A Randomized, Two-period, Cross-over, Phase 2 Study, Comparing Pharmacokinetics, and Assessing Safety and Tolerability of Peripheral and Central i.v. Administration of Melphalan Flufenamide (Melflufen) in RRMM Patients
Phase: PHASE2
Conditions: RRMM
Sponsor: Oncopeptides AB

Protocol OP-109  
Version 2.2, 10 March 2021 
 
Protocol Title: A randomized, two-period, cross-over, Phase 2 study, comparing 
the pharmacokinetics, and assessing safety and tolerability of peripheral and 
central intravenous administration of melflufen in patients with relapsed and 
refractory multiple myeloma. 
 
 
National Clinical Trial number: NCT04412707 

CONFIDENTIAL 
Protocol OP-109  Version 2.2, 10 March 2021 
SOP CD-05 Protocol Development     
Version date 11Mar2018 
Title Page 
Protocol Title: A randomized, two-period, cross-over, Phase 2 study, comparing the 
pharmacokinetics, and assessing safety and tolerability of peripheral and central intravenous 
administration of melflufen in patients with relapsed and refractory multiple myeloma. 
Protocol Number:  
OP-109 
Compound Name: 
Melflufen 
Short Title:  
A Phase 2 study comparing the pharmacokinetics and assessing 
safety and tolerability of peripheral and central i.v. administration 
of melflufen in patients with RRMM. 
Sponsor Name: 
Oncopeptides AB 
Legal Registered Address:  Västra Trädgårdsgatan 15 
SE-111 53 Stockholm, Sweden 
Clinical Research  
PSI CRO AG 
Organization (CRO): 
Baarerstrasse 113a 
6300 Zug, Switzerland 
Regulatory Agency Identifying Number(s): 
IND: 
 116362 
EudraCT: 
2019-004127-21 
Approval Date: 
Version 1.0: 02 December 2019 
Amendment 1 Version 2.0: 30 April 2020 
Amendment 2 Version 2.1: 23 December 2020 
Amendment 3 Version 2.2: 10 March 2021 
CONFIDENTIAL 
This document contains confidential information belonging to Oncopeptides AB. Except as may 
be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold 
such information in confidence and not to disclose it to others (except where required by 
applicable law) nor use it for unauthorized purposes. In the event of actual or suspected breach of 
this obligation, Oncopeptides AB should be promptly notified. 

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Protocol OP-109  Version 2.2, 10March 2021 
 
 
2 
Signature Page – Sponsor and Lead Investigator 
 
Protocol Title: A randomized, two-period, cross-over, Phase 2 study, comparing the 
pharmacokinetics, and assessing safety and tolerability of peripheral and central intravenous 
administration of melflufen in patients with relapsed and refractory multiple myeloma. 
Protocol Number:   
OP-109 
 
 
 
 
Sponsor: 
 
 
 
 
 
_______________________________________________ 
_______________________ 
 
Date 
Clinical Study Physician 
Oncopeptides AB 
Luntmakargatan 46 
111 37 Stockholm, Sweden 
Phone: 
  
 
 
 
 
________________________________________________ 
_______________________ 
 
Date 
Clinical Operations Director 
 
 
 
 
 
 
 

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Protocol OP-109  Version 2.2, 10March 2021 
 
 
3 
Protocol Agreement Page - Principal Investigator 
 
Protocol Title: A randomized, two-period, cross-over, Phase 2 study, comparing the 
pharmacokinetics, and assessing safety and tolerability of peripheral and central intravenous 
administration of melflufen in patients with relapsed and refractory multiple myeloma. 
Protocol Number:   
OP-109 
 
 
 
 
By signing this protocol acceptance page, I confirm I have read, understood, and agree to 
conduct the study in accordance with the current protocol.  
 
________________________________________________ 
 
Name of study center 
 
________________________________________________ 
 
Principal Investigator Name (Printed)  
 
 
________________________________________________ 
__________________________ 
Principal Investigator (Signature) 
Date 
 
 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), with applicable local regulations, and with the ethical principles laid 
down in the Declaration of Helsinki. 
Confidential information contained in the clinical study protocol will not be used for any purpose 
other than the evaluation and conduct of the clinical investigation, unless prior written approval 
has been obtained from the sponsor Oncopeptides AB. 
 
 
 
 
 
 

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Protocol OP-109  Version 2.2, 10March 2021 
 
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3 
10-Mar-2021 
Amendment 2 
23-Dec-2020 
Amendment 1 
30-Apr-2020 
Original Protocol 
02-Dec-2019 
Amendment 3 (10-March-2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study. 
Overall Rationale for the Amendment: 
Non-substantial amendment due to update of assigned safety CRO from PSI PVG Unit to TFS. 
SAE reporting email address updated to safety.report@oncopeptides.com.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.4.1  
Time Period and Frequency 
for Collecting AE and SAE 
Information 
All SAEs will be recorded and 
reported to the assigned 
Pharmacovigilance CRO, TFS PSI 
pharmacovigilance (PVG) unit, 
within 24 hours, as indicated in 
Appendix 3. The investigator will 
submit any updated SAE data to 
the TFS PVG unit within 24 hours 
after becoming aware of the 
updated SAE data.  
Investigators are not obligated to 
actively seek AE or SAE after 
EoT visit and conclusion of the 
study participation. However, if 
the investigator learns of any 
SAE, including a death, at any 
time after a patient has been 
discontinued from the study, and 
he/she considers the event to be 
reasonably related to the study 
treatment or study participation, 
the investigator must promptly 
notify TFS the PVG unit. 
Safety CRO changed for 
the study from PSI to TFS  

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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 3:  
Adverse Events: Definitions 
and Procedures for 
Recording, Evaluating, 
Follow-up, and Reporting 
 
Several sections within the 
appendix 
• It is not acceptable for the 
investigator to send photocopies 
of the patient’s medical records to 
the assigned Pharmacovigilance 
CRO (TFS PSI Safety Desk) in 
lieu of completion of the SAE 
form and AE/SAE eCRF page. 
• There may be instances when 
copies of medical records for 
certain cases are requested by 
assigned Pharmacovigilance CRO 
(TFS PSI Safety Desk). In this 
case, all patient identifiers, with 
the exception of the patient 
number, will be redacted on the 
copies of the medical records 
before submission to assigned 
Pharmacovigilance CRO (TFS PSI 
Safety Desk). 
 
• There may be situations in 
which an SAE has occurred and 
the investigator has minimal 
information to include in the 
initial report to assigned 
Pharmacovigilance CRO (TFS PSI 
Safety Desk). However, it is very 
important that the investigator 
always make an assessment of 
causality for every event before 
the initial transmission of the SAE 
data to assigned 
Pharmacovigilance CRO (TFS PSI 
Safety Desk). 
• The investigator is obligated to 
perform or arrange for the conduct 
of supplemental measurements 
and/or evaluations as medically 
indicated or as requested by 
assigned Pharmacovigilance CRO 
(TFS PSI Safety Desk) to 
elucidate the nature and/or 
causality of the AE or SAE as 
fully as possible. This may include 
Safety CRO changed for 
the study from PSI to TFS  

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Section # and Name 
Description of Change 
Brief Rationale 
additional laboratory tests or 
investigations, histopathological 
examinations, or consultation with 
other health care professionals. 
 
SAE Reporting to 
safety.report@oncopeptides.com 
SafetyDesk@psi cro.com via 
Paper CRF 
 
• SAE reports are completed on 
paper and transferred to PSI PVG 
unit TFS , either via email to 
safety.report@oncopeptides.com 
safetydesk@psi cro.com , or 
facsimile can be used as back-up 
only if emailing reports is not 
possible (local fax numbers is are 
provided in the Investigator Site 
File). 
• In rare exceptional 
circumstances and in the absence 
of facsimile equipment, 
notification to the CRA or 
Medical Monitor by telephone is 
acceptable with a copy of the SAE 
data collection tool sent by 
overnight mail or courier service. 
• Initial notification via 
telephone does not replace the 
need for the investigator to 
complete and sign the SAE CRF 
pages within the designated 
reporting time frames. 
Contacts for SAE reporting: 
Nickolai Usachev, Senior 
Manager PVG Unit, PSI  
Email:  nickolai.usachev@psi
cro.com   
Mobile phone:  +79219445972 
 

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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 4:  
Contraceptive Guidance and 
Collection of Pregnancy 
Information  
Pregnancy Reporting to 
assigned Safety CRO, TFS PSI; 
via Paper Pregnancy Reporting 
Form 
 
• Facsimile or Eemail 
transmission of the Pregnancy 
paper Reporting Form is the 
preferred method to transmit this 
information to the assigned Safety 
CRO. If emailing the report is not 
possible facsimile can be used as a 
back-up method.  
(FAX: [country specific] or 
Email: 
safety.report@oncopeptides.com 
safetydesk@psi cro.com or use 
the fax number provided in the 
Investigator Site file). 
• In rare exceptional 
circumstances and in the absence 
of email facsimile or email 
facismile equipment, notification 
to of the CRA or Medical Monitor 
by telephone is acceptable with a 
copy of the Pregnancy data 
collection tool sent by overnight 
mail or courier service. 
Safety CRO changed for 
the study from PSI to TFS  
Protocol  
Administrative updates and 
corrected typos. 
Administrative update 
 
 
 
 
 
 

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Table of Contents 
Protocol Amendment Summary of Changes Table ....................................................................4 
Table of Contents ...........................................................................................................................8 
List of Tables ................................................................................................................................11 
1. 
Protocol Summary ........................................................................................................12 
1.1. 
Synopsis ..........................................................................................................................12 
1.2. 
Schema ............................................................................................................................17 
1.3. 
Inclusion Criteria ............................................................................................................17 
1.4. 
Exclusion Criteria ...........................................................................................................18 
1.5. 
Schedule of Activities (SoA) ..........................................................................................20 
2. 
Introduction ...................................................................................................................26 
2.1. 
Study Rationale ...............................................................................................................26 
2.2. 
Background .....................................................................................................................27 
2.2.1. 
Multiple Myeloma ..........................................................................................................27 
2.2.2. 
Melflufen.........................................................................................................................27 
2.3. 
Benefit/Risk Assessment ................................................................................................30 
3. 
Objectives and Endpoints ............................................................................................30 
4. 
Study Design ..................................................................................................................32 
4.1. 
Overall Design ................................................................................................................32 
4.1.1. 
Treatment duration ..........................................................................................................33 
4.2. 
Scientific Rationale for Study Design ............................................................................33 
4.3. 
Justification for Dose ......................................................................................................34 
4.4. 
End of Treatment Definition ...........................................................................................34 
4.5. 
End of Study Definition ..................................................................................................34 
4.5.1. 
End of PK and Peripheral Safety Study ..........................................................................34 
4.5.2. 
End of Study ...................................................................................................................35 
5. 
Study Population ...........................................................................................................35 
5.1. 
Inclusion Criteria ............................................................................................................35 
5.2. 
Exclusion Criteria ...........................................................................................................36 
5.3. 
Lifestyle Considerations .................................................................................................37 
5.4. 
Screen Failures ................................................................................................................37 
5.5. 
Population Diversity .......................................................................................................38 
6. 
Study Intervention ........................................................................................................38 
6.1. 
Study Treatment (s) Administered ..................................................................................38 
6.1.1. 
Study Regimens and Administration ..............................................................................39 
6.1.2. 
Melflufen Preparation and Administration .....................................................................39 
6.1.3. 
Dexamethasone Administration ......................................................................................42 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................42 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................43 
6.4. 
Study Treatment Compliance .........................................................................................43 
6.5. 
Concomitant Therapy .....................................................................................................43 

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6.5.1. 
Required Concomitant Therapy ......................................................................................43 
6.5.2. 
Recommended Concomitant Therapy .............................................................................43 
6.5.3. 
Prohibited Concomitant Therapy ....................................................................................44 
6.6. 
Dose Modifications .........................................................................................................45 
6.6.1. 
Criteria for initiation of therapy Cycle 1 Day 1 ..............................................................45 
6.6.2. 
Criteria for Initiation of a New Cycle of Treatment .......................................................46 
6.6.3. 
Dose Reduction Steps .....................................................................................................46 
6.6.4. 
Dose Modification Guidelines for Melflufen, Based on Toxicity ..................................47 
6.6.5. 
Dose Modifications for dexamethasone ..........................................................................49 
6.7. 
Intervention after the End of the Study ...........................................................................51 
7. 
Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal........................................................................................51 
7.1. 
Discontinuation of Study Treatment ...............................................................................51 
7.2. 
Patient Discontinuation/Withdrawal from the Study ......................................................51 
7.3. 
Lost to Follow Up ...........................................................................................................52 
8. 
Study Assessments and Procedures.............................................................................52 
8.1. 
Study Procedures ............................................................................................................53 
8.1.1. 
Procedures during screening ...........................................................................................53 
8.1.2. 
Procedures during study treatment phase, all cycles ......................................................54 
8.1.3. 
Procedures Day 1, all cycles ...........................................................................................54 
8.1.4. 
Procedures Day 8, 15 and 22 ..........................................................................................55 
8.1.5. 
Procedures if melflufen or dexamethasone are discontinued .........................................56 
8.1.6. 
Procedures after active study treatment phase ................................................................56 
8.1.7. 
Procedures at End of Treatment Visit .............................................................................56 
8.1.8. 
Procedures during Progression Free Survival Follow-up ...............................................57 
8.2. 
Efficacy Assessments .....................................................................................................58 
8.2.1. 
M protein Response assessment......................................................................................58 
8.2.2. 
Skeletal X-rays and low-dose CT scans..........................................................................58 
8.2.3. 
Extramedullary myeloma (plasmacytoma) assessment ..................................................59 
8.3. 
Safety Assessments .........................................................................................................59 
8.3.1. 
Physical Examinations ....................................................................................................59 
8.3.2. 
Local tolerance assessments ...........................................................................................59 
8.3.3. 
Vital Signs .......................................................................................................................59 
8.3.4. 
Electrocardiograms .........................................................................................................60 
8.3.5. 
Clinical Safety Laboratory Assessments ........................................................................60 
8.3.6. 
Bone Marrow Aspiration (BMA) ....................................................................................61 
8.4. 
Adverse Events and Serious Adverse Events .................................................................61 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................61 
8.4.2. 
Follow-up of AEs and SAEs ...........................................................................................62 
8.4.3. 
Regulatory Reporting Requirements for SAEs ...............................................................62 
8.4.4. 
Pregnancy ........................................................................................................................62 
8.4.5. 
Fatal Events .....................................................................................................................63 
8.4.6. 
Laboratory Test Abnormalities .......................................................................................63 
8.4.7. 
Additional Laboratory Reporting Guidelines .................................................................63 

