least 12 months 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. 
- 
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.  
- 
We will review the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a woman with a new undetected pregnancy. 
Non-childbearing potential is defined as follows (by other than medical reasons): 
- 
≥45 years of age and has not had menses for >1 year 
- 
Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and 
oophorectomy must have a follicle stimulating hormone value in the postmenopausal range 
upon screening evaluation 
- 
Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical 
records of the actual procedure. 
9. Male participants: contraceptive use should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.   


 
 
 
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Male participants are eligible to participate if they agree to the following during the intervention 
period and for 6 months after the last dose of study treatment to allow for clearance of any altered 
sperm: 
a. 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 and 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 when having sexual intercourse 
with a woman of childbearing potential  
10. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE), version 5.0) must be ≤ Grade 1 at the time of enrolment except for 
alopecia and Grade 2 peripheral neuropathy. 
 
5.2 Exclusion Criteria:  
1. Systemic anti-myeloma therapy within ≤14 days or 5 half-lives, whichever is shorter, or plasmapheresis 
within 7 days prior to the first dose of study drug 
2. Systemic treatment with high dose steroids (equivalent to 60 mg prednisone daily for ≥4 days) within 
the past 14 days if administered to treat MM or non- MM disease 
3. Prior allogeneic stem cell transplant (SCT). Note: Participants who have undergone syngeneic 
transplant may be allowed, if no history of GvHD 
4. Current corneal epithelial disease except mild punctate keratopathy  
5. Evidence of active bleeding 
6. Any major surgery within the last four weeks 
7. Presence of active renal condition (infection, requirement for dialysis or any other condition that could 
affect participant’s safety).  Participants with isolated proteinuria resulting from MM are eligible, 
provided they fulfil entry criteria (as defined by inclusion criteria #7) 
8. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including 
lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or 
compliance to the study procedures.  
9. Current unstable 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 non-cirrhotic chronic liver disease (including Gilbert’s syndrome or 
asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.   
10. Other malignancies are excluded, except for malignancy from which the patients have been disease-
free for more than 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, prostate cancer or in situ cervical cancer that has undergone potentially curative 
therapy. 
11.  Evidence of cardiovascular risk including any of the following: 


 
 
 
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a. Evidence of current clinically significant uncontrolled arrhythmias, including clinically 
significant ECG abnormalities including second degree (Mobitz Type II) or third degree 
atrioventricular (AV) block. 
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), 
coronary angioplasty, or stenting or bypass grafting within 3 months of screening. 
c. Class III or IV heart failure the New York Heart Association functional classification system 
d. Uncontrolled hypertension 
12. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically 
related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any other 
components of the study treatment. 
13. Active infection requiring treatment. 
14. Known HIV infection. 
15. 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.  Note:  presence of Hep B surface antibody 
(HBsAb) indicating previous vaccination will not exclude a participant. 
16. 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: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, 
only if a confirmatory negative Hepatitis C RNA test is obtained. Hepatitis RNA testing is optional and 
participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA 
testing. 
17. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of 
screening. 
18. Pregnant or lactating female 
19. Concomitant administration of strong P-glycoprotein inhibitors and inhibitors of OATP.  
 
5.3 Screen Failures 
• 
Screen failures are patients who consent to participate in the study but are not enrolled/treated.  
Screen failure is expected and will be documented to ensure transparent reporting to meet the 
Consolidated Standards of Reporting Trials.  
• 
Patients who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6.0 Treatment 
Study treatment is defined as any investigational treatment intended to be administered to a study participant 
according to the study protocol.  Belantamab will be administered intravenously. Cyclophosphamide and 
dexamethasone will be administered orally.  
6.1 Belantamab Mafodotin 
Belantamab Mafodotin is to be administered at a calculated dose of 1.9 mg/kg on day 1 of 3 weeks cycle 
arm A or 2.5 mg/kg on days 1 of 6 weeks cycle Arm B as an IV infusion, via an infusion pump.  
Premedication is not required prior to infusion unless deemed medically necessary by the Investigator and 
it should be administered according to institutional recommendations. 


 
 
 
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Dose form Lyophilized powder, 100 mg/vial in single-use vial for reconstitution 
Instructions Reconstitute Belantamab lyophilized powder 100 mg/vial 2.0mL of water for injection (WFI); 
dilute with saline before use.  
Route of administration Delivered as IV solution over at least 30 minutes.   
Manufacturer: GSK/Baxter 
6.1.1 Belantamab Dose Modification 
Adjustments Due to Body Weight: The actual body weight in kg at baseline (assessed on Cycle 1 Day 
1 prior to dosing) will be used for dose calculation of Belantamab in all patients.  If the change of 
body weight is greater than 10%, the dose must be recalculated based on the actual body weight at 
the time of dosing.  
6.1.2 
Belantamab Mafodotin ( GSK2857916) Dose Reductions 
Starting dose 
1st reduction 
2nd reduction 
Arm A 
            1.9 mg/kg q3w 
 
1.9 mg/kg day1 q6w 
Discontinue 
treatment 
permanently    
Arm B 
            2.5 mg/kg q6w 
 
1.9 mg/kg day 1 q6w 
Discontinue 
treatment 
permanently     
 
If the patient cannot tolerate the drug after the allowed dose reductions, he or she must be withdrawn from 
the study for lack of tolerability. 
If a dose is delayed, the patient should wait for the next scheduled dose to resume treatment; earlier re-
start may be considered only for patients who have recovered from toxicity to < G1. 
The dose and dosing timing interval changes of administration of belantamab mafodotin ( GSK2857916) 
doesn’t occur during the phase I portion (Cohort) of this study (exceptions are Belantamab related corneal 
adverse events) and only can occur during the phase II portion (Expansion Cohort) 
 
6.1.3  Corneal Supportive Care Guidelines 
We have established a close collaboration with an ophthalmologist, a Co-Investigator, who will be 
responsible for assessing patients managing those who develop a corneal event. 
Preservative-free artificial tears should be used in all patients. 1 drop in each eye every 4-6 hours and can 
be increased to 1 drop in each eye as frequently as every 2 hours, as needed. 
Changes in visual acuity, which commonly manifests as changes in corneal epithelium, have been observed 
on ocular exams with antibody drug conjugates, including those conjugated to MMAF.  
Further information regarding changes in the corneal epithelium associated with belantamab mafodotin, 
including a grading scale and prophylactic measures are in Appendix 5. 
A baseline ocular examination is required for all patients. Patients should undergo on treatment ocular 
examinations per SOA as defined (Section 8.3). If a participant subsequently develops a change in visual 
acuity or other ocular symptoms, the participant should be evaluated by an eye care specialist and followed 
as frequently as clinically indicated. If steroid eye drops are deemed medically necessary and prescribed, 
intraocular pressure must be monitored if used for >7 days. 
Participants who have corneal signs per the Keratopathy Visual Acuity (KVA) scale for treatment-related 
corneal toxicities present at end of study treatment will continue to be followed every 3 months for up to 


 
 
 
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12 months, or until full resolution of findings: defined as a return to participant’s baseline, or until deemed 
clinically stable by a qualified eye care specialist, whichever comes first.  
 
6.1.4 Dose Modification for Belantamab-Related Adverse Events 
Toxicity 
Grade/Symptoms 
Recommendations for Belantamab Mafodotin 
Elevated serum creatinine not 
explained by sepsis, TLS, fever, 
dehydration, etc. 
increases from baseline 
by >0.5 mg/dL 
• 
Repeat within 48 hours 
• 
If confirmed: withhold therapy 
Serum creatinine  
Grade 3-4  
 
(Defined as >3.0x 
ULN) 
Or >3.0 mg/dL  
• 
Permanently discontinue belantamab mafodotin 
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 pre-held dose 
• 
If confirmed/no evidence of disease progression 
• 
Interrupt belantamab mafodotin 
• 
Repeat testing within 4 weeks 
• 
If spot urine <2000 mg/g (224 mg/mmol), may 
restart belantamab mafodotin at same dose 
level  
• 
If it remains >2000 mg/g after 4 weeks, 
discontinue belantamab mafodotin  
Urine Dipstick 
2+ 
• 
May continue belantamab mafodotin dosing 
• 
Confirm by quantitative assessment using 
albumin/creatinine ratio 
>3 
• 
Interrupt treatment and follow up for recovery. 
Implement quantification of albumin/creatinine 
ratio 
Thrombocytopenia 
(on days of dosing) 
 
Graded according to NCI-CTCAE 
criteria 
Grade 3 
• 
No bleeding: continue treatment with 1 dose level 
reduction. Consider reverting to previous dose 
once thrombocytopenia recovered to Grade 2 or 
less. 
• 
With bleeding: withhold the dose, continue 
treatment after recovery with 1 dose level 
reduction. 
• 
Supportive treatment (e.g., transfusion), as 
clinically indicated and per local practice. 
Grade 4 
• 
Withhold the dose. Consider restarting with 1 dose 
level if reduction if recovered to < Grade 3 only if 
there is no active bleeding at time of treatment 
restart 
• 
If thrombocytopenia is considered disease related, 
is not accompanied by bleeding, and recovers with 
transfusion to >25x109/L continuing treatment with 
dose reduction may be considered. 
Afebrile Neutropenia 
 
Graded according to NCI-CTCAE 
criteria 
Grade 3-4 
(Defined as ANC 
<1.0x109/L) 
• 
If noted on Day 1 of any cycle, withhold 
belantamab mafodotin dose 
• 
Resume belantamab mafodotin at pre-held dose 
once neutropenia recovers to Grade ≤ 2 (ANC ≥ 
1.0x109/L) on Day 1 of the subsequent cycle. 
• 
Prophylactic antibiotics, per physician discretion 
and local institutional guidance. Consider growth 
factors. 


