Clinical trial NCT04412707
Conditions: RRMM
Keywords: central intravenous administration peripheral intravenous administration central venous catheter (CVC) peripheral venous catheter (PVC)
Sponsor: Oncopeptides AB
Start date: 2020-08-04; Completion date: 2022-01-10
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
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. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy.

Detailed description:

Arms: arm 1: Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if \> 75 years of age 20 mg. Cycle 1 will be administered via a Peripheral Venous Catheter (PVC) and cycle 2 and onwards melflufen will be administered via a Central Venous Catheter (CVC). arm 2: Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if \> 75 years of age 20 mg. Cycle 1 will be administered via a Central Venous Catheter (CVC) and cycle 2 will be administered via a Peripheral Venous Catheter (PVC). From cycle 3 and onwards melflufen will be administered via CVC.
Interventions: intervention 1: Melphalan intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Peripheral versus central administration intervention 2: Oral tablets

Protocol documents:
Prot_000.pdf: 
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. 


CONFIDENTIAL 
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 
 
 
 
 
 
 
 


CONFIDENTIAL 
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 
 
 
4 
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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Protocol OP-109  Version 2.2, 10March 2021 
 
 
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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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Protocol OP-109  Version 2.2, 10March 2021 
 
 
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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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Protocol OP-109  Version 2.2, 10March 2021 
 
 
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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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34 
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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Protocol OP-109  Version 2.2, 10 March2021 
 
 
102 
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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Protocol OP-109  Version 2.2, 10 March2021 
 
 
103 
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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105 
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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106 
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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Protocol OP-109  Version 2.2, 10 March2021 
 
 
107 
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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Protocol OP-109  Version 2.2, 10 March2021 
 
 
108 
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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Protocol OP-109  Version 2.2, 10 March2021 
 
 
109 
11. 
References 
Brookmeyer R, Crowley J. A Confidence interval for the median survival time. Biometrics; 
1982; 38: 29-41. 
Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group Consensus 
Approach to the Treatment of Multiple Myeloma Patients who are Candidates for Autologous 
Stem Cell Transplantation. Blood. 2011; 117(23):6063-6073. 
Chauhan, D., A. Ray, K. Viktorsson, et al. (2013). "In vitro and in vivo antitumor activity of a 
novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells." Clin Cancer 
Res 19(11): 3019-3031. 
Chng WJ, Dispenzieri A, Chim C-S, et al. IMWG consensus on risk stratification in multiple 
myeloma. Leukemia 2014; 28: 269–277. 
Gallant P. Schultz AA. Evaluation of a visual infusion phlebitis scale for determining appropriate 
discontinuation of peripheral intravenous catheters. Journal of Infusion Nursing. 
2006;29(6):338–345 
Gullbo, J, Wickström M, Tullberg M, et al., Activity of Hydrolytic Enzymes in Tumour Cells is 
a Determinant for Anti-Tumour Efficacy of the Melphalan Containing Prodrug J1. J Drug 
Target. 2003c; 11(6):355-363. 
Jordan K, Proskorovsky I, Lewis P, et al. Effect of general symptom level, specific adverse 
events, treatment patterns, and patient characteristics on health-related quality of life in patients 
with multiple myeloma: results of a European, multicenter cohort study. Support Care Cancer. 
2014;22:417-26. 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 
1958; 53 (282) 457-81. 
Kristinsson S, Anderson W, Landgren O et al. Improved long-term survival in multiple myeloma 
up to the age of 80 years. Leukemia 2014; 28: 1346-1348.  
Kumar S, Paiva B, Anderson K, et al. International Myeloma Working Group Consensus Criteria 
for Response and Minimal Residual Disease Assessment in Multiple Myeloma. The Lancet 
Oncology. 2016; 17(8):e328-e346 
Levey A, Inker L. Assessment of Glomerular Filtration Rate in Health and Disease: A State of 
the Art Review. Clin Pharmacol Ther. 2017; 102(3):405-419. 
NCCN Guidelines Multiple Myeloma Version 2.2019 
Paccagnella A, Salvagno L, Chiarion-Sileni V, et al. Peptichemio in pretreated patients with 
plasmacell neoplasms. Eur J Cancer Clin Oncol. 1986; 22 (9): 1053-1058. 
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple 
Myeloma: A Report from International Myeloma Working Group. J Clin Oncol. 2015 33:26, 
2863-2869 
Pérez Fidalgo JA, García Fabregat L, Cervantes A, et al. Management of chemotherapy 
extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol. 2012; Suppl 7: vii167-73    