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8.5. 
Treatment of Overdose ...................................................................................................64 
8.6. 
Pharmacokinetics ............................................................................................................64 
8.7. 
Pharmacodynamics .........................................................................................................65 
8.8. 
Genetics ..........................................................................................................................65 
8.9. 
Biomarkers ......................................................................................................................65 
8.10. 
Health outcome and Quality of Life measures ...............................................................67 
8.10.1. Patient Reported Outcome Assessments .........................................................................67 
8.10.2. Patient treatment satisfaction, nurse convenience and nurse 
preference of administration ...........................................................................................67 
8.10.3. Use of health services and hospitalization ......................................................................67 
8.10.4. Eastern Cooperative Group Oncology Performance Status ............................................68 
9. 
Statistical Considerations .............................................................................................68 
9.1. 
Sample Size Determination ............................................................................................68 
9.2. 
Populations for Analyses ................................................................................................68 
9.3. 
Statistical Analyses .........................................................................................................69 
9.3.1. 
General Considerations for the Statistical Analysis........................................................69 
9.3.2. 
Efficacy Analyses ...........................................................................................................69 
9.3.3. 
Safety Analyses ...............................................................................................................71 
9.3.4. 
Statistical evaluation of PK parameters ..........................................................................72 
9.3.5. 
Exploratory analyses .......................................................................................................72 
9.4. 
Interim Analyses .............................................................................................................73 
9.4.1. 
Data Safety Monitoring Committee (DSMC) .................................................................73 
10. 
Supporting Documentation and Operational Considerations ..................................75 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................75 
10.1.1. Regulatory and Ethical Considerations ...........................................................................75 
10.1.2. Financial Disclosure........................................................................................................75 
10.1.3. Informed Consent Process ..............................................................................................75 
10.1.4. Data Protection................................................................................................................76 
10.1.5. Dissemination of Clinical Study Data.............................................................................76 
10.1.6. Data Quality Assurance ..................................................................................................76 
10.1.7. Source Documents ..........................................................................................................77 
10.1.8. Study and Site Closure ....................................................................................................77 
10.1.9. Publication Policy ...........................................................................................................78 
10.1.10. Compensation for health damage of subjects/insurance .................................................78 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................79 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................82 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................88 
10.5. 
Appendix 5: NCI CTCAE Version 5.0 ...........................................................................92 
10.6. 
Appendix 6: Eastern Cooperative Oncology Group (ECOG) 
Performance Scale ..........................................................................................................92 
10.7. 
Appendix 7: IMWG Uniform Response Criteria ............................................................93 
10.8. 
Appendix 8: Line of Therapy Definition ........................................................................95 

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10.9. 
Appendix 9: ISS and R-ISS Score ..................................................................................96 
10.10. 
Appendix 10: Definition of Relapsed Disease per IMWG 
definitions .......................................................................................................................97 
10.11. 
Appendix 11: Assessment of Q-Tc interval:...................................................................97 
10.12. 
Appendix 12: Estimated Glomerular Filtration Rate (eGFR) by 
CKD-EPI equation ..........................................................................................................98 
10.13. 
Appendix 13: Visual infusion Phlebitis Score ................................................................99 
10.14. 
Appendix 14: EQ-5D-5L ................................................................................................99 
10.15. 
Appendix 15: Treatment satisfaction, nurse convenience and 
nurse preference ............................................................................................................100 
10.16. 
Appendix 16:  Use of health services and hospitalization ............................................103 
10.17. 
Appendix 17: Management of chemotherapy extravasation: 
ESMO-EONS Clinical Practice Guidelines ..................................................................103 
10.18. 
Appendix 18: Abbreviations .........................................................................................104 
11. 
References ....................................................................................................................109 
 
 
List of Tables 
 
Table 2-1 
Summary of Melflufen Treatment related Grade 3 or 4 AE ............................. 29 
Table 3-1 
Objectives and Endpoints .................................................................................. 30 
Table 4-1  
Study Design ..................................................................................................... 33 
Table 6-1  
Study Drugs ....................................................................................................... 38 
Table 6-2 
Dose reduction steps for melflufen ................................................................... 47 
Table 6-3 
Dose reduction steps for dexamethasone .......................................................... 47 
Table 6-4 
Dose modification guidelines for hematologic toxicity .................................... 48 
Table 6-5 
Dose modifications for toxicity related to dexamethasone ............................... 50 
Table 8-1 
PK sampling timepoints .................................................................................... 64 
Table 8-2  
Summary of biomarker assessments ................................................................. 65 
Table 10-1  
Protocol-Required Laboratory Assessments at Local Lab ................................ 79 
Table 10-2 
Protocol-Required Laboratory Assessments at Central Lab ............................. 80 
Table 10-3 
Blood and Bone Marrow Volumes .................................................................... 81 
Table 10-4 
Highly Effective Contraceptive Methods .......................................................... 88 
 
 
 
 

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1. Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
A randomized, two-period, cross-over, Phase 2 study, comparing the pharmacokinetics, and 
assessing safety and tolerability of peripheral and central intravenous administration of melflufen 
in patients with relapsed and refractory multiple myeloma. 
Short Title:  
A Phase 2 study comparing the pharmacokinetics and assessing safety and tolerability of 
peripheral and central i.v. administration of melflufen in patients with RRMM. 
Rationale:  
The outcome in relapsed and refractory multiple myeloma (RRMM) is still unsatisfactory despite 
recent improvements in treatment. Thus, new therapeutic options are needed. Melphalan 
flufenamide (hereinafter referred to as melflufen) is a peptide-drug conjugate that is rapidly taken up 
by multiple myeloma (MM) cells due to its high lipophilicity (Chauhan et al 2013, Wickström et 
al 2017). Once inside the myeloma cell, the activity of melflufen is determined by its immediate 
cleavage by peptidases into hydrophilic alkylator payloads that are entrapped (Wickström et al 
2017, 2010, Gullbo et al 2003). Melflufen is 50-fold more potent than melphalan in myeloma 
cells in vitro due to the increase of intracellular alkylator activity (Chauhan et al 2013, 
Wickström et al 2017).  
Melflufen has been evaluated in combination with low dose dexamethasone in patients with 
RRMM in a Phase 1/2 clinical trial (O-12-M1, NCT01897714). The trial established the 
recommended dose at 40 mg of melflufen every 28 days combined with 40 mg dexamethasone 
weekly. As of the database lock 9th November 2017, there were 45 patients treated with 40 mg 
melflufen every 28 days in combination with weekly dexamethasone. The Overall Response 
Rate (ORR) (Partial Response [PR] or better) was 31% and the Clinical Benefit Rate (CBR) 
(Minimal response [MR] or better) was 49%. The patients had a median of 4 prior lines of 
therapy, including Immunomodulatory Drugs (IMiDs), Proteasome Inhibitors (PIs) and 
alkylators. The median progression free survival (PFS) was 5.7 months based on 41 events, and 
the overall survival (OS) was 20.7 months based on 23 events in the 45 patients (Richardson et al 
2020). 
There are also ongoing clinical studies in RRMM patients, including a phase 2 study in patients 
refractory to pomalidomide and/or an anti-CD38 antibody (anti-CD38 mAbs) (OP-106 Horizon, 
NCT02963493), a phase 2 study in patients with impaired renal function (OP-107 Bridge, 
NCT03639610), a phase 1/2 study where melflufen and dexamethasone are combined with 
daratumumab or bortezomib (OP-104 Anchor, NCT03481556), and a randomized phase 3 study 
(OP-103 Ocean, NCT03151811) comparing melflufen and dexamethasone to pomalidomide and 
dexamethasone. 
Current labeling of several other alkylating agents such as melphalan, bendamustine and 
cyclophosphamide, allows for peripheral vein administration but local reactions at the infusion 
site have been observed for several alkylating compounds. In addition, in trials with 

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Overall Design: 
This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety 
and tolerability and efficacy of peripheral and central intravenous administration of melflufen in 
patients with RRMM, see Appendix 10. It is an international study, enrolling patients in US and 
Europe. The study will enroll patients following at least 2 lines of prior therapy.  
Patients will be randomized (1:1) to Arm A or Arm B, see 1.2 Schema. For each arm, treatment 
will be given in 28-day cycles and may be given in an outpatient treatment setting. PK samples 
will be collected at Day 1 of Cycles 1 and 2. 
Number of Patients: 
Approximately 25 participants will be randomly assigned to study treatment, the main PK and 
local tolerability analysis will take place when there are 20 PK evaluable patients given at least 
two doses of melflufen with PK sampling, sufficient to evaluate all PK parameters, one PK 
sampling series following peripheral administration and one PK sampling series following 
central administration. If a patient is not able to receive two doses of 40 mg melflufen, including 
an observation period of 28 days after the second dose, with sufficient PK samples taken, they 
will be replaced, if necessary to achieve 20 PK evaluable patients. 
Intervention Groups and Duration: 
Arm A: 
• In Cycle 1, melflufen 40 mg will be administered as a 30-minute infusion via a peripheral 
venous catheter (PVC). From cycle 2 and onwards melflufen will be administered as a 
30-minute infusion via a central catheter*. 
• Dexamethasone will be given p.o. at the standard dose of 40 mg weekly, at day 1, 8, 15 
and 22. Patients ≥ 75 years of age should receive a dose of dexamethasone p.o. of 20 mg 
weekly. 
Arm B:  
• In Cycle 1, melflufen 40 mg will be given as a 30-minute infusion via a central catheter. 
At Cycle 2, melflufen will be administered as a 30-minute infusion via a PVC. From 
Cycle 3 and onwards melflufen will be administered as a 30-minute infusion via a central 
catheter*. 
• Dexamethasone will be given p.o. at the standard dose of 40 mg weekly, at day 1, 8, 15 
and 22. Patients ≥ 75 years of age should receive a dose of dexamethasone p.o. of 20 mg 
weekly. 
Dose modifications and delays in therapy may be implemented based on patient tolerability. In 
the event of a cycle delay unrelated to dexamethasone toxicity, it is recommended to continue 
dexamethasone weekly.  
* After 6 patients have received peripheral infusion with adequate PK data, a data and safety 
monitoring committee (DSMC) will assess the safety and tolerability of received peripheral 
infusion. The DSMC may then allow continuation with peripheral infusion in Cycle 3 and 

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onwards (in both Arm A and B). The investigator in agreement with the patient will determine 
whether continued treatment will use peripheral or central administration. 
Data and Safety Monitoring Committee: 
An independent DSMC will perform surveillance of efficacy/safety balance at regular intervals 
and on an as needed basis during the study, to safeguard the interest of study patients. The 
DSMC will consist of the lead investigator, Sponsor representative(s), the CRO global medical 
monitor and headed by an independent chairperson. All activities and processes surrounding the 
DSMC will be outlined in the DSMC Charter.  
The DSMC will assess the benefit/risk profile of the study. All reported Grade 3-4 treatment-
related non-hematological adverse events (AEs), all local toxicities at the peripheral injection site 
as well as all serious adverse events (SAEs), and as well as efficacy and PK data will then be 
presented to the DSMC.  
If the DSMC considers the benefit/risk profile different from previous knowledge of efficacy and 
safety the DSMC may recommend change to the protocol, additional safety monitoring or 
stopping further recruitment. 
After 6 patients have received 2 cycles of 40 mg melflufen, one cycle via central and one cycle 
via peripheral infusion with adequate PK data and with an observation period of at least 28 days, 
a DSMC will assess the safety and tolerability of received infusions. The DSMC may then allow 
continuation with peripheral infusion in Cycle 3 onwards (in both Arm A and B). The 
investigator in agreement with the patient will determine whether continued treatment will use 
peripheral or central administration.  
If no major safety signals have been reported, recruitment may continue during preparations for 
DSMC meeting.  
Following a DSMC evaluation of data from at least 20 PK evaluable patients with an observation 
period of at least 28 days from the second dose of melflufen, the main PK and safety and 
tolerability study may be concluded. 
A patient is considered to have completed the PK study when administered two 40 mg doses of 
melflufen with PK sampling, one PK sampling series following peripheral administration and 
one PK sampling series following central administration and that the sampling series are 
sufficient to evaluate all PK parameters. Patients in both arm A and B will receive treatment until 
there is documented PD according to IMWG-URC guidelines, unacceptable toxicity, the 
patient/treating physician determines it is not in the patient´s best interest to continue or patient´s 
withdrawal of consent. 
 
 
 
 
 
 

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1.2. 
Schema 
 
1.3. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
1. Male or female, age 18 years or older; 
2. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol; 
3. A prior diagnosis of MM with documented disease progression in need of treatment at 
time of screening;  
4. Measurable disease defined as any of the following: 
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)  
• ≥ 200 mg/24hr of monoclonal protein in the 24hour urine collection by 
electrophoresis (UPEP)  
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to 
lambda free light chain (FLC) ratio 
5.  Received at least 2 prior lines of therapy and is refractory to an IMiD and a PI. The 
definition of refractory includes intolerance to an IMiD/PI after at least two 28-day 
cycles of therapy, see Appendix 10 and Appendix 8. 
6. Adequate peripheral arm veins for repeated intravenous infusions 
7. Life expectancy of ≥ 6 months; 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 
6. Patients with ECOG performance status > 2 solely based on bone pain secondary to 
MM may be eligible following consultation and approval of medical monitor; 
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula 
(QTcF) interval of ≤ 470 msec, see Appendix 11  

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10. Adequate organ function with the following laboratory results during screening 
(within 21 days) and immediately before study treatment administration on Cycle 1 
Day 1: 
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth 
factors cannot be used within 10 days (14 days for pegfilgrastim) prior to 
initiation of study treatment) 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions during the 
10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dL (Red blood cell [RBC] transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients diagnosed 
with Gilbert’s syndrome that have been reviewed and approved by the Medical 
Monitor 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN 
• Renal function: Estimated glomerular filtration rate (eGFR) by CKD-EPI formula 
of ≥ 45 mL/min, see Appendix 12. 
11. Must have or be willing to have an acceptable central catheter (Port a Cath, 
peripherally inserted central catheter [PICC] line, or central venous catheter [CVC]) 
and a PVC; 
12. a) Male patients: A male patient is eligible if he agrees to use contraception as 
detailed in Appendix 4 of this protocol during the treatment period and for at least 3 
months after the last dose of study treatment and refrains from donating sperm during 
this period   
b) Female patients: A female patient is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
I. 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
or 
II. 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
during the treatment period and for at least 28 days after the last dose of study 
treatment 
1.4. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Primary refractory disease (i.e. never responded with at least MR to any prior 
therapy);  
2. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory 
(platelet count fails to increase by > 10,000 cells/mm3 after a transfusion of an 
appropriate dose of platelets);  
3. Any medical conditions that, in the Investigator’s opinion, would impose excessive 
risk to the patient or would adversely affect his/her participating in this study.  
Examples of such conditions are: a significant history of cardiovascular disease (e.g., 
myocardial infarction, significant cardiac conduction system abnormalities, 
uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months); 

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4. Known active infection that is uncontrolled or has required intravenous systemic 
therapy within 14 days of randomization. Patients that have required oral anti-
infective treatment within 14 days of randomization should be discussed with the 
Medical Monitor; 
5. Other malignancy diagnosed or requiring treatment within the past 3 years with the 
exception of adequately treated basal cell carcinoma, squamous cell skin cancer, 
carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in 
active surveillance;  
6. Pregnant or breast-feeding females; 
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse compliance or follow-up evaluation; 
8. Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection; 
9. Concurrent known or suspected amyloidosis or plasma cell leukemia;   
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
11. Known central nervous system (CNS) or meningeal involvement of myeloma   
12. Any of the following treatments, within the specified timeframe 
• Previous cytotoxic therapies, including cytotoxic investigational agents, for 
MM within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.  
• The use of live vaccines within 30 days before initiation of therapy.  
• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.  
• Other investigational therapies and monoclonal antibodies within 4 weeks of 
initiation of therapy. 
• Prednisone up to but no more than 10 mg orally q.d. or its equivalent for 
symptom management of comorbid conditions is permitted but dose should be 
stable for at least 7 days prior to initiation of therapy.  
Other washout times may be considered following consultation with the medical 
monitor.   
13. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy 
(Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);   
14. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation 
of therapy;   
15. Prior allogeneic stem cell transplantation with active graft-versus-host-disease; 
16. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of 
therapy (this does not include limited course of radiation used for management of 
bone pain within 7 days of initiation of therapy);   
17. Known intolerance to the required dose and schedule of steroid therapy, as 
determined by the investigator; 
18. Known hypersensitivity reaction to melphalan, melflufen or its excipients  
19. Prior treatment with melflufen  