 
 
 
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Toxicity 
Grade/Symptoms 
Recommendations for Belantamab Mafodotin 
• 
Local guidance must be followed for 
hematological monitoring, if more conservative 
than the protocol specifications. 
• 
In cases of frequent recurrent neutropenia (ANC 
<1.0x109/L), consider dose reduction 
Febrile neutropenia 
 
Graded according to NCI-CTCAE 
criteria 
Grade 3-4 
(Defined as: single 
temp of 38.3 °C and 
ANC <1.0×109/L   
• 
Withhold the dose and immediately hospitalize 
participant with appropriate management, per 
local institutional guidance. 
• 
Consider additional supportive treatment (e.g. 
growth factors). 
• 
Upon recovery, consider dose reduction of 
belantamab mafodotin, if neutropenia was drug-
related. 
Infusion reaction a 
 
Graded according to NCI-CTCAE 
criteria 
Grade 1/ 2 
• 
Interrupt infusion and provide supportive care. 
Once symptoms resolve to grade 0/1, resume at 
lower infusion rate; reduce the infusion rate by at 
least 50%. 
Grade 3 
• 
Continuation only allowed after recovery to < 
Grade 1 and with pre-medication, and extension of 
infusion time to 2-4 hours.  
Grade 4 
• 
Permanently discontinue 
Pneumonitis 
Graded according to NCI-CTCAE 
criteria 
Grade 2 
• 
Withhold treatment with belantamab mafodotin  
• 
Upon recovery to Grade 1, restart treatment at 1 
dose level reduction dose level. 
Grade 3-4 
• 
Permanently discontinue treatment with 
belantamab mafodotin 
a. 
If symptoms resolve within one hour of stopping infusion, the infusion may be restarted at one dose level reduction of 
the original infusion rate (e.g., from 100 mL/h to 50 mL/h). Otherwise, dosing will be held until symptoms resolve and 
the participant must be pre-medicated for the next scheduled dose. 
 
 
 
 
 
 
 
 
 
 
6.1.5 Dose Modification Guidelines for Corneal-Related Adverse Events Associated with 
belantamab mafodotin 
Grade per KVA 
scale 
Grade 1 
Grade 2 
Grade 3 
Grade 4 


 
 
 
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*Recommended 
Dosage 
Modifications 
Continue 
treatment at 
current dose. 
Withhold 
belantamab 
mafodotin until 
improvement in 
both corneal 
examination 
findings and 
changes in 
BCVA to Grade 
1 or better and 
resume at same 
dose. 
Withhold 
belantamab 
mafodotin until 
improvement in 
both corneal 
examination 
findings and 
changes in BCVA to 
Grade 1 or better 
and resume at 
reduced dose. 
If already on lowest 
dose, participant 
continues treatment at 
same dose after 
resolution to grade 1 
with delays allowed up 
to 3 months 
 
Consider permanent 
discontinuation of 
belantamab mafodotin. 
If based on benefit risk 
assessment, treatment 
of belantamab 
mafodotin is being 
considered, withhold 
treatment until 
improvement in both 
corneal examination 
findings and change in 
BCVA to Grade 1 or 
better and resume at 
reduced dose. 
If already on lowest dose, 
participant continues 
treatment at same dose. 
*Dose modification should be based on the most severe grade. If eyes differ in severity, dose 
modification guideline should be applied based on the more severe eye. 
6.2 
Cyclophosphamide  
Chemistry: 2[bis (2chloroethyl)amino]tetrahydro-2H-1,3,2-oxazophosphorine 2-oxide mono-hydrate.  
Cyclophosphamide (cytoxan) is biotransformed principally in the liver to active alkylating metabolites 
which cross-link to DNA. 
Toxicity from cyclophosphamide includes bone marrow suppression usually occurs 10 to 12 days after 
administration; nausea, vomiting, anorexia, abdominal discomfort, diarrhea and stomatitis; reversible 
alopecia; hemorrhagic cystitis which can frequently be prevented with increased hydration; fibrosis of the 
bladder; cardiac toxicity which may potentiate doxorubicin-induced cardiotoxicity; rare anaphylactic 
reaction, skin rash, hyperpigmentation, interstitial pulmonary fibrosis, cross sensitivity with other 
alkylating agents.  Treatment with cyclophosphamide may cause significant suppression of the immune 
system. Second malignancies, most frequently of the urinary bladder and hematologic systems, have been 
reported when cytoxan is used alone or with other anti-neoplastic drugs.  Malignancies may occur several 
years after treatment has been discontinued.  Cyclophosphamide interferes with oogenesis and 
spermatogenesis and may cause sterility in both sexes which is dose and duration related.  
Cyclophosphamide is teratogenic, and women of childbearing potential should avoid becoming pregnant.  
Increased myelosuppression is enhanced with chronic administration of phenobarbital.  The occurrence of 
acute leukemia has been reported rarely in patients treated with anthracycline/alkylator combination. 
This drug is commercially available in 50 mg tablets 
6.2.1 Dose Modification for Cyclophosphamide Related Adverse Events 
Thrombocytopenia 
on days of dosing 
• 
Grade > 3  
o 
Hold treatment until recover ≤ grade 2. 
o 
If disease-related (BM > 70%), treat with transfusion support  
o 
If persistent after 2 cycles, dose reduce 


 
 
 
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Febrile 
neutropenia 
• 
Grade 3 
o 
Withhold Cyclophosphamide   
o 
Supportive treatment (GCSF, antibiotics) 
o 
On recovery resume at same dose  
Neutropenia  
• 
Grade ≥3 
o 
On Day 1 hold Belantamab  
o 
On recovery to < Grade 2 resume belantamab at same dose 
• 
Recurrent episodes, dose reduce 
 
6.3 
Dexamethasone  
Dexamethasone (Decadron) is a synthetic adrenocortical steroid and is readily absorbed from the 
gastrointestinal tract.  Chemically, dexamethasone is 9-fluoro-11ß, 17, 21-thrihydroxy-16α-methyl-pregna-
1, 4-diene-3, 20-dione. Dexamethasone is insoluble in water. 
Possible adverse effects are:  fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, exacerbation of infection (e.g., 
tuberculosis), exacerbation or symptoms of diabetes, psychosis, muscle weakness, osteoporosis, vertebral 
compression fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, convulsions, 
vertigo and headache, endocrine abnormalities, ophthalmic changes, and metabolic changes.  Some patients 
have experienced itching and other allergic, anaphylactic or other hypersensitivity reactions.  Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia and arthralgia, Phenutoin, 
phenobarbital and ephedrine enhance metabolic clearance of corticosteroids. Corticosteroids should be used 
cautiously in patients with hypothyroidism, cirrhosis, ocular herpes simplex, existing emotional instability 
or psychotic tendencies, nonspecific ulcerative colitis, diverticulitis, fresh intestinal anastomoses, peptic 
ulcer, renal insufficiency, hypertension, osteoporosis and myasthenia gravis.  Immunization procedures 
should not be undertaken in patients on corticosteroids. Natural and synthetic glucocorticoids are absorbed 
from the GI tract.  Glucocorticoids have salt-retaining properties, although dexamethasone lacks this 
property.  Anti-inflammatory property can modify the body’s immune system.  On the other hand, 
glucocorticoids suppress the body’s response to viral as well as bacterial infections. 
Formulation:  Dexamethasone is available commercially in six potencies (0.25 mg, 0.5 mg, 0.75 mg, 1.5 
mg, 4 mg, and 6 mg) in capsule or tablet form.  
6.3.1 Dose Modification for Dexamethasone Related Adverse Events 
Hypertension 
• 
Grade > 2  
o 
Hold dexamethasone and start therapy for HTN  
o 
Restart therapy once BP is grade ≤1 
Diabetes  
• 
Grade > 3 
o 
Withhold dexamethasone and treat (oral hypoglycemic)  
o 
On recovery to grade ≤1 restart at lower dose  
Mood changes 
• 
Grade ≥2 and Recurrent, dose reduce  
 