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 (X) Only if indicated 
a) All patients must sign an (IRB/IEC/REB)-approved ICF within 28 days of randomization and prior to any study related procedures. 
b) Medical History including, demographics, prior and current medical illness and conditions, prior surgical procedures. 
c) MM history including characteristics include date of initial diagnosis, ISS, R-ISS stage and cytogenetics at diagnosis (if previously evaluated). ISS and 
R-ISS stage at time of study entry, see Appendix 9. Prior surgery and/or radiation and anticancer therapy, including start and stop dates, documentation 
of best response, date of progressive disease and relapsed or refractory status, see Appendix 10.   
d) A physical exam, including height (screening only), weight and assessment for extramedullary myeloma (plasmacytoma) will be conducted at screening, 
Day 1 of each cycle and End of Treatment visit. A symptom directed physical examination will be conducted as needed during treatment. 
e) Vital signs including blood pressure, pulse, respiration rate, temperature, to be assessed at screening, pre and post melflufen infusion and at End of 
treatment visit. Weight to be recorded on Day 1 of each cycle. 
f) 
All WOCBP must have a medically supervised negative serum or urine pregnancy test prior to the initiation of therapy at each cycle.  
g) A 12-lead ECG will be performed at screening and End of Treatment visit and as clinically indicated. QTc interval to be assessed by Fridericia formula, 
see Appendix 11. 
h) Chest X-ray is optional if low-dose CT is performed for skeletal assessment. 
i) 
Hematology: CBC with differential, and platelet count should be taken at screening and at day 1, 8, 15 and 22 of all cycles, prior to initiation of therapy, 
and at the end of treatment (EOT) visit. If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive therapy (Granulocyte 
colony stimulating factor (G-CSF), blood or platelet transfusion) in the two preceding cycles, then CBC assessments may be excluded on Day 8 and Day 
22. If needed due to logistic reasons, the blood sampling may be done up to 23 hours prior to the scheduled dosing on Day 1 after consultation with 
medical monitor.  
j) 
Chemistry should be taken at screening, at day 1 of all cycles, prior to initiation of therapy and at End of Treatment visit. eGFR will be evaluated using 
CKD-EPI formula, see Appendix 12. During Progression free survival follow-up (PFS-FU) Serum calcium and albumin (corrected calcium) required if 
evidence of PD. 
k) Blood samples for biomarkers should be collected before dosing at Cycle 1 Day 1 and at EOT visit. 
l) 
Bone marrow aspirate (BMA) to be collected at screening for % plasma cells, morphology, cytogenetics by Interphase Fluorescence In Situ 
Hybridization (iFISH), and for exploratory biomarker analysis. A repeat sample is required in patients with suspect CR to confirm response and may be 
needed to confirm progression, if taken, samples will also be used for biomarker analysis.  

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m) SPEP and UPEP and serum and urine IFE (if SPEP or UPEP are not detectable and to confirm a CR), quantitative immunoglobulins per routine lab 
practice and SFLC assay (only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hours and SPEP is < 0.5 g/dL]) are to be 
conducted at screening, Cycle 1 Day 1. prior to each cycle even if treatment is delayed and at End of Treatment visit. Quantitative immunoglobulins 
need to be repeated for patients with IgA or IgD myeloma. In the event treatment is delayed, ≥ 2 weeks, response assessments are required to be 
repeated on the day the new cycle starts. If treatment is discontinued at or beyond 6 weeks the response assessments should then be repeated on the day 
of the decision (or as soon as possible ≥ 30 days after last dose of study drug) as part of the EOT visit.  
n) Known or suspected extramedullary myeloma are to be assessed at screening, as clinically indicated and to confirm response or progression. The same 
method of evaluation should be used throughout the study (e.g. Computerized tomography [CT]/ magnetic resonance imaging [MRI]/positron emission 
tomography computerized tomography [PET-CT]). All imaging assessments with measurements should be documented in the eCRF. Imaging 
assessments at screening do not need to be repeated if completed within 28 days of initiation of therapy. 
o) Assessment of lytic bone lesions can be done either by skeletal survey, or low dose CT scan. Required ≤ 6 weeks prior to initiation of treatment. 
Additional imaging assessments may be performed at the investigator’s discretion and should be documented in the electronic Case Report Form 
(eCRF). Repeat imaging assessments (same technique as used at screening) at any time when clinically indicated or to confirm PD. Limited X-rays or 
scans may be performed as clinically indicated if able to confirm PD.  
p) Treatment cannot begin prior to randomization and must begin ≤ 5 days after randomization. 
q) Evaluate if the melflufen dose should be given, delayed or reduced 
r) 
Evaluate if the dexamethasone dose should be given, held, reduced, delayed or permanently discontinued.  
s) 
PK Samples will be drawn in connection to the first two melflufen infusions, Cycle 1 and Cycle 2.  
t) 
Concomitant medications and procedures: All blood products and medications within 21 days prior to first dose until the EOT Visit. 
u) Special attention to patient evaluation of pain and other symptoms from the peripheral infusion site, see Appendix 13. SAEs will be collected from 
signing of the ICF until 30 days after last dose of study treatment or initiation of subsequent therapy whichever occurs first. AEs will be collected from 
the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy 
whichever occurs first. Any SAE that occurs after this timepoint and is considered related to melflufen or study participation in the opinion of the 
investigator will be collected. 
v) When administered melflufen via PVC the peripheral infusion site should be inspected pre and post infusion on Day 1, and on Day 8, including 
assessment of any local reaction such as redness, swelling, signs of phlebitis or extravasation using the common terminology criteria for adverse events 
(CTCAE) version 5.0, see Appendix 5 and Visual infusion Phlebitis (VIP) scale, see Appendix 13. All signs of extravasations or phlebitis should be 
photo documented at least daily until resolution, see section 6.1.2 for detailed instructions. 
w) Treatment satisfaction scale will be completed after received administration of melflufen on Day 1 of Cycle 1 and Cycle 2. Treatment preference scale 
will be completed prior to any procedures on Day 1 of Cycle 3 only, and prior to being told anything related to health, see appendix 15. 

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x) The questionnaire should be completed on Day 1, prior to any procedures on the day of the visit and prior to being told anything related to health, it 
should be administered even if the treatment is not given, at the time of EOT visit, and at PFS-FU visits until time of progression or starting a new 
treatment. See Section 8.1 and Appendix 14. 
y) End of Treatment visit should be scheduled 30 days after last dose of study treatment (melflufen or dexamethasone) or as soon as possible if the decision 
to remove patient from therapy occurs later than 30 days after last dose (such as in the case of a prolonged cycle). If a new treatment for MM is to be 
introduced sooner than 30 days after last dose of study drug the EOT visit should occur as close as possible before the first dose of the new drug. 
Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT visit are to be followed until resolution (≤ Grade 2) or initiation of subsequent 
therapy. SAEs should be followed until resolution or stabilization with no expected resolution.   
z) Patients who discontinue therapy for reasons other than disease progression should continue to have monthly disease assessments done until 
documented progression or initiation of subsequent therapy, second primary malignancy should also be followed and documented. Confirmed 
progression requires 2 consecutive M protein assessments at any time (including the same day for SPEP/FLC). The second assessment must be a 
separate serum and urine sample. If the second consecutive M protein sample can only be obtained after the start of subsequent therapy, it may still be 
used as confirmation of PD. Documentation of the date and regimen of the first subsequent anti-cancer treatment should be completed if it occurs during 
PFS-FU 
aa) Nurse convenience and preference scales will be completed after the patient was given the administration of melflufen on Day 1 of Cycle 1 and Cycle 2, 
see Appendix 15. 
bb) Use of health services and days of hospitalization will be completed by the patient at screening, on Day 1 of each cycle, at time of EOT visit, and PFS-
FU prior to any procedures on the day of the visit and prior to being told anything related to health, see Appendix 16. 
 
 

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2. 
Introduction 
Melflufen is a first in class anti-cancer peptide-drug conjugate designed for targeted enrichment 
of alkylating moieties in tumor cells and belongs to a novel class of drugs called peptide-drug 
conjugates. Once monthly intravenous (i.v.) melflufen, in combination with weekly 
dexamethasone, has shown encouraging clinical results in relapsed and RRMM patients (see 
current Investigator’s Brochure [IB] for details). In clinical studies to date, melflufen has only 
been administered via a central vein, but peripheral vein administration might be potentially 
preferable to some patients if the safety and tolerability profile is acceptable. 
2.1. 
Study Rationale 
The outcome in RRMM is still unsatisfactory despite recent improvements in treatment. Thus, 
new therapeutic options are needed. Melflufen is a peptide-drug conjugate that is rapidly taken 
up by MM cells due to its high lipophilicity (Chauhan et al 2013, Wickström et al 2017). Once 
inside the myeloma cell, the activity of melflufen is determined by its immediate cleavage by 
peptidases into hydrophilic alkylator payloads that are entrapped (Wickström et al 2017, 2010, 
Gullbo et al 2003). Melflufen is 50-fold more potent than melphalan in myeloma cells in vitro 
due to the increase of intracellular alkylator concentration (Chauhan et al 2013, Wickström et al 
2017). 
Melflufen has been evaluated in combination with low dose dexamethasone in patients with 
RRMM in a Phase 1/2 clinical trial (O-12-M1, NCT01897714). The trial established the 
recommended dose at 40 mg of melflufen every 28 days combined with 40 mg dexamethasone 
weekly. As of the database lock 9th November 2017, there were 45 patients treated with 40 mg 
melflufen every 28 days in combination with weekly dexamethasone. The Overall Response 
Rate (ORR) (PR or better) was 31% and the CBR (MR or better) was 49%. The patients had a 
median of 4 prior lines of therapy, including IMiD, PIs and alkylators. The median progression 
free survival (PFS) was 5.7 months based on 41 events, and the overall survival (OS) was 20.7 
months based on 23 events in the 45 patients (Richardson et al 2020). 
There are also ongoing clinical studies in RRMM patients, including a phase 2 study in patients 
refractory to pomalidomide and/or an anti-CD38 mAbs (OP-106 Horizon, NCT02963493), a 
phase 2 study in patients with impaired renal function (OP-107 Bridge, NCT03639610), a phase 
1/2 study where melflufen and dexamethasone are combined with daratumumab or bortezomib 
(OP-104 Anchor, NCT03481556), and a randomized phase 3 study (OP-103 Ocean, 
NCT03151811) comparing melflufen and dexamethasone to pomalidomide and dexamethasone. 
Current labeling of several other alkylating agents such as melphalan, bendamustine and 
cyclophosphamide, allows for peripheral vein administration but local reactions at the infusion 
site have been observed for several alkylating compounds. In trials with Peptichemio, a mixture 
of six synthetic peptides containing m-L-phenyl alanine mustard, (which is the alkylating moiety 
of e.g. melphalan), phlebitis was very common leading to oedema and phlebosclerosis. 
(Paccagnella et al 1986). In guidelines for clinical management of extravasations, opinions differ 
on the tissue damaging potential of melphalan, but in the ESMO guidelines it is described as an 
irritant (Pérez-Fidalgo 2012). Nonclinical local tolerance testing by intradermal injection in mice 
showed no difference between melphalan and melflufen at clinically relevant concentrations 
(data on file). In clinical studies to date, melflufen has only been administered via a central vein, 

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but peripheral vein administration might be potentially preferable to some patients if the safety 
and tolerability profile is acceptable.  
2.2. 
Background 
2.2.1. 
Multiple Myeloma 
MM is a malignancy of the differentiated plasma cells that affects the older patient with a median 
age at onset of 65 to 70 years and a slight male predominance. MM is the second most common 
hematologic malignancy and 32,110 patients were estimated to be diagnosed with myeloma in 
the United States in 2019 with a median 5-year survival of 52.2% (SEER 2019). 
The disease is characterized by clonal proliferation of plasma cells in the bone marrow and the 
production of excessive amounts of a monoclonal immunoglobulin (usually of the IgG or IgA 
type or free urinary light chain [paraprotein, M-protein or M-component]). Patients with MM 
may experience significant decrement to quality of life, including bone pain, bone fractures, 
fatigue, anemia, infections, hypercalcemia, and renal function compromise (including renal 
failure) (Jordan et al. 2014). The disease course for MM varies with the disease stage at 
diagnosis, cytogenetic profile, as well as age and patient comorbidities. Survival in myeloma is 
significantly variable depending on host factors, tumor burden, biology and response to treatment 
(Chng et al. 2014). However, the disease remains ultimately fatal. 
There are currently 7 classes of Food and Drug Administration (FDA) approved drugs available 
for the treatment of MM, including steroids (prednisone and dexamethasone), IMiDs 
(thalidomide, lenalidomide and pomalidomide), PIs (bortezomib, carfilzomib and ixazomib), 
histone deacetylase inhibitors (panobinostat), conventional chemotherapy (melphalan, 
cyclophosphamide, doxorubicin), including high dose melphalan with autologous stem-cell 
transplantation (ASCT), monoclonal antibodies (elotuzumab and daratumumab) and recently 
conditionally approved nuclear export inhibitors (selinexor). The selection of treatment in 
RRMM is challenging. The National Comprehensive Cancer Network (NCCN) guidelines 
(NCCN 2.2019) and an  overview published in the Mayo Clinic Proceedings (Kumar et al. 2016) 
detail an array of single agent, doublet and triplet combination regimens that can be considered. 
Patients for whom stem cells were cryopreserved early in the disease course, and who are 
transplant candidates, may benefit from ASCT as salvage therapy (Cavo et al. 2011). In general, 
MM patients will receive an average of 4 to 8 different treatment regimens during their life span. 
Recent improvements in therapies have significantly increased the expected life span for these 
patients, especially for younger patients (Kristinsson et al 2014). However, despite the 
availability of effective therapies, the optimal combinations and sequencing of these agents with 
other therapies and with one another is still unclear. Only 20 to 30% of the RRMM patients 
typically respond to any particular treatment and ultimately patients relapse from all available 
options. Given the inevitable relapses seen in these patients, new approaches to therapy are 
clearly still needed. 
2.2.2. 
Melflufen 
Melflufen, a first-in-class anti-cancer peptide-drug conjugate, is rapidly taken up by MM cells 
due to its high lipophilicity (Wickström 2017). Once inside the myeloma cell, melflufen is 