6.4 Guidelines for Therapy-Related Adverse Events Not Otherwise Specified 
Severity Management 
Follow-up 
Grade 1 Administer treatment  
Close follow-up to evaluate for increased severity, no dose modification necessary 
Grade 2 Symptoms resolved in ≤7 days: continue after resolution at the current dose 
Symptoms ongoing >7 days or worsening: delay therapy or consider dose reductions  


 
 
 
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6.4.1 Liver Chemistry Stopping Criteria 
• Designed to assure participant safety and evaluate liver event etiology.  
• Liver Safety Required Actions and Follow up Assessments are detailed in Appendix F. 
• Discontinuation of study treatment for abnormal liver tests is required when the participant 
satisfies any of the stopping rules as shown in Figure below.  
Stopping and Increased Monitoring Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN 
 
 
 
 
6.5 Therapy Compliance 
• 
Belantamab will be administered intravenously to patients at UMMC.  Study treatment is based on 
body weight calculation and may be reduced for toxicity for individual participants according to 
protocol guidelines.  
Grade 3 
Delay treatment till recovery to G1 or less.  Dose reductions as appropriate  
If resolve to ≤G1 within 48 hours may continue treatment, no dose reductions 
If resolve > 7 days…continue therapy with dose reductions  
Grade 4 Stop therapy and wait until G1 or less…continue therapy with dose reductions If 
grade 4 persist or recur after dose reduction stopping then discontinue therapy  


 
 
 
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• 
The date and time of each dose administered in the clinic will be recorded. The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a member 
of the study site staff other than the person administering the study treatment and documented in 
source. 
• 
Cyclophosphamide and dexamethasone will be administered on day 1 only and will be given in 
infusion. 
6.6 
Concomitant Therapy 
• 
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrolment or receives during the 
study must be recorded. 
6.7 
Discontinuation of Study Treatment  
Study treatment may be permanently discontinued for any of the following reasons: 
• 
Disease progression or unacceptable toxicity. 
• 
Participant has met any of the protocol defined safety stopping criteria 
• 
Deviation(s) from the protocol 
• 
Request of the participant or proxy (withdrawal of consent by participant or proxy) 
• 
Investigator’s discretion 
• 
Concurrent illness that prevents further administration of study treatment(s) 
• 
Pregnancy  
• 
Patient is lost to follow-up  
Safety Stopping Criteria 
• 
Liver toxicity   
• 
Infusion-Related Reactions: Premedication is not required prior to infusion unless deemed 
medically appropriate by the investigator following evaluation of infusion-related reactions (IRRs). 
Premedication should be considered in any participant who experienced an IRR at first or any 
subsequent infusion with belantamab mafodotin. For infusion reactions of any grade/severity, 
immediately interrupt the belantamab mafodotin infusion and manage symptoms. Once reaction 
symptoms resolve, resume the infusion at a reduced rate. Premedication may be required with 
subsequent infusions. A participant that experiences a Grade 4 IRR associated with belantamab 
mafodotin should be permanently withdrawn from the study. 
• 
For corneal Events follow table above (6.1.4)  
 
7.0 Correlative Studies 
Performed by University of Maryland Translational laboratory Shared Services (TLSS) and Flow 
Cytometry Shared Services (FCSS) 
 
7.1 Tear Film Collection Procedure for Cytokine Assessment  
7.1.1 
Patients will be instructed to withhold eye drop application at least 4 hours prior to examination.  
Right eyes will be measured first.  Non-stimulated (basal) tear samples will be collected from the 
inferior-temporal tear film of participants’ eyes using a glass microcapillary tube (approximately 
5μl/eye).  Following collection, samples will be kept on ice and sent to the cytokine lab for 
centrifugation and storage, until required for cytokine analyses. The time period of storage for all 
tear samples will be less than 24 months.  


 
 
 
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7.1.2  Samples will be collected from patients before study entry, on cycle 2- day-1 and at time of 
development of any corneal events. 
7.1.3 
We will use BioLegend's LEGENDplex™ platform. This is a bead-based immunoassay that utilizes 
the same basic principles of sandwich immunoassays, whereby a soluble analyte is captured 
between two antibodies. The advantage is that a small amount of liquid sample can be analyzed on 
over 10 cytokine expressions.  
7.1.4 
We will assess the following Human Essential Immune Response Panel: IL-4, IL-2, CXCL10 (IP-
10), IL-1β, TNF-α, CCL2 (MCP-1), IL-17A, IL-6, IL-10, IFN-γ, IL-12p70, TGF-β1 (Free Active), 
CXCL8 (IL-8).  
7.1.5 
Methods : tear samples and standard cytokines with known concentration are stained by TLSS on 
96 well plate, 50 µL sample is required. 5 µL tear can be diluted to 50 µL, (sensitivity effects will 
be considered).  Standard curve and samples are performed in duplicates. Unfixed samples are used 
for staining. TLSS fix the samples at the last step before flow cytometry analysis. FCSS will acquire 
samples on BD Canto II cytometer, generate figures and reports.  
7.2 
Peripheral Blood Collection for Immune Profile 
7.2.1 
Blood samples will be collected from patients before study entry, and on cycle 2- day-1. The time 
period of storage for all blood samples will be less than 24 months.  
7.2.2 
Blood will be collected and delivered to TLSS in (K2 EDTA tube). TLSS will isolate PBMCs by 
ficoll gradient. FCSS will prepare antibody cocktail and TLSS stains the cells and fix samples. 
FCSS will acquire samples on Cytek Aurora cytometer. Data analysis by FCSS, figures and reports 
generated. Detailed PBMC staining protocol is provided in Appendix I. 
7.2.3 
PBMC immunophenotyping Panel includes  
• 
Treg: CD25, CD127  
• 
Teff, Tcm, Tnaive, Tem: CD45RA, CCR7.  
• 
Th1, 2, 9, 17, 22: CCR6, CCR4, CCR10, CXCR3, CXCR5.  
• 
NK cells: CD56.  
• 
Activated T cells: HLA-DR, CD27, CD38 
 
8.0 Study Procedures  
• 
A signed, written informed consent form must be obtained before any study procedures 
• 
All screening procedures must be completed within 30 days prior to first dose. 
• 
On-study visits have a ±3-day window 
• 
PFS follow-up visits have a ±7-day window 
• 
Survival follow-up visits have a ±14-day window 
 
 
 
 
 
 
 
8.1 
List of Clinical Laboratory Tests 


 
 
 
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Hematology (each cycle) 
CBC + automated Differential  
Chemistry (each cycle)  
BUN/Cr/Electrolytes/ Mag, Phos, 
eGFR 
LFTs (AST, ALT, Alk Phos, total Bili); 
Albumin; total protein; LDH 
Pregnancy Test (urine or blood- per local practice)
Urine (each cycle)  
glucose, protein, blood and ketones by dipstick 
Spot Urine (albumin/creatinine ratio) 
At screening  
C-reactive protein; Troponin I; HBsAg, HbcAb, Hep C antibody. 
 
8.2  
Disease Assessment  
Standard disease assessments for RRMM will include the following assessments:  
• 
UPEP, Urine Immunofixation, 24 hr. collection for urine M-protein  
• 
SPEP, Serum M-protein, serum immunofixation 
• 
Calcium corrected for albumin 
• 
IgG, IgM, IgA 
• 
Serum Kappa, lambda free LC, FLC ratio  
• 
Bone marrow at screening and to confirm CR.  
• 
Imaging of extramedullary disease if indicated  
• 
Skeletal surveys or PET/CT as clinically indicated at screening and after 
achieving VGPR or better at 6 months or whichever comes earlier 
• 
Response evaluation with each cycle will be performed according to the IMWG 
Uniform Response Criteria for Multiple Myeloma 
8.3 
Ocular Examinations and Procedures 
Participants will be assessed by UMM ophthalmologist at screening/baseline in both arms. 
A full screening/baseline ophthalmic examination for all participants must include for both 
eyes (OU): 
• Best corrected visual acuity. 
• Documentation of manifest refraction and the method used to obtain best corrected 
visual acuity. 
• Current glasses prescription (if applicable). 
• Anterior segment (slit lamp) examination with focus on the cornea and lens, 
including fluorescein staining of the cornea 
• Intraocular pressure measurement  
• Dilated fundoscopic exam. 
On treatment and follow-up ophthalmic exam should be performed for both eyes (OU) as 
described below and in the Schedule of Activities:  
• Best corrected visual acuity. 
• Documentation of manifest refraction and the method used to obtain best corrected 
visual acuity. 


 
 
 
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• Anterior segment (slit lamp) examination with focus on the cornea and lens, 
including fluorescein staining of the cornea 
• Intraocular pressure measurement (if clinically indicated)  
• Dilated fundoscopic exam (if clinically indicated) 
The end of treatment and last follow-up ophthalmic exam, if required, should match the 
screening/baseline exam. Additional examinations should be performed at the discretion 
of the treating eye specialist. 
8.4 
PFS Follow-up: 
Patients who discontinue treatment in absence of disease progression will be followed 
every 3 months for disease response assessments until new anti-cancer therapy is initiated 
or progression is documented, or death occurs. Follow up duration is 9 months. 
8.5 
Overall Survival Follow-up: 
Patients who discontinue treatment due to disease progression will be followed for survival 
and subsequent disease response assessments by chart review every 3 months. Follow up 
duration is 9 months. 
8.6  
Reporting Adverse Events  
8.6.1  Definitions 
Adverse Event: An AE is defined as any untoward medical occurrence in a clinical trial 
subject. The event does not necessarily have a causal relationship with study treatment. 
The Investigator is responsible for ensuring that any AEs observed by the Investigator or 
reported by the subject are recorded in the subject’s medical record. If a new primary 
malignancy appears, it will be considered an AE. 
An abnormality identified during a medical test [e.g., laboratory parameter, vital sign, 
electrocardiogram (ECG) data, physical exam] should be defined as an AE only if the 
abnormality meets 1 of the following criteria: 
• Induces clinical signs or symptoms 
• Requires active intervention  
• Requires interruption or discontinuation of study medication or  
• the abnormality is clinically significant in the opinion of the Investigator 
The Definition of a Serious Adverse Event (SAE): 
SAE is defined as any of the following: 
• Any death that occurs while the patient is enrolled in the study including the follow-up 
period or within 28 days of completing the study 
• Immediately life-threatening AE 
• Requires inpatient hospitalization* 
• Prolongation of an existing hospitalization 
• Congenital anomaly/birth defect 
• Medically important event** 
• Disability/incapacity (persistent or significant) 
Associated with liver injury and impaired liver function: ALT ≥3 x ULN and total 
bilirubin ≥2 x ULN (>35% direct), or ALT ≥3 x ULN and INR >1.5.  


 
 
 
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*Exception: Preplanned (at time of informed consent) hospitalization for elective 
procedures, for protocol compliance or social reasons, or for observation will not be 
considered criteria for an SAE. The reason for the planned hospitalization should be 
documented. Complications experienced during these hospitalizations must be 
reported as SAEs if hospitalization is prolonged due to AE, or if the complication meets 
other serious criteria). 
**Medical and scientific judgment should be exercised in determining whether 
situations or events should be considered serious adverse events:  an important medical 
event may not be immediately life-threatening or result in death or require 
hospitalization but may jeopardize the patient or require intervention to prevent one of 
the above outcomes, as listed above, and these events must be considered serious.  
Examples of such events are allergic bronchospasm, blood dyscrasias, or convulsions 
that may require intensive treatment in an emergency room or at home but do not result 
in hospitalization, or development of drug dependency or drug abuse.  
CTCAE term (AE description) and Grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to 
a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP web site. 
Attribution of the AE: 
• Related: There is a reasonable possibility of a causal relationship between the 
medicinal product and AE, i.e. there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• Not Related: A causal relationship between the medicinal product and the AE 
cannot be established, based on consideration of factors described above.  
 
8.6.2  Adverse Event of Special Interest (AESI) for Belantamab Mafodotin 
An Adverse Event of Special Interest (AESI) is defined as any AE (serious or non-serious) 
that is of scientific and medical concern specific to the study treatment. AESI’s for 
belantamab mafodotin include the following:  
• Thrombocytopenia 
• Infusion related reactions 
• Corneal events  
8.6.3  Assessment of Adverse Events 
Each AE will be assessed by the Investigator for severity and for a causal relationship with 
the study treatment as outlined below.  
 
8.6.3.1 Severity Assessment 


 
 
 
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• All AEs will be assessed by the Investigator for severity according to Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0: 14 June 2010; National 
Institutes of Health (NIH), National Cancer Institute (NCI). The CTCAE v5.0 is 
available on the NCI/NIH website. 
• Please note that there is a distinction between serious and severe AEs: Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 8.6.1.  For 
example, a mild degree of gastrointestinal bleeding requiring an overnight 
hospitalization for monitoring purposes may be considered an SAE but is not 
necessarily severe.  
8.6.3.2 Relationship to Study Drug  
The Investigator must provide a causality assessment regarding the relationship of the 
event with the study drug for all AEs.  One of the following categories should be selected 
based on medical judgment, considering all contributing factors: 
• Related: There is a reasonable possibility of a causal relationship between the 
medicinal product and AE, i.e. there are facts, evidence, and/or arguments to suggest 
a causal relationship, rather than a relationship cannot be ruled out. Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration will be 
considered and investigated. 
• Not Related: A causal relationship between the medicinal product and the AE cannot 
be established, based on consideration of factors described above.  
The Investigator may change their opinion of causality in light of follow-up information, 
and provide an updated causality assessment, in the originally completed SAE form, as 
applicable. 
8.6.4 Reporting of Adverse Events 
8.6.4.1 Investigators are responsible for monitoring the safety of patients who have entered this 
study and for alerting the UMGCCC Data and Safety Monitoring and Quality Assurance 
Committee (DSM/QAC) and the FDA to any event that seems unusual, even if this event 
maybe considered an unanticipated. 
8.6.4.2 Any adverse experiences which occur at any time during the clinical study or within 30 
days of receiving the last dose of study medication, whether or not related to the study 
drug, will be collected by the study team into the Case Report Forms and submitted to the 
site Institutional Review Board (IRB) per institutional policy. 
8.6.5  Reporting of Serious Adverse Events 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 30 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to the 
protocol therapy, must be reported locally to the site Institutional Review Board (IRB) per 
local policy. Follow up to a serious adverse event should be reported at least within 7 
working days. The event should also be reported locally to the site Institutional Review 


 
 
 
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Board (IRB) per local policy.  The serious adverse event must also be reported to the FDA 
using FDA Form 3500A (MedWatch Form) within 7 days. If the serious event is 
unexpected fatal, or life threatening it must be reported to the FDA as soon as possible but 
no later than 7 calendar days following the initial receipt of the information. 
 
8.6.6  Reporting to GSK  
• All SAEs, pregnancies, and follow up information must be reported to GSK on an SAE 
Report Form within 24 hours of becoming aware of the initial event or follow-up 
information.  
• The Sponsor Institution must provide a causality assessment and must sign, and date 
all SAE Report Forms. 
• If supporting documentation is included in the submission to GSK (e.g., hospital 
reports, consultant reports, death certificates, autopsy reports, etc.), please redact any 
patient identifiers (including Medical Record number). 
 
 
 
 
 
8.6.6.1 Quarterly AE/SAE Reporting to GSK on a quarterly basis the Sponsor Institution will 
provide GSK with a line listing of all adverse events (serious and non-serious) received during 
a defined quarter. The line listing will include a subject ID, the AE term, onset date, outcome, 
causality assessment, severity, and study drug dosing information.    
8.6.7  Collection of Pregnancy Information  
Male participants 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 participants 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 participants who become pregnant: 
GSK SAE and Pregnancy Reporting Information 
Email: OAX37649@gsk.com 
Or 
eFax number: +44(0) 208754 7822 


 
 
 
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• 
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 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 participants, 
he or she may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant on study will discontinue treatment.  
8.6.8  Reporting Product Complaints for Belantamab Mafodotin 
Any written, electronic or oral communication that alleges dissatisfaction related to 
manufactured clinical drug product with regards to its manufacturing, testing, packaging, 
or shipping, must be reported by the Sponsor Institution or qualified designee to GSK 
within 1 working day of first becoming aware of the possible defect to GSK QA at gsk-
rd.complaints@gsk.com. The product and packaging components in question, if available, 
must be stored in a secure area under specified storage conditions until it is determined 
whether the product is required to be returned for investigation of the defect.  If the product 
complaint is associated with an SAE, the SAE must be reported separately in accordance 
with the protocol, and the SAE report should mention the product quality complaint. 
9.0 
Statistical Analysis 
9.1 
Study Objectives 
The primary objectives of this study are to: (1) characterize the safety and tolerability of 
chemotherapeutic regimen belantamab mafodotin, cyclophosphamide, and dexamethasone 
in patients with relapsed/refractory multiple myeloma and (2) Identifying the maximum 
tolerated dose and recommended Phase 2 dose. 
The primary endpoints are the occurrence of regimen limiting toxicities (RLTs), treatment-
emergent adverse events, treatment-related adverse events, and clinically significant 
changes as described earlier in the protocol.   