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immediately cleaved by peptidases, leading to entrapment of the hydrophilic alkylator payloads. 
(Wickström et al 2017, 2010, Gullbo et al 2003).  
In primary patient-derived MM tumor cells, melflufen demonstrated approximately 50-100 fold 
higher efficacy than melphalan, explained by the 50-fold higher intracellular concentration of 
alkylating moieties achieved after melflufen vs. melphalan exposure in the culture (Chauhan 
2013, Ray 2016, Wickström et al. 2017,). 
Mechanistic studies have shown that melflufen induces rapid, irreversible DNA damage; 
accumulation of reactive oxygen species and apoptosis associated with mitochondrial 
dysfunction and release of cytochrome c, activation of caspases and poly adenosine diphosphate 
(ADP) ribose polymerase cleavage. Moreover, melflufen inhibits angiogenesis and MM cell 
migration. (Chauhan et al. 2013, Ray et al 2016, Strese et al. 2013).   
Importantly, in vitro studies in MM cell lines resistant to dexamethasone, bortezomib, and 
melphalan have demonstrated melflufen efficacy at same concentrations as observed in the 
parental, non-resistant cell lines (Chauhan 2013). Likewise, in the in vivo efficacy studies with 
different human tumors, including MM, superior antitumor activity yet seemingly comparable 
toxicity of melflufen was observed compared to equimolar dosage of melphalan (Wickström et 
al. 2007, Chauhan et al. 2013).  
Melflufen has been evaluated in combination with low dose dexamethasone in patients with 
RRMM in a Phase 1/2 clinical trial (O-12-M1, NCT01897714). The trial established the 
recommended dose at 40 mg of melflufen every 28 days combined with 40 mg dexamethasone 
weekly. As of the database lock 9th November 2017, there were 45 patients treated with 40 mg 
melflufen every 28 days in combination with weekly dexamethasone. The Overall Response 
Rate (ORR) (PR or better) was 31% and the CBR (MR or better) was 49%. The patients had a 
median of 4 prior lines of therapy, including IMiD, PIs and alkylators. The median progression 
free survival (PFS) was 5.7 months based on 41 events, and the overall survival (OS) was 20.7 
months based on 23 events in the 45 patients (Richardson et al 2020). 
There are also ongoing clinical studies in RRMM patients, including a phase 2 study in patients 
refractory to pomalidomide and/or daratumumab (OP-106 Horizon, NCT02963493), a phase 2 
study in patients with impaired renal function (OP-107 Bridge, NCT03639610) ), a phase 1/2 
study where melflufen and dexamethasone are combined with daratumumab or bortezomib (OP-
104 Anchor, NCT03481556), and a randomized phase 3 study (OP-103 Ocean, NCT03151811) 
comparing melflufen and dexamethasone to pomalidomide and dexamethasone. 
The safety profile of melflufen suggested by preclinical studies is supported by clinical data from 
the completed O-12-M1 and ongoing clinical trials. 
As of 6th February 2019, 263 patients with RRMM had received at least one dose of melflufen.  
The most common treatment emergent adverse events (TEAE) in the trials O-12-M1 OP-104 
(Anchor) and OP-106 (Horizon) were hematological events, such as thrombocytopenia, 
neutropenia and anemia. This is not unexpected since hematological events are common both as 
a consequence of MM disease and of treatment with alkylators. These events were assessed to be 
dose-related, reversible and monitorable.  
Treatment related Grade 3 and 4 Adverse Events (AE)s were reported in 37 patients out of 45 
patients (82%) in the O-12-M1 trial. Those related to melflufen and occurring in ≥ 5% of the 

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• To assess Quality of Life (QoL) based on 
Patient Reported Outcome (PRO) 
EQ-5D-5L 
• Value and changes from baseline in VAS 
and EQ-index 
• Number of patients by category and 
dimension 
• To assess Use of health 
services and days of hospitalization 
• Number of health services 
• Number and days of hospitalization 
a) All tumor response and progression-dependent endpoints are as assessed by investigators according to the 
IMWG-URC (Kumar et al. 2016), see Appendix 7.   
 
4. 
Study Design 
4.1. 
Overall Design 
This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety 
and tolerability, and efficacy of peripheral and central intravenous administration of melflufen in 
patients with RRMM, see Appendix 10. It is an international study, enrolling patients in US and 
Europe. The study will enroll patients following at least 2 lines of prior therapy and is refractory 
to an IMiD and a PI. 
Patients will be randomized (1:1) to Arm A or Arm B, see Table 4-1. For each arm, treatment 
will be given in 28-day cycles and may be given in an outpatient treatment setting. PK samples 
will be collected at Day 1 of Cycles 1 and 2. 
Arm A: 
• At Cycle 1, melflufen 40 mg will be administered as a 30-minute infusion via a peripheral 
venous catheter (PVC). From cycle 2 and onwards melflufen will be administered as a 30-
minute infusion via a central catheter*. 
• Dexamethasone will be given p.o. at the standard dose of 40 mg weekly, at day 1, 8, 15 and 
22. Patients ≥ 75 years of age should receive a dose of dexamethasone p.o. of 20 mg weekly. 
Arm B:  
• At Cycle 1, melflufen 40 mg will be given as a 30-minute infusion via a central catheter. At 
Cycle 2, melflufen will be administered as a 30-minute infusion via a PVC. From Cycle 3 
and onwards melflufen will be administered as a 30-minute infusion via a CVC*. 
• Dexamethasone will be given p.o. at the standard dose of 40 mg weekly, at day 1, 8, 15 and 
22. Patients ≥ 75 years of age should receive a dose of dexamethasone p.o. of 20 mg weekly. 
 
 
 
 

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Table 4-1  
Study Design 
 
 
Dose modifications and delays in therapy may be implemented based on patient tolerability. In 
the event of a cycle delay unrelated to dexamethasone toxicity, it is recommended to continue 
dexamethasone weekly.  
* After 6 patients have received peripheral infusion with adequate PK sampling, a DSMC will 
assess the safety and tolerability of received infusions. The DSMC may then allow continuation 
with peripheral infusion in Cycle 3 and onwards (in both Arm A and B) to further study local 
tolerability with repeat peripheral infusions. The investigator in agreement with the patient will 
determine whether continued treatment will use peripheral or central administration.  
4.1.1. 
Treatment duration 
Patients in both arm A and B will receive treatment until any of the following events is reached:  
• there is documented PD according to the IMWG-URC guidelines (Kumar et al.2016) to 
be confirmed on two consecutive assessments, and verified by the Medical Monitor prior 
to treatment discontinuation, see Appendix 7. 
• unacceptable toxicity. 
• the patient/treating physician determines it is not in the patient’s best interest to continue 
• patient’s withdrawal of consent.  
4.2. 
Scientific Rationale for Study Design 
The study will enroll patients with RRMM that have received at least 2 lines of prior therapy and 
are refractory to an IMiD and a PI. This population is expected to be similar to what was studied 
in the O12-M1 study in which ORR was 31%, PFS was 5.7 months and median overall survival 
(OS) was 20.7 months (Richardson et al, 2020) and is therefore reasonable to include in this trial. 
Current labeling of several other alkylating agents such as melphalan, bendamustine and 
cyclophosphamide, allows for peripheral vein administration but local reactions at the infusion 
site has been observed for several alkylating compounds. However, in trials with Peptichemio, a 
mixture of six synthetic peptides containing m-L-phenyl alanine mustard (which is the alkylating 

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moiety of e.g. melphalan), phlebitis was very common leading to oedema and phlebosclerosis. 
(Paccagnella et al 1986). In clinical studies to date, melflufen has only been administered via a 
central vein, but peripheral vein administration might be potentially preferable to some patients if 
the safety and tolerability profile is acceptable.  
The data on local tolerance in non-clinical trials with melflufen suggest that the compound, like 
many cytotoxic agents, has a propensity to cause damage to the vascular endothelium and 
surrounding tissue particularly when there is extravasation. However, when comparing the 
damage to the tissue after direct intradermal injection in mice with clinically recommended 
infusion solution concentrations, melflufen appears no worse than either melphalan or 
bendamustine, two alkylators routinely administered peripherally in the clinical setting. 
PK assessments for melflufen and the metabolites desethyl-melflufen and melphalan after central 
administration of melflufen in previous clinical studies demonstrate a very rapid disappearance 
of melflufen from plasma with an elimination half-life of less than 5 minutes. The peak 
concentration of melphalan is observed with a delay after end of melflufen infusion indicating 
formation of melphalan in tissues followed by a slow out-transport from tissues to plasma (data 
on file). The pattern and rate constants for these events are expected to be similar after peripheral 
and central administration but should be verified in a clinical study.  
These data support performance of a small crossover clinical study to compare PK of peripheral 
versus central infusion of melflufen and to verify local tolerance of the peripheral infusion in 
humans since this administration route could be feasible for some patients that would not prefer 
or are not suitable for placement of a CVC. 
4.3. 
Justification for Dose 
The dose and schedule of melflufen was established in the Phase 1/2 trial (O-12-M1) with 
melflufen in combination with weekly dexamethasone in RRMM patients as 40 mg on Day 1 of 
a 28-day cycle. The same dosing schedule has been used in the ongoing trials OP-106, OP-103 
and OP-107. Hematologic toxicity is the most common AE reported, with thrombocytopenia 
being the most clinically important AE.  
4.4. 
End of Treatment Definition 
A patient is considered to have completed study treatment when all study drugs (melflufen and 
dexamethasone) are discontinued for any reason. 
4.5. 
End of Study Definition 
4.5.1. 
End of PK and Peripheral Safety Study 
A patient is considered to have completed the PK study when administered two 40 mg doses of 
melflufen with PK sampling, one PK sampling series following peripheral administration and 
one PK sampling series following central administration and that the sampling series are 
sufficient to evaluate all PK parameters. If a patient is not able to receive two doses of 40 mg, 
including an observation period of 28 days after the second dose, with sufficient PK samples 
taken, they will be replaced. 
The main PK analysis will take place when there are 20 PK evaluable patients. 
 

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4.5.2. 
End of Study 
A patient is considered to have completed the study if he/she has completed all phases of the 
study including follow up visits for time to next anti-myeloma treatment. 
A patient is considered to end the study when he/she complete the study or withdraw from the 
study for any reason prior to completion. 
The end of the study is defined as the date when the last patient completes the last study visit 
(which may be a follow-up visit), or the date the Sponsor determines to terminate the study.   
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
1. Male or female, age 18 years or older; 
2. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol; 
3. A prior diagnosis of MM with documented disease progression in need of treatment at 
time of screening;  
4. Measurable disease defined as any of the following: 
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)  
•  ≥ 200 mg/24hr of monoclonal protein in the 24hour urine collection by 
electrophoresis (UPEP)  
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to 
lambda free light chain (FLC) ratio 
5.  Received at least 2 prior lines of therapy and is refractory to an IMiD and a PI. The 
definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles 
of therapy, see Appendix 10 and Appendix 8; 
6. Adequate peripheral arm veins for repeated intravenous infusions 
7. Life expectancy of ≥ 6 months; 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 6; 
Patients with ECOG performance status > 2 solely based on bone pain secondary to MM 
may be eligible following consultation and approval of medical monitor; 
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula 
(QTcF) interval of ≤ 470 msec, see Appendix 11; 
10. Adequate organ function with the following laboratory results during screening (within 
21 days) and immediately before study treatment administration on Cycle 1 Day 1: 

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• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth 
factors cannot be used within 10 days (14 days for pegfilgrastim) prior to 
initiation of study treatment) 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions during the 
10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dL (Red blood cell [RBC] transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients diagnosed 
with Gilbert’s syndrome that have been reviewed and approved by the Medical 
Monitor 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN 
• Renal function: Estimated glomerular filtration rate (eGFR) by CKD-EPI formula 
of ≥ 45 mL/min, see Appendix 12. 
11. Must have or be willing to have an acceptable central catheter (Port a Cath, peripherally 
inserted central catheter [PICC] line, or central venous catheter [CVC]) and a PVC; 
12. a) Male patients: A male patient is eligible if he agrees to use contraception as detailed 
in Appendix 4 of this protocol during the treatment period and for at least 3 months after 
the last dose of study treatment and refrain from donating sperm during this period  
b) Female patients: A female patient is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies: 
i. 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
or 
ii. 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
during the treatment period and for at least 28 days after the last dose of 
study treatment 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Primary refractory disease (i.e. never responded with at least MR to any prior therapy);  
2. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet 
count fails to increase by > 10,000 cells/mm3 after a transfusion of an appropriate dose of 
platelets);  
3. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk 
to the patient or would adversely affect his/her participating in this study. Examples of 
such conditions are: a significant history of cardiovascular disease (e.g., myocardial 
infarction, significant cardiac conduction system abnormalities, uncontrolled 
hypertension, ≥ Grade 3 thromboembolic event in the last 6 months); 
4. Known active infection that is uncontrolled or has required intravenous systemic therapy 
within 14 days of randomization. Patients that have required oral anti-infective treatment 
within 14 days of randomization should be discussed with the Medical Monitor; 
5. Other malignancy diagnosed or requiring treatment within the past 3 years with the 
exception of adequately treated basal cell carcinoma, squamous cell skin cancer, 

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carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active 
surveillance;  
6. Pregnant or breast-feeding females; 
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse compliance or follow-up evaluation; 
8. Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection; 
9. Concurrent known or suspected amyloidosis or plasma cell leukemia;   
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
11. Known central nervous system (CNS) or meningeal involvement of myeloma;   
12. Any of the following treatments, within the specified timeframe 
• Previous cytotoxic therapies, including cytotoxic investigational agents, for MM 
within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.  
• The use of live vaccines within 30 days before initiation of therapy.  
• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.  
• Other investigational therapies and monoclonal antibodies within 4 weeks of 
initiation of therapy. 
• Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom 
management of comorbid conditions is permitted but dose should be stable for at 
least 7 days prior to initiation of therapy.  
Other washout times may be considered following consultation with the medical monitor.   
13. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy 
(Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);   
14. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of 
therapy;   
15. Prior allogeneic stem cell transplantation with active graft-versus-host-disease; 
16. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of 
therapy (this does not include limited course of radiation used for management of bone 
pain within 7 days of initiation of therapy);   
17. Known intolerance to the required dose and schedule of steroid therapy, as determined by 
the investigator; 
18. Known hypersensitivity reaction to melphalan, melflufen or its excipients  
19. Prior treatment with melflufen     
5.3. 
Lifestyle Considerations 
No restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently eligible to be enrolled. A minimal set of screen failure information is required to 

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Note:  Please refer to the Pharmacy Manual for complete instructions on preparation and 
administration of melflufen  
• Melflufen is administered i.v. either via a peripheral catheter or through a central 
catheter, which should be inserted according to standard local practice. All patients 
must have an acceptable catheter for infusion (PVC, Port A Cath, PICC line or CVC).   
• Melflufen degrades in solution. It is very important to adhere to the timelines for 
preparation that are outlined in the Pharmacy Manual. This requires very good 
coordination between staff at the pharmacy and the patient treatment area. 
• Melflufen is reconstituted in 40 mL glucose 5% infusion solution per 20mg vial of 
melflufen. The reconstituted melflufen is diluted to 250 mL in cold 0.9% saline 
infusion solution and should be refrigerated as recommended in the Pharmacy 
Manual. 
Before infusion: 
• Document vital signs prior to start of infusion. 
• Prepare the central/peripheral catheter by flushing with approximately 20 mL of 0.9% 
saline. 
• Inspect infusion site.  
• Take a photo of PVC infusion site after cannulation but before administration at each 
cycle when using PVC. 
Infusion: 
• 
The melflufen should be administered as a 30-minute intravenous infusion. Following 
DSMC meeting and general approval for peripheral administration in later cycles 
(>=C3), and if peripheral venous administration is chosen, consider alternating between 
right and left arm, if good veins in both arms.  
• Record start and stop time for infusion. 
• Inspect infusion site for any signs of extravasation. 
After infusion: 
• First flush the central/peripheral catheter with approximately 20 mL of 0.9% saline. Then 
follow with additional flushing as per institutional guidelines if necessary. 
• Document vital signs after stop of the infusion. 
• When applicable, the peripheral infusion site should be inspected, including assessment 
of any local reaction such as redness, swelling, signs of phlebitis or extravasation using 
CTCAE 5.0, see Appendix 5 and VIP, see Appendix 13.  
• When applicable, take a photo of PVC infusions site 15 minutes and 4 hours after 
removal of cannula. When a peripheral infusion is given at a later stage, following 
approval of DSMC, only a 15-minute post-removal photo is applicable.  
• All signs of extravasations or phlebitis should be photo documented at least on the day of 
infusion and the day following infusion. If VIP grading is above 1 it should be continued 
to be documented daily until grade 1 or resolution.  