 
 
 
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The secondary endpoints are the overall response rate of the better tolerated regimen in an 
expansion cohort, the percentage of patients with confirmed partial (or better) response, 
duration of response, time to response, time to progression, progression-free survival 
(PFS), Overall survival (OS) and the percentage of patients with confirmed partial (or 
better) response. 
The exploratory endpoint is to obtain exploratory data on cytokine levels in the tears and 
T cell subsets in the peripheral blood before and after initiation of therapy (cycle 2 day 1).  
9.2  
Sample Size 
9.2.1 
Phase I We will use 3+3 design as shown below 
  
 
 
 
 
 
 
 
 
• 
The total sample size will range from 6 to 24 (3 to 12 per arm), using a standard 3+3 design.  
• 
Arm A: Recruitment will stop if there are 2 or 3 patients with RLT among the first 3 recruited 
subjects in Dose 1, resulting in a minimum sample size of 3. Otherwise, 3 more patients will be 
recruited for Dose 2. If there are 2 or 3 RLTs, the trial will stop recruitment. Otherwise, 3 more 
patients will be recruited. Therefore, the maximum number of patients for Arm A is 12. 
• 
Arm B: The procedures will be similar to Arm A, with sample size ranging from 3 to 12.  
• 
The better tolerated regimen, defined as full dosing for 2 cycles with no dose reductions or grade 3 
or higher CTA-defined toxicity will be explored in the expansion cohort.  
9.2.2. Phase II (expansion cohort):   
• 
The sample size of the expansion cohort is driven by the study primary endpoint of overall response 
rate (ORR). We will use a 2-stage Fleming procedure, with a maximum sample size of 40 patients 
(20 in the each stage). We assume that an ORR less than 40% to be of no interest and 60% of 
definitive interest. Assuming an 80% power for response detection (type II error = 0.20) and a one-
sided type I of 0.05, we will need 20 patients enrolled in each stage. At the completion of stage 1, 
if there are ≤ 7, the trial will be stopped for futility; if there are ≥ 14 responses, the null hypothesis 
will be rejected and the regimen will be recommended for further studies. If there are 8 to 13 
responses, the trial will continue to stage 2. At the completion of stage 2, ≤21 responses will imply 
no further recommendation for investigation but with ≥ 22 responses, the null hypothesis will be 
rejected, and the regimen will be recommended for further investigation. 
 
 
Dose level 1 x 3 patients 
Proceed to level 2 x 3 patients 
RLT 1/3 patients 
No RLT 
RLT >2/3 patients 
Add 3 patients on Level 1 
Dose escalation stopped 
1/6 patients had RLT 
>2/6 patients had RLT 


 
 
 
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9.2.3 
Stopping criteria for Toxicity 
- Grade 4 keratopathy > 1% that develop at any time points in the study with no resolution to grade 
2 or better in 2 months 
- Any Grade 4 nonhematologic toxicity with a cumulative incidence > 5% that last more than 7 
days. 
-   Grade 4 hematologic toxicity (thrombocytopenia, neutropenia and anemia) > 10% that last more 
than 7 days 
- Any study related death > 2% (expected death rate for the study population)  
 
9.3 
Statistical analysis: 
9.3.1 
Phase I:  
The analysis will be done on the safety set, which will include all subjects that are enrolled and 
receive at least 1 cycle of one of either the two regimens. Safety analyses will be conducted on an 
ongoing basis.  
Adverse Events 
• 
The occurrence of all treatment-emergent adverse events will be tabulated by system organ class. 
Numbers and percentages will be tabulated overall and by dose level and by relationship to study 
drugs. 
• 
Tables will include reports of adverse events, fatal adverse events, serious adverse events, adverse 
events leading to withdrawal from investigational product or other protocol-required therapies, and 
significant treatment-emergent adverse events. 
• 
Particular attention will be paid to the main adverse events of the primary adverse events of the 
drugs included in the regimens, such as corneal epithelium changes and visual acuity.  
• 
Clinical chemistry, hematology, bone marrow, and urinalysis data will be listed and reviewed for 
each subject.  Values outside the normal laboratory reference ranges will be flagged as high or low 
on the listings.  Depending on the size and scope of changes in laboratory data, summaries of 
laboratory data over time and/or changes from baseline over time may be provided.   
9.3.2 
Phase II:  
• Numbers, percentages, and 95% confidence intervals will be reported for the overall 
response rates, in the intention to treat set. Safety analyses will be reported, as described 
earlier. For other covariates, the analyses will include summary statistics, including number 
and percentage for categorical variables and number of patients, mean, standard deviation, 
median, minimum, and maximum for continuous variables. Time-to-event analyses (e.g., 
time to progression) will be performed using Kaplan-Meier methods with two-sided 95% 
confidence intervals.  
9.3.3 
Planned Analyses 
• 
In Phase I, there will be continuous monitoring and reporting of the safety and efficacy data, as 
they become available.  


 
 
 
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• 
In Phase II, the first analysis will be conducted after the conclusion of the first stage, i.e., when the 
first 21 patients have completed at least 2 cycles on therapy. The second (and final) analysis will 
be conducted at the completion of the study, when all 40 subjects are enrolled and accessible for 
efficacy and toxicity.   
 
10.0 
STUDY OVERSIGHT AND DATA REPORTING/REGULATORY REQUIREMENTS 
10.1  
Data Quality Assurance 
The University of Maryland Data Safety Monitoring / Quality Assurance Committee (DSM/QAC) 
is charged with providing peer review and monitoring of local and national research protocols 
involving cancer patients treated at the University of Maryland Greenebaum Comprehensive 
Cancer Center (UMGCCC), according to the SOP on file with the IRB and reviewed by NCI. Data 
specialists coordinate and monitor data generated by Investigator-initiated and pharmaceutical 
sponsored trials. They are responsible for the timely acquisition and accuracy of all data for the 
studies to which they are assigned. They work closely with Investigators to collect required data in 
an accurate and timely manner. In addition, they are responsible for registration and randomization 
of patients entered on clinical trials. The UMGCCC DSM/QAC will be the Data Safety Monitoring 
Board of Record for this study. They will review all adverse events recorded for each dose level at 
all study sites and approve dose escalation to each new level (Safety Monitoring). In addition, 
cumulative monitoring of all study subjects will occur every 6 months (semi-annual review).  
The UMGCCC Clinical Protocol and Data Management/Clinical Trials Office maintains an up-to-
date, comprehensive database (OnCore®) of clinical trials conducted by Investigators, accessible to 
collaborating sites. The UMGCCC Clinical Protocol and Data Management/Clinical Trials Office 
will be responsible for auditing and collating data from collaborating sites using the OnCore system 
and examination of primary source documentation. 
10.2  
SAE and Reporting Definitions 
In the event of an SAE (see Section 8.6.1), the first concern will be for the safety of the subject. 
SAEs will be reported according University of Maryland, Baltimore IRB policies and procedures. 
If the event meets the criteria for FDA mandatory IND safety reporting (serious + unexpected), 
UMGCCC will report the event to the FDA using the MedWatch form (FDA Form 3500A). Events 
which are assessed as “unexpected fatal or life-threatening” should be reported to FDA as soon as 
possible, but no later than 7 calendar days following the PI’s initial receipt of the information. All 
other unexpected serious suspected adverse reactions suggesting significant risk to human subjects 
should be reported to FDA no later than 15 calendar days following the PI’s initial receipt of the 
information.  
10.3  
MedWatch 3500A Reporting Guidelines 
A MedWatch 3500A form should be submitted to GSK, the Sponsor, for each SAE. In addition to 
completing appropriate patient demographic and suspect medication information, the report should 
include the following information within the Event. Description (Section 5 of Part B) of the 
MedWatch 3500A form: 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment and outcome, if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational product 
and suspect medication 


 
 
 
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Additional information in follow-up may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form 
• 
Summarizing new information and faxing it with a cover letter including subject identifiers (i.e., 
D.O.B., initials, subject number), protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being submitted 
(The subject identifiers are important so that the new information is added to the correct initial 
report.) 
Occasionally, the Sponsor may contact the reporter for additional information, clarification or 
current status of the subject for whom an adverse event was reported. For questions regarding SAE 
reporting, you may contact the Sponsor.   
10.4  
Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that caused or 
contributed to an adverse event. The following general guidance may be used. 
• 
Yes: If the temporal relationship of the clinical event to belantamab mafodotin administration 
makes a causal relationship likely and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
• 
No: If the temporal relationship of the clinical event to belantamab mafodotin administration makes 
a causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the observed event. 
10.5  
Safety Reporting Requirements for IND Holders 
The Sponsor will be bound by the following reporting requirements as IND holder, in accordance 
with 21 CFR 212.32. 
10.6 
Calendar-Day Telephone or Fax Report: 
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of. belantamab 
mafodotin. An unexpected adverse event is one that is not already described in the Investigator’s 
Brochure. Such reports are to be telephoned or faxed to the FDA within 7 calendar days of first 
learning of the event. Each telephone call or fax transmission (fax number for IND Safety Reports: 
1 (800) FDA 0178) should be directed to the FDA new drug review division in the Center for Drug 
Evaluation and Research or in the product review division for the Center for Biologics Evaluation 
and Research, whichever is responsible for the review of the IND. 
10.7 
Calendar-Day Written Report: 
The Sponsor is also required to notify the FDA and all participating Investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered possibly related to the use of 
belantamab mafodotin. An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure. New information will be submitted to the IRB as well, according to the 
policies of the local IRB.  
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed with the IND concerning similar 
events should be analyzed. The new report should contain comments on the significance of the new 
event in light of the previous, similar reports. 


 
 
 
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Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA (fax 
number for IND Safety Reports: 1 (800) FDA 0178) and all participating Investigators within 15 
calendar days of first learning of the event.  
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor shall, within 60 days of the 
anniversary date that the IND went into effect, submit a brief report of the progress of the 
investigation according to 21 CFR § 312.32:  
10.8 
Study Initiation 
Before the start of this study and the shipment of investigational agent to the UMGCC, the 
following documents must be on file: 
• 
U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal Investigator.  The 
names of any Sub-Investigators must appear on this form. Investigators must also complete all 
regulatory documentation as required by local regulations 
• 
Current curricula vitae and license of the Principal Investigator 
• 
Final Protocol and ICF 
• 
A signed and dated Investigator’s Brochure 
• 
Written documentation of IRB approval of protocol and ICF (identified by title and date of 
approval) 
• 
Written documentation from the FDA assigning an IND number to the trial and the approval to 
begin the study 
• 
A signed Confidentiality Agreement 
• 
Approval letter of IND 
10.9 Institutional Review Board Approval 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated. In addition, any 
advertising materials must be approved by the IRB. The study will be conducted in accordance with 
U.S. FDA, applicable national and local health authority and IRB requirements. The Principal 
Investigator is responsible for keeping the IRB apprised of the progress of the study and of any 
changes made to the protocol as deemed appropriate. An annual progress report will be submitted to 
the IRB. The Principal Investigator must also keep the IRB informed of any significant adverse 
events. 
Investigators are required to promptly notify the IRB of all adverse drug reactions that are both 
serious and unexpected. This generally refers to serious adverse events that are not already identified 
in the Investigator’s Brochure and that are considered possibly or probably related to the study drug 
by the investigator. The Investigator must immediately forward to the IRB any written safety report 
or update provided by or on behalf of the Sponsor (e.g., IND safety report, Investigator’s Brochure, 
safety amendments, etc.). 
10.10 Informed Consent 
The informed consent documents must be signed by the patient before his or her participation in the 
study. The case history for each patient shall document that informed consent was obtained prior to 
participation in the study. A copy of the informed consent documents must be provided to the patient 
or the patient’s legally authorized representative. If applicable, they will be provided in a certified 
translation of the local language. Original signed consent forms must be filed in the site study binder 
or in each patient’s study file. 
 


 
 
 
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10.11 Study Monitoring Requirements 
The Investigator and other appropriate study staff will make available to the Sponsor monitor all 
documentation relevant to the study. Such documentation includes: 
• 
Case Report Forms—must be legible, accurate, and up to date. 
• 
Serious AE reporting. 
• 
Patient Files—should substantiate the data entered in the CRFs about laboratory data, patient 
histories, treatment regimens, etc. 
• 
Patient Exclusion Log—should record the reason any patient was screened for the study and 
found to be ineligible. 
• 
Drug Dispensing Log—should record the total amount of study drug received and returned to 
the company, and the amount distributed and returned or destroyed. This information must agree 
with the information entered in the CRFs. 
• 
Informed Consent Forms—completed consent forms from each patient must be available and 
verified for proper documentation. 
• 
Informed Consent Log—must identify all patients who signed an Informed Consent Form so 
that the patients can be identified by audit. 
10.12 Data Collection 
Data recorded on Case Report Forms (CRFs) must be legible and complete. Blue or black ink must 
be used in completing these forms. CRFs will be completed on a timely basis. 
Electronic Data Capture system (REDCap) will be used for CRF entry. The Investigator must review 
all final CRFs. Upon data base lock, the final eCRF will be printed and signed by the Principal 
Investigator. The frequency of monitoring may vary depending on enrollment rate and the quality 
of data collected. The Investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. 
The collected samples will be destroyed if the patients withdraw the consent.    
10.13 Study Medication Accountability 
All study drug required for completion of this study will be provided by the Sponsor. The recipient, 
UMGCCC, will acknowledge receipt of the drug by returning the drug receipt form indicating 
shipment content and condition. Damaged supplies will be replaced. 
Study drug accountability records should be maintained by the site in accordance with the 
regulations. The original drug supply request of belantamab mafodotin will be submitted to the 
Sponsor or Sponsor’s representative along with the form “Approval for Drug Re-Supply”, indicating 
which personnel will be able to submit drug re-supply requests. 
All subsequent drug re-supply requests will be directly submitted to the Sponsor or Sponsor’s 
representative from the site. At the time of study closure, the unused, used and expired study drug 
will be destroyed at the site per Institutional SOPs or returned to the Sponsor or Sponsor’s 
representative. 
 
10.14 Disclosure of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. Upon the patient’s permission, medical information may 
be given to his or her personal physician or other appropriate medical personnel responsible for his 


 
 
 
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or her welfare. This medical information must be made available to the Sponsor and authorized 
representatives of the Sponsor, upon request, for source verification of study documentation. 
Data generated by this study must be available for inspection upon request by representatives of the 
U.S. FDA, local health authorities, the Sponsor and their authorized representative(s), collaborators 
and licensees and the IRB. 
 
10.15 Retention of Records 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these records 
must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable national 
and local health authorities are notified. 
10.16 Study Completion 
The following data and materials are required before a study can be considered complete or 
terminated: 
• 
Copies of protocol amendments and IRB approval/notification, if appropriate 
• 
Copies of the IRB final report, documentation of submission to the IRB and to the FDA. 
• 
A summary of the study prepared by the Principal Investigator (Study report, manuscript and/or 
abstract) 
• 
All regulatory documents (e.g. updated curriculum vitae for each Principal Investigator, updated 
U.S. FDA Form 1572) 
This protocol is monitored at several levels, as described in this section. This protocol will be 
reviewed and approved by the UMGCCC Research Committee (CRC) and UM IRB. The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported adverse 
events from other trials testing the same drug(s).  The Protocol Principal Investigator and statistician 
have access to the data at all times through the UMGCCC OnCore Clinical Trials Management 
System. The protocol will be monitored by the UMGCCC Data Safety Monitoring Committee 
(DSMB). 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-escalation 
require sign-off by the Protocol Principal Investigator.  In addition, for the Phase 1 portion, the 
Protocol Principal Investigator will review at least monthly, or more frequently, the accrual, progress, 
and adverse events and unanticipated problems.   
During the Part B Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly review accrual, progress.  Decisions to proceed to the second stage of a Phase 2 
trial will require sign-off by the Protocol Principal Investigator and the study Sponsor. 
All Study Investigators who register/enroll patients on a given protocol are responsible for timely 
submission of data via REDCap and timely reporting of adverse events for that particular study.  This 
includes timely review of data collected on the electronic CRFs submitted to UMGCCC via the 
REDCap system. 
This study will be reviewed regularly and monitored closely by the UMGCCC DSMB and per 
UMGCCC guidelines.  
 