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The planned and actual administered dose as well as the start and stop time for the infusion, 
should be documented in the source documents and on the appropriate eCRF page.  
See Section 6.2 for melflufen supply, storage and accountability. Refer to the Pharmacy Manual 
for details on melflufen preparation and administration.   
6.1.2.1. 
Documentation of Phlebitis and/or Extravasation 
Each incident of extravasation and/or Phlebitis must be correctly documented.  
• Date and time 
• Signs and symptoms 
• Area for Extravasation or Phlebitis  
• Approximate amount of drug extravasated, if applicable 
• Actions taken with time and date 
• Photographic documentation using a digital camera  
• Use a pen to mark the area to be photographed 
• Place a tape measure with millimeter measure aside the marked area 
• Measure the longest possible axis of the area and the longest axis perpendicular to this 
axis in mm.  
• Place the photo in the patient’s medical records/patient’s binder as source data 
• Outcome 
• Report extravasation, phlebitis, or other infusion site reactions as AEs, according to 
procedure described in Appendix 3 
• Continue to monitor the infusion site until all signs and symptoms of extravasation, 
phlebitis or other infusion site reactions have resolved. 
6.1.2.2. 
Handling of Phlebitis and/or Extravasation 
Extravasation 
Any definite or suspected extravasation should be managed according to the ESMO-EONS 
guidelines (Pérez-Fidalgo 2012).  
In case of a suspected extravasation: 
• the administration of melflufen should immediately be stopped.  
• the cannula should be left in place and gentle aspiration be performed to remove as much 
extravasated solution as possible.  
• the removed volume should be documented.  
• then remove the cannula.  
• mark the outline of the extravasated area, apply local dry compresses and elevate the 
limb. 
Please refer to the ESMO-EONS practice guidelines, see appendix 17. 

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Phlebitis 
If phlebitis ≥ grade 2 according to the VIP scale occurs during melflufen infusion (see Appendix 
13) the infusion should be aborted and the remaining amount should be administered via a 
central catheter. Topical treatment may be administered as clinically indicated.  
6.1.3. 
Dexamethasone Administration 
 
Dexamethasone should be administered orally on Day 1, 8, 15 and 22. Dexamethasone is best 
administered prior to melflufen when both drugs are given on the same day (Day 1 of each 
cycle). For Day 1 administrations of dexamethasone, actual time will be collected in the eCRF. 
Dexamethasone may be given even if the melflufen is delayed (continued weekly during cycle 
delays, at the investigator’s discretion).  
On Day 1 of each Cycle the patient will be provided dexamethasone for one full cycle. Review 
of compliance will be done on Day, 8, 15 and 22 of each cycle and during unscheduled visits if 
melflufen is being delayed. 
6.2. 
Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drugs received and any discrepancies are reported 
and resolved before use of the study drugs. Temperature logs during transport shall be 
archived on site. 
• Only patients enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study drugs. All study drugs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized 
site staff. 
• The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drugs accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
• Drug accountability will be reviewed by the Clinical Research Organization (CRO) 
monitor during site visits and at the completion of the study.  
• At study close-out, and as appropriate during the course of the study, all unused study 
drug packaging and any associated supplies should be discarded, with the Sponsor’s 
approval, according to the site drug destruction policy following review and approval of 
the policy by the site CRO monitor. A copy of the drug destruction policy and the 
completed drug accountability log should be provided to the CRO monitor. 
• Further guidance and information for the final disposition of unused study drugs are 
provided in the Pharmacy Manual.   
 
 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This open label trial will accrue approximately 25 patients in a 1:1 ratio in order to have 20 
evaluable patients.  
All patients meeting the required eligibility criteria, to be verified by the Medical Monitor, will 
be randomized to Arm A or Arm B using Medidata RAVE system for randomization. When the 
patient has been approved for randomization by the Medical Monitor, prior to the start of study 
treatment, the site will enter data in RAVE to obtain what arm the patient is randomized to. 
Treatment cannot begin prior to randomization and must begin ≤ 5 days after randomization. 
However, pretreatment tests/procedures must remain within the screening timelines specified in 
the SoA.   
6.4. 
Study Treatment Compliance 
Compliance with melflufen will be assured by administration of the study treatment under the 
supervision of the investigator or his/her designee and should be documented in the study drug 
administration and accountability records. Compliance with dexamethasone will be verified by 
accountability, patient inquiry and documented in the source documents and eCRF 
Drug accountability will be reviewed by the CRO monitor during site visits and at the 
completion of the study. At study close-out, and as appropriate during the study, all unused study 
drug packaging and any associated supplies should be discarded according to the site drug 
destruction policy following review and approval of the site CRO monitor 
6.5. 
Concomitant Therapy 
Any blood products, medications and vaccines (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the patient is receiving within 28 days prior 
to the initiation of therapy or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Required Concomitant Therapy 
Males and females of child-bearing potential shall be required to use effective contraceptive 
methods (or abstinence) prior to initiation of study treatment while on therapy and for 28 days after 
last dose of study treatment for women and 3 months for men. The best method should be 
determined in consultation with the Investigator, see Appendix 4. 
6.5.2. 
Recommended Concomitant Therapy 
• Pneumocystis prophylaxis  
All patients are recommended to receive pneumocystis prophylaxis concomitant 
treatment according to the NCCN Guidelines, Prevention and Treatment of Cancer-

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related Iinfection (NCCN 2019) or institutional guidelines. 
http://www.nccn.org/professionals/physician gls/pdf/infections.pdf 
o Trimethoprim/sulfamethoxazole – Prophylaxis: single or double strength daily or 
double strength 3 x per week. May require adjustment for renal insufficiency. 
o Patients who are found to be intolerant of pneumocystis prophylaxis while on 
study may continue on study at the discretion of the investigator   
• Antimicrobial prophylaxis:   
o For patients with history of cytomegalovirus (CMV) infection that required 
treatment, prophylactic treatment per NCCN Guidelines, Prevention and 
Treatment of Cancer-related Infections (NCCN 2019) or institutional guidelines is 
recommended.  
o Patients with neutropenia are strongly recommended to receive antimicrobial 
prophylaxis throughout the treatment period per NCCN Guidelines, Prevention 
and Treatment of Cancer-related Infections (NCCN 2019) or institutional 
guidelines.  
• Thrombocytopenia and neutropenia are known consequences of MM but also the most 
common expected AEs associated with melflufen. Careful attention is to be paid to the 
monitoring of blood counts. General supportive measures, together with appropriate 
blood and platelet transfusions and hematopoietic growth factors should be 
administered if necessary. It is recommended, at the investigator’s discretion, that 
platelet transfusion should be avoided within ≤ 5 days of the next dose in order to 
assess endogenous platelet recovery and avoid the possibility of excessive 
myelosuppression (Excluding Cycle 1, Day 1 which adheres to the guidelines in 
Section 6.6.1 for use of growth factors and platelet transfusions prior to the first dose of 
therapy).  
• Prophylactic treatment with anti-emetic(s) prior to melflufen administration is 
recommended. Subsequent anti-emetic drugs against emesis should be administered at 
the discretion of the investigator.   
• Patients should receive full supportive care while on study at the investigator’s 
discretion, including red blood cell transfusions, anti-diarrheals, analgesics, etc.   
• Bisphosphonate therapy i.v. or p.o. should be administered if indicated in accordance 
with institutional guidelines.   
• Other prophylactic treatment for patient related concomitant conditions or risks may be 
considered.   
6.5.3. 
Prohibited Concomitant Therapy 
• Concurrent therapy with any approved or investigative anticancer therapeutic drug with 
activity against MM, including alpha interferon and/or chronic use of clarithromycin, is 
not allowed  
• Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel 
disease) prednisone > 10 mg/day (or its equivalent) are not permitted.  

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• Other investigative agents should not be used during the study 
• Radiation therapy to a limited area for bone pain to a pre-existing lesion may be 
considered in consultation with the medical monitor and approval of the sponsor 
• The use of live vaccines is prohibited during the study and for 90  days after last dose 
of study treatment. 
• The prophylactic use of G-CSF and platelet transfusions are not permitted to render the 
patient eligible for trial participation except as described within the inclusion criteria 
section 5.1 
• Thrombopoietin receptor agonists are not permitted 
6.6. 
Dose Modifications 
Dose modifications are permitted according to guidelines described in this section.   
• Toxicity should be assessed using CTCAE version 5.0, see Appendix 5. 
• All dose modifications should be based on the worst preceding toxicity.   
• Each suspected adverse drug reaction (ADR) should be attributed to a specific drug 
(melflufen and/or dexamethasone), if possible, so that the dose modifications can be 
made accordingly.   
• No dose escalations are permitted in any given patient once a dose level has been 
reduced. 
• Dose modifications different from those stated in the protocol should only be made in 
consultation with the medical monitor or Sponsor; unless required for immediate 
patient safety.   
• All interruptions or changes to study treatment administration must be recorded in the 
eCRF.   
• In case of dose reduction of any study therapy due to an AE, the dose should not be re-
escalated to the higher dose once the AE resolves. 
6.6.1. 
Criteria for initiation of therapy Cycle 1 Day 1 
Prior to initiation of therapy, patients must continue to meet eligibility criteria including ECOG 
performance status of ≤ 2 and the Cycle 1 Day 1 laboratory results must also meet the entry 
criteria noted below:  
• ANC ≥ 1,000 cells/ mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days 
[14 days for pegfilgrastim] prior to initiation of therapy) 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusion during the 
previous 10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dl (RBC transfusions are permitted)  
• eGFR by CKD-EPI formula of ≥ 45 mL/min 
See Section 6.5 for required, recommended and prohibited concomitant medications.  

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6.6.2. 
Criteria for Initiation of a New Cycle of Treatment  
The following guidelines apply to all cycles following Cycle 1. Patients should be assessed at the 
beginning of each cycle according to the tests and evaluations outlined for Day 1 in the SoA. 
Refer to Section 6.6.4 below for dose modifications of melflufen related to toxicity. 
To begin a new cycle of treatment the following hematologic and non-hematologic criteria must 
be met: 
Hematologic: 
• ANC must be ≥ 1,000 cell/mm3 (1.0 x109/L) 
• Platelet count must be ≥ 50,000 cell/mm3 (50.0 x 109/L) (platelet transfusions not 
recommended within ≤ 5 days of dosing, see Section 6.5.2) 
Non-hematologic: 
• All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except 
peripheral neuropathy Grade 2 without pain, alopecia any grade and fatigue ≤ Grade 2. 
If these criteria are not met on the scheduled Day 1, the new cycle should be delayed, and 
patients should be re-evaluated weekly. Refer to Section 6.6.4 for guidelines on dose 
modification of melflufen due to drug related toxicity.  
• The maximum amount of time for which study therapy may be delayed due to drug 
related toxicity is 28 days from a scheduled Day 1 (Day 57).   
• If melflufen is delayed for more than 28 days (Day 57) due to drug related toxicity the 
patient will be removed from the study treatment and enter PFS-FU. If, however, the 
patient was clearly benefiting from therapy, the patient may be able to continue treatment 
at the Investigator’s discretion and in consultation with the medical monitor, after 
resolution of the AE.  
Refer to Section 6.6.5 for guidelines on dose modification of dexamethasone due to drug related 
toxicity. 
In the event of a cycle delay, unrelated to dexamethasone toxicity, dexamethasone may be 
continued weekly at the investigators’ discretion.  
6.6.3. 
Dose Reduction Steps 
6.6.3.1. 
Dose Reduction Steps for Melflufen 
Dose modifications of melflufen for drug related toxicity are permitted. Multiple dose reductions 
are permitted, however, the lowest dose permitted is 20 mg. If a patient is unable to tolerate the 
lowest dose of melflufen due to drug related toxicity the patient must be withdrawn from 
treatment and enter PFS-FU. However, if, in the opinion of the investigator, it is in the patient’s 
best interest to continue treatment on a lower dose (15 mg or 10 mg), this may be considered 
after review and approval of the medical monitor, and after resolution of the AE. Prior to each 
cycle of melflufen the criteria for initiation of therapy must be met (See Section 6.6.2 ). Table 
6-2 describes the dose reduction steps for melflufen. 
 

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Patients who discontinue treatment for a study related AE including abnormal laboratory value 
must be followed as described in Section 8.1.6. 
6.6.4.2. 
Dose Modifications for Non-Hematologic Toxicity  
In order to start a new cycle of therapy the resolution of all non-hematologic toxicity must be 
to ≤ Grade 1 or baseline except peripheral neuropathy Grade 2 without pain, alopecia any grade, 
fatigue ≤ Grade 2. (Also see section 6.6.2). The following guidelines should be followed:   
• If the criteria for initiation of a new cycle of therapy are not met on Day 29 (the next 
scheduled Day 1 of any given cycle), dose should not be given, and the patient should 
be re-evaluated weekly. 
• If cycle prolongation of more than 14 days is needed to meet the criteria for initiation of 
a new cycle, a one-step dose reduction is necessary. 
• The option to “hold one week” for further resolution of toxicity is permitted at the 
investigator’s discretion based on the timelines in Table 6-4 above.  
• If cycle prolongation of more than 28 days (beyond Day 57) is needed, study treatment 
is to be discontinued unless in the investigator’s opinion the patient is benefitting from 
therapy. Continuation must be discussed with the medical monitor or Sponsor on a case 
by case basis.  
• Grade 3 or 4 treatment related non-hematologic toxicity that occurs or persists on Day 
29 (scheduled Day 1) of any cycle requires a one-step dose reduction when the criteria 
for a new cycle are met with the following exceptions:  
o The toxicity can be managed with appropriate therapy or the risk of recurrence 
may be reduced by the use of appropriate prophylactic therapy (e.g. anti-emetics 
and anti-diarrheas for nausea, vomiting and diarrhea) 
AND/OR 
o The toxicity was transient and/or does not warrant a dose reduction in the opinion 
of the investigator in consultation with the medical monitor (headache, abnormal 
laboratory value, fatigue). 
Alternate dose modification may be considered in discussion with the medical monitor or the 
sponsor. 
Continued dosing with or without dose reduction may be considered after contact with the 
medical monitor in case of non-study treatment related cycle prolongations (for example: 
influenza). 
Patients who discontinue treatment for a study related AE including abnormal laboratory value 
must be followed as described in Section 8.1.6. 
 