 
 
 
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11.0  
References  
Alley SC, Zhang X, Okeley NM, Anderson M, Law CL, Senter PD, et al. The pharmacologic basis for 
antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330(3):932-8. 
Chari A, Vogl DT, Gavriatopoulou M, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory 
Multiple Myeloma. N Engl J Med 2019; 381(8): 727-38. 
Dougherty BE, Nichols JJ, Nichols KK. Rasch analysis of the Ocular Surface Disease Index (OSDI). Invest 
Ophthalmol Vis Sci. 2011;52(12):8630-5. 
Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to 
CD38-targeted monoclonal antibody therapy. Leukemia 2019; 33(9): 2266-75. 
Heylmann D, Bauer M, Becker H, et al. Profiles of pro-iHuman CD4+CD25+ regulatory T cells are sensitive 
to low dose cyclophosphamide: implications for the immune response. PLoS One. 2013 Dec 23;8(12): 
e83384. 
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. 
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of progression and survival 
in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international 
myeloma working group study. Leukemia. 2012;26(1):149-57. 
Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, et al. gamma-Secretase directly 
sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015; 6:7333. 
Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma 
(DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020 Feb;21(2):207-221.  
Macsai M, Nariani A, Gan H, Lassman A, Merrell R, Gomez E, et al. Corneal Toxicity of ABT-414 in 
Glioblastoma (GBM): Clinical Manifestations, Ophthalmological Findings and Management. Investigative 
Ophthalmology & Visual Science. 2016 Sep 26;57(12):269-269. 
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. 
Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, et al. Expression of BCMA, TACI, 
and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103(2):689-94. 
Pirogova OV, Moiseev IS, Surkova EA, et.al. Profile of inflammatory cytokines in allogenic stem cell 
transplantation with post-transplant cyclophosphamide Cytokine. 2017 Nov;99:148-153. 
Roghanian A, Hu G, Fraser C, et al. Cyclophosphamide Enhances Cancer Antibody Immunotherapy in the 
Resistant Bone Marrow Niche by Modulating Macrophage FcγR Expression. Cancer Immunol Res. 2019 
Aug 26. 
Sanchez E, Li M, Kitto A, Li J, Wang CS, Kirk DT, et al. Serum B-cell maturation antigen is elevated in 
multiple myeloma and correlates with disease status and survival. Br J Haematol. 2012;158(6):727-38. 
Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, et al. Role of B-cell-activating factor in adhesion 
and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 
2006;66(13):6675-82. 
Thompson JA, Motzer R, Molina AM, Choueiri TK, Heath EI, Kollmannsberger CK, et al. Phase I studies 
of anti-ENPP3 antibody drug conjugates (ADCs) in advanced refractory renal cell carcinomas (RRCC). J. 
Clin. Oncol. 2015; 33:2503. 
Trudel S, Lendvai N, Popat R, et al. Targeting B-cell maturation antigen with GSK2857916 antibody–drug 
conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion 
phase 1 trial. The Lancet Oncology 2018; 19(12): 1641-53. 


 
 
 
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Appendix A  
Ocular Grading Scale 
Grade 1:  
 
Mild superficial keratopathy (change from baseline) 
Grade 2: 
 
Moderate superficial keratopathy 
 
Peripheral microcysts not involving the central visual axis 
 
Mild central microcysts with peripheral clearing 
Grade 3:  
 
Severe superficial keratopathy 
 
Diffuse microcysts involving the central visual axis 
Early limbal stem cell deficiency or epithelial irregularity suggestive of limbal stem cell 
deficiency 
Grade 4: 
 
Moderate or greater limbal stem cell deficiency 
 
Corneal epithelial defect or ulceration 


 
 
 
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Appendix B: ECOG performance status 
 
Grade   Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
 


 
 
 
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Appendix C: IMWG Response Criteria 
 
Sustained MRD-
negative 
MRD negativity in the marrow by next-generation sequencing (NGS)  
or next-generation flow (NGF), or both, and MRD negativity by imaging for 1 year apart 
Imaging 
plus 
MRD-negative 
MRD negativity as defined by NGF or NGS, and 
Disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT  
Stringent 
complete response 
(sCR) 
CR as defined below, and 
Normal FLC ratio, and 
Absence of clonal plasma cells by immunohistochemistry 
Complete 
response (CR) 
Negative IFE of serum and urine, and 
Disappearance of any soft tissue plasmacytomas, and 
<5% plasma cells in bone marrow aspirates 
In patients in whom the only measurable disease is by sFLC levels,  
CR is defined as a normal FLC ratio (0.26-1.65) in addition to the CR criteria listed above 
Very good partial 
response (VGPR) 
Serum and urine M-protein detectable by IFE but not on electrophoresis, or 
≥90% reduction in serum M-protein plus urine M-protein <100 mg per 24 hours 
In patients in whom the only measurable disease is by sFLC levels,  
VGPR is defined as a >90% decrease in the difference between involved and uninvolved sFLC levels 
Partial 
response 
(PR) 
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg  
In patients in whom the only measurable disease is by sFLC levels,  
PR is defined as a ≥50% decrease in the difference between involved and uninvolved sFLC levels 
If serum and urine M-protein are unmeasurable, and sFLCs are also unmeasurable, 
 ≥50% reduction in bone marrow plasma cells is required in place of M-protein,  
Minimal 
Response 
≥25% but ≤49% reduction of serum M-protein, and 
Reduction in 24-h urine M-protein by 50-89%, and 
If present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas 
Stable 
disease 
(SD) 
Not meeting criteria for CR, VGPR, PR or progressive disease 
Progressive 
disease (PD) 
Any one or more of the following: 
Increase of 25% from lowest confirmed response value in any one or more of the following: 
Serum M-protein (absolute increase must be ≥5 g/L) and/or 
Urine M-protein (absolute increase must be ≥200 mg/24 hours) and/or 
In patients in whom the only measurable disease is by sFLC levels,  
the difference between involved and uninvolved sFLC levels (absolute increase must be >100 mg/L) 
If serum and urine M-protein are unmeasurable, and sFLCs are also unmeasurable,  
bone marrow plasma cell percentage (absolute % must be ≥10%) 
 


 
 
 
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Appendix D 
Study Monitoring 
The Investigator and other appropriate study staff will make available to the Sponsor monitor all 
documentation relevant to the study. Such documentation includes: 
• 
Case Report Forms—must be legible, accurate, and up-to-date. 
• 
Serious AE reporting. 
• 
Patient Files—should substantiate the data entered in the CRFs with regard to laboratory data, 
patient histories, treatment regimens, etc. 
• 
Patient Exclusion Log—should record the reason any patient was screened for the study and 
found to be ineligible. 
• 
Drug Dispensing Log—should record the total amount of study drug received and returned to 
the company, and the amount distributed and returned or destroyed. This information must agree 
with the information entered in the CRFs. 
• 
Informed Consent Forms—completed consent forms from each patient must be available and 
verified for proper documentation. 
• 
Informed Consent Log—must identify all patients who signed an Informed Consent Form so 
that the patients can be identified by audit. 
 
SAE reporting 
• 
When an AE/SAE occurs, we will review all documentation (e.g., hospital progress notes, laboratory, 
and diagnostics reports) related to the event. 
• 
The Investigator will report all SAE to the IRB, FDA within 7 days of learning of occurrence and 
within 24 hours of learning of occurrence to GSK.


 
 
 
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Appendix E 
Permitted Medication 
• 
Patients will continue supportive care during the study, including transfusions of 
blood products, growth factors, and treatment with antibiotics, anti-emetics, 
antidiarrheal, and analgesics, as appropriate.   
• 
Concomitant therapy with bisphosphonates and/or Xgeva are allowed.   
• 
Patients may receive local irradiation for pain or stability control.  
 
Prohibited Medications 
• 
Chronic treatment with oral steroids is prohibited; steroids may be used to treat 
infusion-related reactions.  Inhaled steroids are allowed for management of asthma or 
COPD exacerbations.  Chronic low dose replacement therapy (less than or equal to 10 
mg prednisolone) is allowed in participants with adrenal insufficiency. 
• 
Administration of live or live-attenuated vaccines are contraindicated 30 days prior to 
the first dose of study treatment and while on study. Use of live or live-attenuated 
vaccines is further contraindicated for at least 70 days following the last dose of 
belantamab mafodotin. 
• 
For participants receiving belantamab mafodotin: 
o 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 enzymes in vitro.  Cys-
mcMMAF was shown to be a substrate of P-glycoprotein (P-gp), OATP1B1, 
and OATP1B3 transporters in vitro.   
o Caution should be exercised when belantamab mafodotin is combined with 
strong inhibitors of P-gp, and strong inhibitors of OATP1B1 and OATP1B3 
should be avoided unless considered medically necessary.   
• 
Elimination pathways for have not been characterized in humans; there is no specific  
contraindications for P450 inhibitors or inducers  
• 
Plasmapheresis is prohibited from 7 days prior to first dose through the end of study.  
• 
Any other anti-myeloma therapy not specified in this protocol, and any investigational 
agents are not allowed 
• 
Contact lenses are prohibited while the participant is on study. 


 
 
 
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Appendix F: Liver Safety  
Phase I/II liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant 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 total bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
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, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention  
• 
Report the event to GSK within 24 hours 
• Complete the liver event form and complete SAE data 
collection tool if the event also meets the criteria for an 
SAE2 
• Perform liver event follow up assessments as described 
in the Follow Up Assessment column 
• Monitor the participant until liver chemistries resolve, 
stabilize, 
or 
return 
to 
within 
baseline 
(see 
MONITORING) 
MONITORING: 
If ALT≥3xULN AND total bilirubin  2xULN or INR 
>1.5:  
• Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, total bilirubin and INR) and perform liver 
event follow up assessments within 24 hours 
• Monitor participants twice weekly until liver chemistries 
resolve, stabilize or return to within baseline 
• A specialist or hepatology consultation is recommended 
For All other criteria (bilirubin <2xULN and INR 
1.5):  
• Repeat liver chemistries (include ALT, AST, alkaline 
phosphatase, total bilirubin and INR) and perform liver 
event follow up assessments within 24-72 hours  
• Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline 
• 
  
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver chemistry assessment until the 
aminotransferases values show downward trend 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), 
gamma glutamyl transferase [GGT], glutamate dehydrogenase [GLDH], 
and serum albumin. 
• 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 liver event form 
• Record use of concomitant medications on the concomitant medications 
report form including acetaminophen, herbal remedies, recreational 
drugs and other over the counter medications 
• Record alcohol use on the liver event alcohol intake form 
If ALT 3xULN AND total bilirubin 2xULN or INR >1.5 obtain the 
following in addition to the assessments listed above: 
• 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 assay should be conducted (where 
available) to assess potential acetaminophen contribution to liver injury 
unless acetaminophen use is very unlikely in the preceding week. (e.g., 
where the participant has been resident in the clinical unit throughout)  
• Liver imaging (ultrasound, magnetic resonance, or computerised 
tomography) to evaluate liver disease; complete Liver Imaging form 
• Liver biopsy may be considered and discussed with local specialist if 
available, for instance: 
o In patients when serology raises the possibility of autoimmune 
hepatitis (AIH) 
o In patients when suspected DILI progresses or fails to resolve on 
withdrawal of study intervention 
o In patients with acute or chronic atypical presentation:  
• If liver biopsy conducted complete liver biopsy form. 
 
 
 
 
 
 
 


 
 
 
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1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT  3xULN and total 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 total bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants 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. 
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. In those with underlying chronic hepatitis B at study entry 
(identified by positive hepatitis B surface antigen) quantitative hepatitis B DNA and hepatitis delta antibody.  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]. 
 
Phase I/II liver chemistry increased monitoring criteria with continued study intervention 
Liver Chemistry Increased Monitoring Criteria and Actions with Continued Study Intervention Liver Monitoring Event 
Criteria 
Actions 
 
ALT 3xULN but <5xULN and total bilirubin 
<2xULN or INR ≤1.5, 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 participant safety.  
• Participant can continue study intervention  
• Participant must return weekly for repeat liver chemistries (ALT, AST, 
alkaline phosphatase, total bilirubin and INR) until they resolve, stabilise 
or return to within baseline  
• If at any time participant meets the liver chemistry stopping criteria, 
proceed as described above 
• If, after 4 weeks of monitoring, ALT <3xULN and total bilirubin <2xULN 
and INR ≤1.5, monitor participants twice monthly until liver chemistries 
resolve 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. 


 
 
 
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Appendix G: Ocular Monitoring  
Ocular Monitoring Changes in Corneal Epithelium: Severity Grading and Mitigation 
Strategy  
In order to minimize the changes in corneal epithelium associated with belantamab mafodotin, 
patients must receive prophylactic preservative-free artificial tears.  The recommended 
administration is to use one drop in each eye at least 4 to 8 times daily, beginning on Cycle 1 Day 
1 until the subject discontinues treatment.  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. 
 
Corticosteroid eye drops are not required but can be used if clinically indicated per discretion of 
an eye-care specialist. Allow at least 5-10 minutes between administration of artificial tears and 
steroid eye drops (if administered). 
 
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 
patient and the physician, the following may be considered:  
 
• 
Beginning with the start of each belantamab mafodotin infusion, patients may apply 
cooling eye masks to their eyes for approximately 1 hour or as much as tolerated.   
• 
Patients 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. 
 
An ophthalmology or optometry (if ophthalmology is not available) consult is required for all 
patients who develop signs or symptoms of changes in corneal epithelium or require steroid eye 
drops for more than 7 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Changes in corneal epithelium must be graded according to the KVA scale (table 5).  
 
 
  
Table 5: Keratopathy Visual Acuity (KVA) Scale for Treatment-related Corneal 
Toxicities: 
Grade per KVA scale 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Corneal 
Toxicities 
Corneal 
examination 
finding(s) 
Mild 
superficial 
keratopathya 
Moderate 
superficial 
keratopathyb 
Severe 
superficial 
keratopathyc 
Corneal 
epithelial 
defectd 
Change 
in 
BCVAe 
Decline from 
baseline of 1 
line 
on 
Snellen Visual 
Acuity 
Decline from 
baseline of 2 or 
3 lines (and 
Snellen Visual 
Acuity 
not 
worse 
than 
20/200) 
Decline 
from 
baseline 
by 
more 
than 
3 
lines 
(and 
Snellen Visual 
Acuity 
not 
worse 
than 
20/200) 
Snellen 
Visual 
Acuity 
worse 
than 
20/200 
a Mild superficial keratopathy (documented worsening from baseline), with or without symptoms. 
b Moderate superficial keratopathy with or without patchy microcyst-like deposits, sub-epithelial 
haze (peripheral), or a new peripheral stromal opacity. 
c Severe superficial keratopathy with or without diffuse microcyst-like deposits, sub-epithelial 
haze (central), or a new central stromal opacity. 
d Corneal epithelial defect such as corneal ulcers (with underlying stromal infiltration). 
e Changes in visual acuity due to treatment-related corneal findings.   
• 
For participants who have BCVA worse than 20/20 in either eye at baseline, dose modification for that eye 
will be determined by the worsening of vision from baseline only (not by absolute BCVA at the visits).  
• 
If a participant has a baseline BCVA of 20/200 or worse in an eye, then belantamab mafodotin-related 
changes in vision in the other eye will drive the dose modification. If a participant has baseline BCVA of 
20/200 or worse in both the eyes, then the decision to delay or reduce belantamab mafodotin dose will be 
based on PI’s assessment of benefit vs. risk based on corneal exam findings following a discussion with the 
qualified eye care specialist.   
BCVA- best corrected visual acuity 
 


 
 
 
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Appendix H: Contraceptive Guidance 
 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
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. 
• 
Highly Effective Methodsb That Are User Dependent 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
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. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea 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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Appendix I: Human PBMC Staining Protocol 
 
Materials: 
• 
Wash Buffer: PBS + 5% FBS, Brandon prepare 
• 
Zombie NIR: keep frozen until use.  
• 
FcBlock: BD small white vial.  
• 
Ab Cocktail: keep on ice, in dark until use. 
• 
Fix Buffer: Biolegend brown bottle. 15ml aliquot. Room temp when receiving blood. 
• 
BD Brilliant Stain Buffer: to make antibody cocktail. 
 
Method:  all steps in BSC 
2 million unstained cells will go through the same incubation time and centrifuge, fixation. 
1. 3 million PBMC in ~200 µl DPBS.  No protein allowed. 
2. Add 1 µL Zombie NIR live/dead staining, mix immediately. 15 min in dark, room temperature.  
3. Add about 500 µL Wash Buffer, gentle mix.  
4. 300 x g, 5 min, add 1 µL FcBlock, mix, incubate for 10 min on ice.   
5. Add 50 µL Ab Cocktail, gentle mix, 15-30 min on ice, cover in dark. 
6. Add ~ 500 µL Wash Buffer, gentle mix  
7. 300xg, 5 min. Resuspend in 200 µl Fixation Buffer or > 2 x pellet vol, mix.  40-60 min in dark at 
room temp. 
8. Add ~ 500 µL Wash Buffer, gentle mix, centrifuge. Resuspend in 200 µL Wash Buffer, ready for 
flow analysis.