6.6.5. 
Dose Modifications for dexamethasone 
Dose modifications for dexamethasone are permitted. If a patient is unable to tolerate 
dexamethasone due to dexamethasone related toxicity, dexamethasone may be further reduced or 

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* As for any other reason to discontinue treatment, the patient can still continue in follow up 
(unless consent has been withdrawn for study participation and not only for treatment).  
See the SoA for data to be collected at the time of study treatment discontinuation and follow-up 
and for any further evaluations that need to be completed. 
• If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
• The reason(s) for withdrawal of study participation and the date at which the decision is 
made should be documented. 
7.3. 
Lost to Follow Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Medical Monitor immediately 
upon occurrence or awareness to determine if the patient should continue or discontinue 
study treatment. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 

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8.1. 
Study Procedures 
8.1.1. 
Procedures during screening 
Potential patients will be contacted to determine their interest in participating in this study. All 
patients must sign and date an IRB/IEC/REB approved informed consent form within 28 days of 
randomization and prior to any study related procedure. After providing written informed 
consent, the patients will be evaluated for eligibility by screening tests and conformity to study 
inclusion and exclusion criteria.   
Once a patient is determined to be eligible for screening and satisfy all initial inclusion and 
exclusion criteria (Section 5.1 and Section 5.2 respectively), screening procedures will be 
performed as listed below. If at any point during screening, a finding disqualifies the patient 
from study participation, no further screening tests will be performed.   
The screening visit will occur within 21 days before dosing with any of the study drugs. The 
following assessments will be performed at the screening visit:   
• Demographics  
o Date of birth, age, gender, race and ethnicity 
• Medical history, including the following:  
o Prior and current medical illness and conditions   
o Prior surgical procedures   
• Myeloma history including characteristics 
o Date of initial diagnosis   
o ISS and R-ISS stage and cytogenetics at diagnosis (if previously evaluated)   
o ISS and R-ISS stage at time of study entry, see Appendix 9 
o All prior myeloma treatment, also including surgery and/or radiation, documenting:   
▪ start and stop dates   
▪ assessment of best response   
▪ date of progressive disease and relapsed or refractory status, see Appendix 10   
• Use of Health services and Hospitalization questionnaire, prior to any study visit activities 
(tests, examination or treatment), see Appendix 16. 
• Physical examination, including height, weight and assessment for extramedullary myeloma. 
Baseline symptoms and residual toxicity from previous therapy, including neuropathy 
• Vital signs including blood pressure, pulse, respiration rate and temperature   
• ECOG performance status   
• Pregnancy test, only for WOCBP   
• 12- lead electrocardiogram (ECG); QTc interval to be assessed by Fridericia formula, see 
Appendix 11   
• Blood tests;  
o Hematology: CBC with differential and platelet count 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric acid, 
blood urea nitrogen [BUN](or urea), creatinine, eGFR by CKD-EPI formula , glucose 
(fasting), ALT/AST (SGPT/SGOT), alkaline phosphatase, total protein, total bilirubin, 
albumin, and lactate dehydrogenase (LDH). 
o β2-microglobulin   

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• M protein assessments, see Section 8.2.1 
• Hepatitis B screening: HBsAg, Anti-HBs, Anti-HBc 
• Hepatitis C screening: Anti-HCV 
• HIV screening: Anti-HIV1/2 and HIV1/2 antigen 
• Urinalysis  
• Bone marrow aspiration; A total of 10 mL should not be exceeded for all assessments 
included. Refer to Laboratory Manual for additional information.   
1. 
% plasma cells and morphology – may be analyzed locally 
2. 
One sample to be sent to central laboratory for  
a. 
Cytogenetics by iFISH in selected plasma cells. Mandatory probes include 
t(4;14), t(14;16), t(14;20), del(17/17p), 1q amp (1p32/1q21)  
b. Exploratory biomarkers. Remaining material in the sample. 
• Chest X-ray (Optional if low-dose is CT performed for skeletal assessment)  
• Assessment of known or suspected extramedullary myeloma. If imaging is used the method 
of assessment (e.g. CT, MRI or PET-CT) must provide bidimensional measurements with 
same method to be used throughout the study. 
• Skeletal X-ray or low-dose CT scan; required if previous assessment is > 6 weeks from 
initiation of therapy. 
• Review prior/concomitant medications  
• Inclusion/Exclusions criteria review 
• SAE monitoring 
The Investigator will review each patient’s screening data and document the patient’s 
acceptability for study participation. The patient may be randomized upon approval by the 
Medical Monitor.   
For patients who fail screening, the Investigator will record demographics and reason for screen 
fail, eligibility criteria and any SAE in the appropriate sections of the eCRF and note the reason 
for exclusion. These documents and the patient’s signed informed consent form will be retained 
in the study files. 
8.1.2. 
Procedures during study treatment phase, all cycles 
The following procedures will be performed during active study treatment at the times specified 
in the SoA. All procedures are applicable at all cycles unless otherwise specified.   
8.1.3. 
Procedures Day 1, all cycles 
• Inclusion/Exclusions criteria review on Cycle 1 day 1, for subsequent cycles criteria for 
initiation of treatment should be fulfilled, see Section 6.6.1 and Section 6.6.2. 
• Use of Health services and Hospitalization and QoL questionnaire EQ-5D-5L, prior to any 
study visit activities (tests, examination or treatment), see Appendix 16 and Appendix 14.  
The questionnaires should be administered even if the treatment is not given. 
• Patient preference scale, Cycle -3 only, prior to any study visit activities, see Appendix 15. 
• Physical examination; including weight and assessment for extramedullary myeloma. 
Extramedullary myeloma that can be followed by physical exam should also be evaluated 
each cycle with measurements documented in the source documents.  
• Assessment of known or suspected extramedullary myeloma as clinically indicated or to 

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confirm a response or progression. If imaging is used the method of assessment (e.g. CT, 
MRI or PET-CT) must provide bidimensional measurements with same method to be used 
throughout the study. 
• Vital signs; including blood pressure, pulse, respiration rate, temperature, to be assessed pre 
and post dose on each dosing day.   
• ECOG performance status   
• Pregnancy test; only for WOCBP   
• Blood tests: 
o Hematology: CBC with differential and platelet count 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric acid, 
blood urea nitrogen [BUN](or urea), serum creatinine, eGFR by CKD-EPI formula, 
glucose (non-fasting), ALT/AST (SGPT/SGOT), alkaline phosphatase, total protein, 
total bilirubin, albumin, and lactate dehydrogenase (LDH)   
o Biomarker assessment (before dosing at Cycle 1 Day 1) 
• Bone marrow aspiration; A total of 5 mL should not be exceeded. Only applicable if to 
confirm a suspected CR or PD.  
o Remaining material in sample to be sent to central laboratory for analysis of 
exploratory biomarkers. Refer to Laboratory Manual for additional information 
• Concomitant medications review   
• M-protein assessments, see Section 8.2.1 on planned Day 1 of each cycle (day 29 of prior 
cycle).  
o  If treatment is delayed an assessment should still be made at day 29 and should be 
repeated prior to next cycle if the delay is 2 weeks or longer, and to confirm any 
response or PD. 
• Myeloma response assessment (from Cycle 2 Day 1 and onwards) 
• Skeletal X-ray or low-dose CT scan; as clinically indicated 
• Administration of dexamethasone, and provide patient with one cycle of Dexamethasone 
• Administration of Melflufen; see Section 6.1.2 
• Patient treatment satisfaction scale, Cycle 1 and 2 only, after received melflufen infusion, see 
Appendix 15. 
• Nurse convenience and Nurse preference scale, following completion of melflufen 
administration, Cycle 1 and 2, see Appendix 15. 
• Pharmacokinetic blood samples; For all patients, cycle 1 and 2 only, see Section 8.6. 
• AE monitoring  
• Inspection of peripheral infusion site, when indicated, see SoA 
8.1.4. 
Procedures Day 8, 15 and 22 
• Physical examination: symptom directed as needed during treatment.   
• Hematology blood tests: CBC with differential and platelet count. If patient tolerability is 
good, i.e. no dose modifications, dose delays or need of supportive therapy (G-CSF, blood or 
platelet transfusion) in the two preceding cycles, then CBC assessments may be excluded 
Day 8 and Day 22. 
• Concomitant medications review 
• Dexamethasone review 

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• AE monitoring 
• Inspection of peripheral infusion site, when indicated, see SoA 
 
If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive 
therapy (Granulocyte colony stimulating factor [G-CSF], blood or platelet transfusion) in the two 
preceding cycles, then visit to site and CBC assessments may be excluded Day 8 and Day 22. 
 
8.1.5. 
Procedures if melflufen or dexamethasone are discontinued 
If melflufen or dexamethasone are discontinued but the other study drug is continued, the 
schedule of assessments should continue as per planned assessment according to Section 8.1.3,  
8.1.4and SoA. 
8.1.6. 
Procedures after active study treatment phase 
Refer to Section 4.1.1 for treatment duration. An EOT visit will be scheduled within 30 days 
(accepted time window ±3 days) of the last dose of study treatment, or as soon as possible if the 
decision to remove patient from therapy occurs later than 30 days after last dose (such as in the 
case of a prolonged cycle). Patients that discontinue therapy for reasons other than disease 
progression will enter PFS follow-up.   
Patients with Grade 3 or 4 thrombocytopenia or neutropenia should be followed until resolution 
to ≤ Grade 2 or start of subsequent therapy. SAEs should be followed until resolution or 
stabilization with no expected resolution.   
Patients who withdraw consent for treatment will continue to be followed for disease progression 
unless they explicitly withdraw consent for these procedures. 
8.1.7. 
Procedures at End of Treatment Visit 
End of Treatment visit should be scheduled 30 days (accepted time window ±3 days) after last 
dose of study treatment or as soon as possible if the decision to remove patient from therapy 
occurs later than 30 days after last dose (such as in the case of a prolonged cycle). Patients with 
PD as the reason for EOT should have the PD confirmed with 2 consecutive assessments and 
verified by the Medical Monitor prior to discontinuation of therapy. If the investigator due to 
suspicion of rapid PD consider it necessary to urgently obtain result for M protein in order to 
assess the disease status, the M protein assessments may be performed at the local laboratory 
following consultation and approval of medical monitor. If M protein samples are sent for 
analysis at the local laboratory samples should also be sent to central laboratory. If a new 
treatment for MM is to be introduced sooner than 30 days after last dose of study drug the EOT 
visit should occur as close as possible before the first dose of the new drug. Patients progressing 
while on treatment, require 2 consecutive M protein assessments at any time (including the same 
day for SPEP/FLC) prior to discontinuation of treatment. The second assessment must be a 
separate serum and urine sample. (If the second consecutive M protein sample can only be 
obtained after the start of subsequent therapy, it may be used as confirmation of PD). 
• Use of Health services and Hospitalization and QoL questionnaire EQ-5D-5L, prior to any 
study visit activities (tests, examination or treatment), see Appendix 16 and Appendix 14.   
• Physical examination; including weight and assessment for extramedullary myeloma  

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• Vital signs; including blood pressure, pulse, respiration rate and temperature 
• ECOG performance status 
• Pregnancy test; only for WOCBP 
• 12-lead ECG, QTc interval to be assessed by Fridericia formula   
• Blood tests;   
o Hematology: CBC with differential and platelet count 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric 
acid, blood urea nitrogen [BUN](or urea), serum creatinine, eGFR by CKD-EPI 
formula, glucose (non-fasting), ALT/AST (SGPT/SGOT), alkaline phosphatase, 
total protein, total bilirubin, albumin, and lactate dehydrogenase (LDH). 
o Biomarker assessment   
• M protein assessments see Section 8.2.1.  
• Myeloma response assessment 
• Known or suspected extramedullary myeloma assessment if clinically indicated and to 
confirm response or progression. If imaging is used the method of assessment (e.g. CT, MRI 
or PET-CT) must provide bidimensional measurements with same method to be used 
throughout the study. 
• Skeletal X-ray or low dose CT scan; as clinically indicated 
• Concomitant medications review 
• Dexamethasone review   
• AE monitoring; Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT visit are 
to be followed until resolution (≤ Grade 2) or initiation of subsequent therapy. SAEs should 
be followed until resolution or stabilization with no expected resolution. 
8.1.8. 
Procedures during Progression Free Survival Follow-up 
Patients who discontinue therapy for reasons other than disease progression should continue to 
have monthly disease assessments done until documented progression or initiation of subsequent 
therapy. 
• Use of Health services and Hospitalization and QoL questionnaire EQ-5D-5L, prior to any 
study visit activities (tests, examination or treatment), see Appendix 16 and Appendix 14. 
• Known or suspected extramedullary myeloma should be assessed as clinically indicated until 
confirmed disease progression. If imaging is used the method of assessment (e.g. CT, MRI or 
PET-CT) must provide bidimensional measurements with same method to be used 
throughout the study. 
• M protein response assessment 8.2.1;  
o  monthly until confirmed disease progression or initiation of next anti-myeloma 
treatment, for patients who discontinue study treatment for reasons other than 
progression.   
o  Confirmed progression requires 2 consecutive M protein assessments at any time 
(including the same day for SPEP/FLC). The second assessment must be a separate 
serum and urine sample. If the second consecutive M protein sample only can be 
obtained after the start of subsequent therapy, it may be used as confirmation of PD. 
o  The first assessment should be performed 4 weeks after the EOT visit. Serum calcium, 
albumin (corrected calcium) required if this is the presenting symptom of progression.  
o  When confirmed progression, the patient has reached end of study, see Section 4.5.2 

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• Myeloma response assessment 
• Second primary malignancies follow-up 
 
8.2. 
Efficacy Assessments  
8.2.1. 
M protein Response assessment 
Samples for M protein assessments should be sent to the central laboratory for analysis, except 
where specified, refer to Laboratory Manual for instructions. A local laboratory assessment for 
M protein analysis may only be used on certain occasions if approved by the medical monitor.  
o M protein assessments: 
o FLC levels (kappa/lambda) including dFLC (difference between involved FLC and 
uninvolved FLC) and FLC ratio (involved FLC/uninvolved FLC)   
▪ FLC assessment is not required in the presence of measurable SPEP and/or 
UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 mg/24 hours), 
▪ FLC is required to confirm sCR, regardless of type of measurable disease. 
o Electrophoresis 
▪ SPEP 
▪ UPEP 
o Quantitative immunoglobulins should be included for patients with IgA and IgD 
myeloma. 
o Immunofixation (IFE) 
▪ Serum immunofixation; 
- 
To be performed at baseline and at any time when M protein by SPEP 
becomes non-detectable to confirm CR. 
▪ Urine immunofixation 
- 
To be performed at baseline and at any time when M protein by UPEP 
becomes not detectable to confirm CR. 
• Serum calcium (corrected calcium to be performed at local laboratory) 
8.2.2. 
Skeletal X-rays and low-dose CT scans 
Skeletal survey includes lateral radiograph of the skull, and anterio-posterior views of femur and 
humeri anterio-posterior and lateral views of the spine, and anterio-posterior views of the pelvis 
and ribs. Low dose CT scan may be used in addition to or in place of conventional X-ray with 
the same technique to be used with each evaluation. Limited X-rays may be performed as 
clinically indicated to confirm PD.   
 
 

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8.2.3. 
Extramedullary myeloma (plasmacytoma) assessment 
• Known or suspected extramedullary myeloma are to be assessed at screening, as 
clinically indicated and to confirm response or progression.  
• Method(s) of evaluation should be able to provide bidimensional measurements and must 
be defined at baseline (for lesions present at screening); methods may include, CT, PET-
CT, MRI or physical examination. For skin lesions, only measurable lesions with a 
caliper should be reported  
• Once the method is selected, extramedullary myeloma lesions should be evaluated with 
the same method throughout the trial.   
• Lesions will be assessed according to IMWG-URC guidelines (Kumar et al 2016) see, 
Appendix 7.   
• Lesions that are evaluable but not measurable (such as malignant ascites or pleural 
effusion) should be reported. These lesions should disappear completely in case of CR or 
increase in size in order to be reported as cause for progression.   
8.3. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.3.1. 
Physical Examinations 
A physical examination, including height (screening only), weight and assessment for 
extramedullary myeloma will be conducted at Screening, Day 1 of each cycle and at the end of 
treatment visit. A symptom directed physical examination will be conducted as needed during 
treatment. Extramedullary myeloma that can be followed by physical examination are to be 
evaluated on Day 1 of each cycle. The timing of the assessment is described in Section 8.1.   
The outcome of the assessments will be recorded as “normal” or “abnormal”. Abnormal findings 
will be assessed as “clinically significant” or “not clinically significant”. Clinically significant 
findings prior to first dose of study treatment will be documented as Medical History. Clinically 
significant findings after first dose will be documented as AEs.   
8.3.2. 
Local tolerance assessments 
The peripheral infusion site should be inspected pre and post infusion, including assessment of 
any local reaction such as but not limited to redness, swelling, signs of phlebitis or extravasation 
and graded using CTCAE 5.0, see Appendix 5 and VIP Score, see Appendix 13. All signs of 
extravasations or phlebitis should be photo documented at least daily until resolution. 
8.3.3. 
Vital Signs 
Vital signs will be measured, at the timepoint specified in the SoA, Sections 6.1.2 and 8.1.3and 
will include temperature, systolic and diastolic blood pressure, pulse and respiratory rate.   
• Blood pressure and pulse measurements will be assessed preferable with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the patient. 

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The outcome of the assessments will be recorded as “normal” or “abnormal”. Abnormal findings 
will be assessed as “clinically significant” or “not clinically significant”. An asymptomatic 
abnormal vital sign finding should only be reported as an AE if it is clinically significant or if it 
fulfils the criteria for an SAE. Vital sign abnormalities should only be reported using one event 
term. For example – a high blood pressure recording (systolic blood pressure of 180) and 
hypertension, both should not be used to record the AE. If an abnormal vital sign value is 
associated with clinical signs and symptoms, the sign/symptom should be reported as an AE and 
the associated vital sign result should be considered additional information. 
 
8.3.4. 
Electrocardiograms 
A 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS and QT. QTc interval should be assessed by 
Fridericia formula, see Appendix 11.   
The ECGs will be taken in supine position, after the patient has been lying down for at least three 
minutes.   
The Investigator (or a qualified observer at the investigational site) will interpret the ECG using 
one of the following categories: “normal” or “abnormal”. Abnormal findings will be assessed as 
“clinically significant” or “not clinically significant”.   
An asymptomatic abnormal ECG finding should only be reported as an AE if it is clinically 
significant or if it fulfils the criteria for an SAE. ECG abnormalities should only be reported 
using one event term. For example, an ECG recording of a rapid heart rate (a PR interval of 120 
ms) and tachycardia, both should not be used to record the AE.  
8.3.5. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.  
• The investigator must review the laboratory report, add an assessment of clinical 
significance, and document this review. The laboratory reports must be filed with the 
source documents.  
• The investigator must record any clinically relevant changes occurring during the study in 
the AE section of the eCRF. Clinically significant abnormal laboratory findings are those 
that: 
o Require concomitant therapy  
o Require medical intervention 
o Require change in study treatment 
o Investigator considers clinically significant for any reason 
• Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EoT visit are to be followed 
until resolution (≤ Grade 2) or initiation of subsequent therapy.   

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• All ANC and platelet counts collected during the protocol participation, i.e. both those 
collected at protocol specified time points and any additional time points (unscheduled 
assessments), must be reported in the eCRF and if applicable also in the SAE report;  
• All ANC and platelet counts associated with a SAE regardless of the nature of the event, 
must be reported in the details of the SAE report.  
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the 
results must be recorded in the eCRF.  
8.3.6. 
Bone Marrow Aspiration (BMA) 
• BMA sample is used  
o to quantify baseline percent plasma cell involvement, assess morphology and 
o for cytogenetics analysis, by use of iFISH.   
o to assess exploratory biomarkers of response.  
• Repeat BMA at time of suspected hematologic CR (optional for PD) for % plasma cells 
and exploratory biomarkers. 
Refer to the Laboratory Manual for details on specimen collection and processing. 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study treatment or study procedures, or that 
caused the patient to discontinue the study. (see Section 7) 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from signing of the informed consent form until 30 days after last 
dose of any study drug or initiation of subsequent therapy whichever occurs first. 
All AEs will be collected from the start of any study drug until 30 days after the last dose of any 
study drug or initiation of subsequent therapy whichever occurs first. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, and not the AE section, unless it is an SAE. 
All SAEs will be recorded and reported to the assigned Pharmacovigilance CRO, TFS, within 24 
hours, as indicated in Appendix 3. The investigator will submit any updated SAE data to TFS 
within 24 hours after becoming aware of the updated SAE data.  

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Investigators are not obligated to actively seek AE or SAE after EoT visit and conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a patient has been discontinued from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must promptly 
notify TFS. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.2. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs, will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures of AEs and SAEs is given in Appendix 3. 
8.4.3. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study treatment under clinical investigation are met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.4.4. 
Pregnancy 
• Details of all pregnancies in female patients and, if indicated, female partners of male 
patients, occurring after the start of any study drug and until 30 days after the last dose of any 
study drug for female patient, and 90 days after the last dose of any study drug for female 
partners of male patients will be collected.  
• If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
 
 

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8.4.5. 
Fatal Events 
• Death is an outcome of a SAE and is not a SAE in itself. When death is an outcome, the 
event(s) resulting in death should be reported (e.g., “pulmonary embolism” with a fatal 
outcome). The appropriate diagnosis or term should be recorded and assigned severity Grade 
5; 
• In instances of death due to “Disease Progression” the cause of death should be indicated as 
the event or condition resulting in death to the extent possible (e.g., “respiratory failure” due 
to progressive MM);   
• Deaths that occur later than 30 days after the last study drug administration should be 
reported as SAEs only if assessed as related to the study treatment. 
 
8.4.6. 
Laboratory Test Abnormalities 
Laboratory abnormalities are usually not recorded as AEs; however clinically significant 
laboratory abnormalities must be recorded as AEs (or serious AEs) if they meet the definition of 
an AE (or serious AE) as described in Appendix 3.   
Clinically significant laboratory abnormalities are those that: 
• Induce clinical signs and symptoms 
• Require concomitant therapy  
• Require medical intervention 
• Require change in study treatment 
• Investigator considers clinically significant for any reason 
The Investigator will record the grade of the clinically significant laboratory abnormality and 
will evaluate its relationship to the study drug and clinical condition. Laboratory AEs should be 
recorded using only one event term per event such as thrombocytopenia for low platelet count 
but not as both (thrombocytopenia and low platelet count). 
8.4.7. 
Additional Laboratory Reporting Guidelines 
Extra attention should be given to reporting all Grade 3 and 4 platelet and neutrophil counts.  
They must be: 
• Collected and reported during the study period and the EOT visit; 
• Ongoing Grade 3 and 4 platelet and ANC values at the time of the EOT visit are to be 
followed until resolution (≤ Grade 2), or stabilization, or initiation of a subsequent therapy;  
• All ANC and platelet counts collected during the treatment period and until the EOT visit, 
i.e. both those collected at protocol specified time points and any additional time points 
(unscheduled assessments), must be reported in the eCRF and if applicable also as an 
AE/SAE;  
• All ANC and platelet counts associated with a SAE regardless of the nature of the event, 
must be reported in the details of the SAE report; 
• Supportive care such as platelet transfusions and G-CSF given for an AE or prophylactic 
reason must be reported in the eCRF and if applicable also in the SAE report.   

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PK 
samples 
if 
available) 
timepoint 
samples) 
back up 
samples 
from the 
PK 
analysis, 
samples 
will be 
used for 
protein 
profiling 
 
 
 

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8.10. 
 Health outcome and Quality of Life measures 
8.10.1. 
Patient Reported Outcome Assessments  
EQ-5D-5L will be used to evaluate functional status and well-being in the study. A 
paper version of the form will be used. The questionnaire should be submitted to patients by site 
personnel familiar with these procedures and/or preferably a QoL dedicated person in the team. 
The patient should complete the questionnaires prior to any procedures on the day of the visit 
and prior to being told anything related to health; the questionnaire should be administered even 
if the treatment is not given. If the patient wishes to have the questions read aloud and then 
answer orally and the study personnel write the answer on the questionnaires, this is acceptable. 
QoL questionnaires will be submitted to patients at Cycle1 Day 1, each subsequent cycle on day 
1, at the time of EOT visit and at PFS-FU visits until time of progression or starting a new 
treatment. If PD/EOT and next treatment occur at the same time, only one assessment is 
required, if the EOT visit is for a reason other than PD, continue QOL assessments each month 
until PD and at time new treatment begins.  
8.10.2. 
Patient treatment satisfaction, nurse convenience and nurse preference of 
administration  
An 11-point numerical rating scale (NRS) will be used to measure patient treatment 
satisfaction. The scale ranges from 0-10, where “0” represents no satisfaction, 
and “10” represents very satisfied. The patient should complete the treatment satisfaction 
NRS after received administration of melflufen on Day 1 of Cycle 1 and 2. Treatment preference 
scale will be completed prior to any procedures on Day 1 of Cycle 3 only, and prior to being told 
anything related to health. If the patient wishes to have the questions read aloud and then answer 
orally and the study personnel write the answer on the questionnaires, this is acceptable.  
An 11-point NRS will be used to measure nurse convenience to administer treatment. The scale 
ranges from 0-10, where “0” represents not convenient at all, and “10” 
represents very convenient. The nurse should complete the convenience NRS after the patient 
was given the treatment on the day of the visit. Nurse convenience should be captured at 
Cycle 1 Day 1 and Cycle 2 Day 1.  
Nurse preference to administration will be measured by asking a question on which type of 
administration the nurse would prefer in treating this patient, this time. The 
administration options indicated are peripheral venous catheter (venflon) and central catheter (= 
a PICC-line, a venous port (“Port-Cath”) or a CVC). The nurse preference to 
administration should be captured after the patient was given the treatment on the day of the 
visit, at Cycle 1 Day 1 and Cycle 2 Day 1. 
8.10.3. 
Use of health services and hospitalization  
Use of health services and days of hospitalization will be captured at screening visit, Day 1 of 
each cycle, at time of EOT visit, and PFS-FU prior to any procedure on the day of the visit and 
prior being told anything related to health. 
 
 

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CBR proportion of patients 
with ≥ MR as best response 
Clinical benefit rate (CBR) i.e. proportion of patients that 
achieve a confirmed minimal response or better (sCR, CR, 
VGPR, PR and MR). CBR will be summarized using the 
same method as for ORR. 
DOR (time from the first 
confirmed response of sCR, 
CR, VGPR or PR to first 
confirmed disease progression, 
or death due to any cause. 
Duration of response (DOR) is defined as the time from the 
first evidence of confirmed assessment of sCR, CR, VGPR, 
or PR to first confirmed disease progression according to the 
IMWG-URC or to death due to any cause. DOR is defined 
only for patients with a confirmed PR or better.  
The distribution of DOR will be summarized using the 
Kaplan Meier (K-M) method (Kaplan et al. 1958). The 
median DOR will be estimated from the 50th percentile of 
the corresponding K-M estimates. The 95% CI for median 
DOR will be constructed using the method of Brookmeyer 
(Brookmeyer et al. 1982) 
DOCB (time from first 
evidence of confirmed 
assessment of sCR, CR, 
VGPR, PR, or MR to first 
confirmed disease progression, 
or to death due to any cause.) 
Duration of clinical benefit (DOCB) will be calculated from 
the first evidence of confirmed assessment of sCR, CR, 
VGPR, PR or MR to first confirmed disease progression, or 
to death due to any cause. Duration of clinical benefit is 
defined only for patients with a confirmed MR or better. 
DOCB will be summarized using the same method as for 
DOR 
TTR (time form randomization 
to the date of the first 
documented confirmed 
response in a patient that has 
responded with ≥ PR (sCR, 
CR, VCPR or PR)) 
Time to response (TTR) will be calculated as time from 
randomization to first documented confirmed response in a 
patient that has responded with PR or better. 
TTR will be presented descriptively for patients with a 
response. 
TTP (time from the date of 
randomization to the date of 
the first documented confirmed 
PD) 
The time to progression (TTP) is defined as the time in 
months from randomization to the date of the first 
documented confirmed progression. TTP will be 
summarized using the same method as for DOR. 
TTNT (time from 
randomization to the date of 
next anti-myeloma treatment) 
Time to next treatment (TTNT) will be calculated from the 
date of initiation of therapy to start of next line of therapy. 
TTNT will be summarized using the same method as for 
DOR. 
PFS (time from the date of 
randomization to the date of 
first documentation of 
confirmed PD or death due to 
any cause) 
Progression free survival (PFS) will be measured from time 
from the date of randomization to the date of first 
documentation of confirmed disease progression (PD) or 
death due to any cause, whichever occurs first.  

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The number (%) of patients experiencing TEAEs will be summarized by MedDRA SOC and PT. 
The denominator for the percentage will be based on the number of patients at in the safety 
analysis set.  
A patient reporting the same AE more than once will be counted only once when 
calculating incidence 1) within a given SOC, and 2) within a given SOC and PT combination. 
For such cases, the maximum CTCAE toxicity grade and strongest causal relationship to study 
treatment for the event will be used in the incidence calculations. Treatment-related AEs, defined 
as AEs with a relationship of possibly or probably related will be summarized in the same way. 
Summaries of TEAEs and treatment-related AEs will be provided according to maximum 
toxicity grade. Grade 3 or higher TEAEs and treatment-related AEs, serious AEs, and TEAEs 
resulting in permanent discontinuation of study treatment will be provided. 
Actual value for all hematology and serum chemistry, will be summarized at each scheduled 
visit. Selected laboratory test results will be assigned toxicity grades using CTCAE 5.0. Shift 
tables assessing the toxicity grade at baseline versus worst toxicity recorded on study will be 
presented. Actual value and change from baseline for weight and vital sign results, including 
blood pressure, pulse, and temperature, will be summarized at each scheduled visit. Any 
clinically significant values will be reported by the investigator as AEs.  
9.3.4. 
Statistical evaluation of PK parameters 
Descriptive statistics for drug concentrations by time point and PK variables will be provided for 
melflufen, melphalan and desethyl-melflufen by route of administration. 
Formal statistical analysis will for each compound be performed on the PK parameters AUC(0-
last) which is referred to as AUC(0-t), AUC(0-inf) and Cmax to assess relative plasma exposure. The 
PK parameters will undergo a logarithmic transformation and will be analyzed using a linear 
mixed effects model which will include terms for period, sequence and treatment as fixed effects 
and subject nested within sequence as a random effect. Adjusted geometric mean ratios (GMRs) 
and 90% confidence intervals (CIs) for the adjusted GMRs for the comparisons between central 
and peripheral administration will be provided. 
The main parameter for evaluation of similarity between routes of administration is melphalan 
AUCinf. Similarity is confirmed when the 90% confidence interval for the GMR is within the 
bioequivalence limits of 0.8 and 1.25.   
9.3.5. 
Exploratory analyses 
Biomarker Analyses Set 
DNA, RNA and protein-based drug response biomarkers including but not limited to 
aminopeptidases and esterases. The population will be presented separately from the main 
clinical study report (CSR).  
 
 

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with repeat peripheral infusions. The investigator in agreement with the patient will determine 
whether continued treatment will use peripheral or central administration. 
If no major safety signals have been reported, recruitment may continue during preparations for 
DSMC meeting.  
Following a DSMC evaluation of data from at least 20 PK evaluable patients with an observation 
period of at least 28 days from the second dose of melflufen, the main PK and safety and 
tolerability study may be concluded. 
 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study patients.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
patient or his/her legally authorized representative and answer all questions regarding the 
study.  
• Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 

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Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study if the update is relevant to the patient. 
• A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.  
10.1.4. 
Data Protection 
• Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred.  
• The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient.  
• The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
• Oncopeptides AB assures that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion 
and finalization of the study report, the results of this study will be either submitted for 
publication and/or posted in a publicly accessible database of clinical study results (the 
study results will be posted in clinicaltrials.gov). Any publication will be a joint 
publication between the sponsor and the investigators and authorship will be determined 
by mutual agreement.  
• The completed original eCRF is the sole property of the sponsor and should not be made 
available in any form to third parties (except to authorized representatives of appropriate 
regulatory authorities) without written permission from the sponsor. 
10.1.6. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF.  
• The data collection tool for the study will be a validated, internet based, electronic data 
capture (EDC) software system called RAVE. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  

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• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.  
• During protocol development, processes and data that are critical to ensure human subject 
protection and the reliability of trial results have been identified and documented in 
Sponsor Oversight document(s). 
• Risk identification and evaluation will be conducted on an ongoing basis by the sponsor 
and CRO, as these are key to managing and mitigating risks. 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• Definition of what constitutes source data can be found in Source Data Location List 
developed for each site. 
10.1.8. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the investigator 
• Discontinuation of further study intervention development 

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10.1.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies in their entirety.   
• Any publication will be a joint publication between Oncopeptides AB and the 
investigators and authorship will be determined by mutual agreement.  
10.1.10. 
Compensation for health damage of subjects/insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the laws 
and regulations of the country in which the study is performed. 
 
 

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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. Lack of menses as a result of chemotherapy does not constitute menopausal status.  
Contraception Guidance: 
Male patients 
From the start of the first dose of study drug until 3 months after the last dose of study drug, 
male study patients must agree to remain abstinent from penile-vaginal intercourse as their usual 
and preferred lifestyle (abstinent on a long term and persistent basis), or use a male condom 
during each episode of penile penetration for the duration of the treatment and for 3 months after 
last dose of melflufen. 
In addition, male patients must refrain from donating sperm for the duration of the treatment and 
for 3 months after last dose of study drug. 
It is not known if melflufen may cause permanent sterility. Therefore, male patients may wish to 
consider cryo-preservation of semen before initiating therapy with melflufen.  
Female patients 
Female patients of childbearing potential are eligible to participate if they, from the start of the 
first dose of study drug until 28 days after the last dose of study drug, agree to use a highly 
effective method of contraception consistently and correctly as described in Table 10-4. 
Table 10-4 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  

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Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
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 treatment. 
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 patient.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
patients participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study treatment, which 
may reduce the efficacy of the contraceptive methods for patients participating in clinical 
studies. In this case, two highly effective methods of contraception should be utilized during 
the treatment period and for at least 3 months after the last dose of study treatment.  
Pregnancy Testing: 
• WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
• Additional pregnancy testing is required on Day 1 of each cycle during the treatment period 
and at the End of Treatment visit and as required locally. 
• Pregnancy testing should also be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• Pregnancy testing should be performed at the local laboratory.  
Collection of Pregnancy Information: 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
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• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Pregnancy CRF pages within the designated reporting time 
frames. 
• 
Contacts for Pregnancy reporting can be found in Pregnancy report completion 
instruction. 

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• No increase in size or number of lytic bone lesions (development of 
compression fractures does not exclude response). 
Stable Disease 
(SD) 
• Not meeting criteria for CR, VGPR, PR, MR or progressive disease. 
Progressive 
Disease 
(PD) 
Increase of > 25% from lowest response value in any one of the following: 
• Serum M-protein (the absolute increase must be > 0.5 g/dL) and/or  
• Urine M-protein (the absolute increase must be > 200 mg/24 hours) 
and/or  
• Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL. 
• Only in patients without measurable serum and urine M-protein and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute % must be ≥ 10%).  
• Definite development of new bone lesions or soft tissue plasmacytomas 
or definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas. 
• Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder. 
 
All response categories require two consecutive assessments made at any time before the 
institution of any new therapy; all response categories also require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. VGPR and CR 
categories require serum and urine studies regardless of whether disease at baseline was 
measurable in serum, urine both or either. Radiographic studies are not required to satisfy these 
response requirements. Bone marrow assessments need not to be confirmed. For progressive 
disease, serum M-protein increases of ≥ 1 g/dL are sufficient to define relapse if starting M-
protein is ≥ 0.5 g/dL. 
IMWG clarification for coding PD: The 25% increase refers to M-protein, FLC, and bone 
marrow results and does not refer to bone lesions, soft tissue plasmacytomas or hypercalcemia. 
Note the lowest response value does not need to be a confirmed value. 
 
 

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10.8. 
Appendix 8: Line of Therapy Definition 
According to the IMWG Consensus panel 1 on uniform reporting criteria in clinical trials 
(Rajkumar 2011, Rajkumar 2015), a line of therapy consists of at least 1 or more cycles of a 
planned treatment regimen. This may consist of single-agent or combination therapy or a 
sequence of treatments administered in a planned manner. For example, a planned induction, 
followed by ASCT followed by maintenance is considered one line of therapy. A new line of 
therapy starts when a planned course is modified to include other treatment agents as a result of 
disease progression, relapse or toxicity or when a planned period of observation is interrupted by 
the need for additional treatment of the disease.    
Modification of drug doses or resuming therapy after holding will not be considered a new line 
of therapy provided that there was no evidence of progression of disease as defined in the 
IMWG-URC guidelines. The definition is further clarified by Rajkumar et al, 2015. 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens (e.g., 3-6 
cycles of initial therapy with bortezomib-dexamethasone [VD] followed by stem cell 
transplantation [SCT], consolidation, and lenalidomide maintenance is considered as 1 line of 
therapy). 
 
New line of therapy 
• A treatment is considered a new line of therapy if any 1 of the following 3 conditions are 
met:  
• Start of a new line of treatment after discontinuation of a previous line: If a treatment 
regimen is discontinued for any reason and a different regimen is started, it should be 
considered a new line of therapy. A regimen is considered to have been discontinued if 
all the drugs in that given regimen have been stopped. A regimen is not considered to 
have been discontinued if some of the drugs of the regimen, but not all, have been 
discontinued. 
• The unplanned addition or substitution of 1 or more drugs in an existing regimen: 
Unplanned addition of a new drug or switching to a different drug (or combination of 
drugs) due to any reason is considered a new line of therapy. 
• SCT: In patients undergoing >1 SCT, except in the case of a planned tandem SCT with a 
predefined interval (such as 3 months), each SCT (autologous or allogeneic) should be 
considered a new line of therapy regardless of whether the conditioning regimen used is 
the same or different. We recommend that data on type of SCT also to be captured. 
 
 

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10.10. 
Appendix 10: Definition of Relapsed Disease per IMWG definitions 
Refractory Myeloma:  
Refractory myeloma is defined as disease that is non-responsive (failure to achieve minimal 
response or develops PD while on therapy) while on primary or salvage therapy or progresses 
within 60 days of last therapy. There are 2 categories of refractory myeloma. 
• Relapsed and refractory myeloma: Relapsed and refractory myeloma is defined as disease 
that is non-responsive while on salvage therapy or progresses within 60 days of last therapy 
in patients who have achieved minimal response or better at some point previously to then 
progressing in their disease course. 
• Primary refractory myeloma: Refractory myeloma is defined as disease that is non-
responsive in patients who have never achieved minimal response or better with any therapy. 
It includes patients who never achieve MR or better in whom there is no significant change in 
M-protein and no evidence of clinical progression; as well as primary refractory, progressive 
disease where patients meet criteria for true progressive disease.     
Relapsed Myeloma: 
Relapsed myeloma is defined as previously treated myeloma, which progresses and requires the 
initiation of salvage therapy but does not meet the criteria for either primary refractory myeloma 
or relapsed and refractory myeloma (Rajkumar et al. 2011). 
 
 
 
10.11. 
Appendix 11: Assessment of Q-Tc interval: 
Q-Tc Fridericia Formula: 
 
 
 
 

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10.12. 
Appendix 12: Estimated Glomerular Filtration Rate (eGFR) by 
CKD-EPI equation 
CKD-EPI equation calculator:  
An online calculator for estimating eGFR may be accessed at the following link: 
 
https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr 
 
CKD-EPI equation: 
 
GFR = 141 * min(Scr/κ,1)α * max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if 
black] 
 
*Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females 
and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
 
(Levey A, Inker L 2017) 
 
 

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10.13. 
Appendix 13: Visual infusion Phlebitis Score 
 
 
 
Permission to use the VIP score in this clinical study has been obtained from IV-team 
The VIP score is a tool recommended by the RCN (Royal college of Nursing) for monitoring 
infusion sites, and have been evaluated, and deemed a reliable tool (Gallant 2006). 
 
 
10.14. 
 Appendix 14: EQ-5D-5L 
 
https://euroqol.org/wp-content/uploads/2019/10/Sample_UK__English__EQ-5D-
5L_Paper_Self_complete.pdf 
 
 

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10.15. 
Appendix 15: Treatment satisfaction, nurse convenience and nurse 
preference 
 
To the patient (with a peripheral catheter) Cycle 1 Day 1, Cycle 2 Day 1: 
1. In total, how satisfied are you with receiving treatment via a peripheral venous catheter? 
Please indicate the number that best describes your satisfaction: 
   □    □    □    □    □    □    □    □    □    □    □ 
   0     1    2     3    4    5    6     7    8     9   10 
  Not   
 
 
                Very 
 satisfied 
 
 
              satisfied 
 
 at all  
 
To the patient (with a central catheter) Cycle 1 Day 1, Cycle 2 Day 1: 
2 In total, how satisfied are you with receiving treatment via a central catheter (= a PICC-line, a 
venous port (“Port-a-Cath”) or a central venous catheter)?  
Please indicate the number that best describes your satisfaction: 
   □    □    □    □    □    □    □    □    □    □    □ 
   0     1    2     3    4    5    6     7    8     9   10 
  Not   
 
 
                Very 
 satisfied 
 
 
               satisfied 
 
 at all  
 
To the Patient Cycle 3 Day 1: 
3. Which type of administration did you prefer? 
 Please indicate the type of administration that best describes your preference: 
  □  Peripheral venous catheter (venflon) 
  □  Central catheter (= a PICC-line, a venous port (“Port-a-Cath”) or a central venous 
catheter) 
  □  No preference 
 
 
 
 

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To the nurse Cycle 1 Day 1 
For patients with a peripheral catheter 
4 In total, how convenient was it to administer the treatment via a peripheral venous catheter?  
Please indicate the number that best describes your convenience: 
  □    □    □    □    □    □    □    □    □    □    □ 
  0     1    2     3    4    5    6     7    8     9   10 
 Not  
 
 
 
               Very 
 convenient 
 
 
              convenient 
 
 at all  
To the nurse Cycle 1 Day 1 
For patients with a central catheter 
5. In total, how convenient was it to administer the treatment via central catheter (= a PICC-
line, a venous port (“Port-a-Cath”) or a central venous catheter)? 
Please indicate the number that best describes your convenience: 
  □    □    □    □    □    □    □    □    □    □    □ 
  0     1    2     3    4    5    6     7    8     9   10 
 Not  
 
 
 
               Very 
 convenient 
 
 
             convenient 
 
 at all  
 
To the nurse Cycle 2 Day 1 
6 In total, how convenient was it to administer the treatment via a peripheral venous catheter 
instead of via a central catheter (= a PICC-line, a venous port (“Port-a-Cath”) or a central 
venous catheter)?  
Please indicate the number that best describes your convenience: 
  □    □    □    □    □    □    □    □    □    □    □ 
  0     1    2     3    4    5    6     7    8     9   10 
 Not  
 
 
 
               Very 
 convenient 
 
 
             convenient 
 
 at all  
 
 
 

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To the nurse Cycle 2 Day 1: 
7. Which type of administration would you have preferred in treating this patient, this time? 
 Please indicate the type of administration that best describes your preference: 
  □  Peripheral venous catheter (venflon) 
  □  Central  catheter (= a PICC-line, a venous port (“Port-a-Cath”) or a central venous 
catheter) 
  □  No preference 
 
 

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10.16. 
Appendix 16:  Use of health services and hospitalization 
 
 
YOUR USE OF HEALTH SERVICES OVER THE LAST MONTH  
 
1. Please could you tell us how many times you have used the following services for any 
problems (not just multiple myeloma) in the last month. If you cannot remember the exact 
number, please give an estimate. For example, if you think it was between 4 and 6 times, please 
put 5. If you haven’t used the service, please enter 0. 
SERVICE 
Number of 
times used 
Telephone health advice 
 
Primary care consultations 
 
Primary care home visits 
 
Nurse home visits 
 
Accident and emergency attendances 
 
Attendance at hospital as an outpatient 
 
 
2. Have you spent any nights as a hospital inpatient in the last month?  
YES [ ]      NO [ ]  
If YES, how many nights were you in hospital for? _________ 
 
Oncopeptides questionnaire, modified from Health-care resource use questionnaire version 
002, dated 11/07/2008. 
 
 
 
10.17. 
Appendix 17: Management of chemotherapy extravasation: ESMO-
EONS Clinical Practice Guidelines 
https://www.esmo.org/Guidelines/Supportive-and-Palliative-Care/Management-of-
Chemotherapy-Extravasation 
 
 

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CVC 
Central Venous Catheter 
DNA 
Deoxyribonucleic Acid 
DOCB 
Duration of Clinical Benefit 
DOR 
Duration of Response 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment 
ESMO 
European Society for Medical Oncology 
FLC 
Free Light Chain 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
H2 
Histamine 2 receptor 
HBV 
Hepatitis B virus 
HbsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent From 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
iFISH 
interphase Fluorescence In Situ Hybridization 
IFE 
Immunofixation  

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Ig 
Immunoglobulin 
IMiD 
Immunomodulatory Drug  
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISS 
International Staging System 
IUD 
Intra Uterine Device 
i.v. 
Intravenously 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Myeloma 
MR 
Minimal Response 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NRS 
Numeric Rating Scale 
ORR 
Overall Response Rate 
PD 
Progressive Disease 
PET-CT 
Positron Emission Tomography Computerized Tomography 
PFS 
Progression Free Survival 
PFS-FU 
Progression Free Survival Follow Up 
PI 
Proteasome Inhibitor 

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PICC 
Peripherally Inserted Central Catheter 
PK 
Pharmacokinetics 
p.o. 
Per os/by mouth/orally 
PPI 
Proton pump inhibitor 
PR 
Partial Response 
PT 
Preferred Term 
PVC 
Peripheral venous catheter 
PVG 
Pharmacovigilance group 
q.d. 
Quaque die/ one a day 
QoL 
Quality of life 
RNA 
Ribonucleic Acid 
RBC 
Red Blood Cell 
REB 
Regional Ethics Board 
R-ISS 
Revised International Staging System 
RRMM 
Relapsed and Refractory Multiple Myeloma 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent Complete Response 
SD 
Stable Disease 
SFLC 
Serum Free Light Chain 
SoA 
Schedule of Activities 
SOC 
System Organ Class 

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SPEP 
Serum Protein Electrophoresis 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TTNT 
Time to Next Treatment 
TTP 
Time to Progression 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
UPEP 
Urine Protein Electrophoresis 
VGPR 
Very Good Partial Response 
VIP 
Visual infusion Phlebitis 
WOCBP 
Woman of Childbearing Potential 
 
 

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11. 
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