CONFIDENTIAL 
Protocol OP-109  Version 2.2, 10 March2021 
 
 
110 
Rajkumar, SV, Harousseau JL, Durie B, et al. Consensus Recommendations for the Uniform 
Reporting of Clinical Trials: Report of the International Myeloma Workshop Consensus Panel 1. 
Blood. 2011; 117(18):4691-4695. 
Rajkumar SV, Richardson P, San Miguel J. Guidelines for Determination of the Number of Prior 
Lines of Therapy in Multiple Myeloma. Blood. 2015; 126:921-922. 
Ray A, Ravillah D, Das DS, et al. A novel alkylating agent Melﬂufen induces irreversible DNA 
damage and cytotoxicity in multiple myeloma cells. British Journal of Haematology, 2016; 174, 
397–409. 
Paul G Richardson, Sara Bringhen, Peter Voorhees, et al. Melflufen plus dexamethasone in 
relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, 
phase 1–2 study. Lancet Heamatology,   2020; 7(5):e395-e407  
SEER (2019). “Surveillance, Epidemiology, and End Results Program Cancer Statistics Stat Fact 
Sheets: Myeloma.” National Cancer Institute; https://seer.cancer.gov/statfacts/html/mulmy.html 
Strese S, Wickström M, Fuchs PF, et al. The novel alkylating prodrug melflufen (J1) inhibits 
angiogenesis in vitro and in vivo. Biochem Pharmacol. 2013 Oct 1;86(7):888-895. 
Wickstrom, M, Nygren M, Larsson R, et al. (2017). "Melflufen - a peptidase-potentiated 
alkylating agent in clinical trials." Oncotarget 8(39): 66641-66655.  
Wickström M. The Alkylating Prodrug J1 Can be Activated by Aminopeptidase N, Leading to a 
Possible Target Directed Release of Melphalan. Biochem Pharmacol, 2010; 79:1281-1290. 

SAP_001.pdf: 
Statistical Analysis Plan  
Version 2.2, 24 January 2022 
 
Protocol OP-109 
 
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 


CONFIDENTAL 
Page 1 of 51 
 
Oncopeptides AB 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL OP-109 
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 code:  
OP-109 
SAP Version:  
Final 2.2 
SAP Date:  
24 January 2022 
Author:  
 
 
 
 


CONFIDENTAL 
Page 2 of 51 
 
DOCUMENT HISTORY 
VERSION HISTORY 
Version # 
Version Date 
1.0 
26 June 2020 
2.0 
17 May 2021 
2.1 
14 July 2021 
2.2 
24 January 2022 
 
 
 
 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
2.0 
Signature page 
The names of PSI project 
manager, OP study statistician 
and OP study physician were 
updated 
To reflect the changes in the 
study team on both PSI and 
OP sides 
 
Introduction 
The referenced protocol 
version changed to the version 
2.2 (10 March 2021) 
To refer to the latest protocol 
version 
 
3.1. Study Design Figure 1. “Study Design” was 
updated following the 
corresponding update in the 
protocol  
For compliance with the 
latest protocol version 
 
6. Analysis 
Populations 
For the safety analysis set the 
clarification regarding the 
analysis by sequence arms 
added 
To avoid any ambiguity 
 
7.1. General 
Conventions and 
Statistical  
Considerations 
a) Additional details added to 
better reflect the general way 
of summaries presentation. 
b) Additional clarifications 
added regarding the 
assignment of measurements 
to particular injection type 
happened just prior to the shift 
to the other injection type  
 
To improve comprehensibility 
and avoid ambiguity  
 
7.2. Definition of 
Baseline, Study 
Visits and Visit 
Baseline definitions were 
updated, including the 
reference to the latest 
To improve comprehensibility 
and avoid ambiguity 


Statistical Analysis Plan: OP-109 
Review Status: Final 
 
Version: 2.2 
 
Version Date: 24 January 2022 
 
 
CONFIDENTAL 
Page 3 of 51 
 
Windows 
measurement prior to the 
dexamethasone/melflufen start 
date  
 
7.3. Handling of 
Missing Data 
For missing start day and 
month case the additional 
clarification for the case with 
incomplete end date added 
To make sure that all 
possible scenarios are 
covered 
 
7.4. Patient 
Disposition 
a) added number and 
percentage of patients 
randomized and never treated 
b) added COVID-19 related 
discontinuations 
c) number of patients died 
removed 
 a) client request 
b) to assess COVID-19 
impact on discontinuation 
c) there is a separate 
summary dedicated to 
Deaths 
 
7.5. Protocol 
Deviations 
Added that major protocol 
deviations are supposed to be 
analyzed not only by deviation 
type, but also by relationship to 
COVID-19 
To assess COVID-19 impact 
on major protocol deviations 
 
7.6.2. Medical 
History and 
Current Medical 
Conditions 
MedDRA version has been 
updated to 24 or higher 
To reflect the actual MedDRA 
version used 
 
7.6.3. Multiple 
Myeloma Disease 
History 
Additional details on derivation 
of the next variables were 
added: bone marrow plasma 
cells (%), cytogenetics 
abnormalities at study entry, 
bone lesion assessments 
To make sure that all data 
collection peculiarities are 
taken into account for 
analysis 
 
7.6.4. Prior MM 
Therapies 
Definitions of frontline 
transplant, time from frontline 
transplant to relapse, double 
and triple class refractoriness, 
as well refractoriness to the 
prior therapy line were updated  
To reflect the current 
sponsor’s view on that 
 
7.6.5. Prior and 
Concomitant 
Medication 
a) WHODD version updated to 
1 March 2021 
b) the first and last dose refer 
to the earliest of 
dexamethasone and melflufen 
and the latest of 
dexamethasone and melflufen 
respectively, instead of 
referring to melflufen only 
a) to reflect the actual 
WHODD version used 
b) to reflect the revised 
approach considering the 
combination of drugs rather 
than melflufen alone 
 
7.7.1. Response 
Clarifications that best overall 
To improve comprehensibility 


Statistical Analysis Plan: OP-109 
Review Status: Final 
 
Version: 2.2 
 
Version Date: 24 January 2022 
 
 
CONFIDENTAL 
Page 4 of 51 
 
Rates 
confirmed response includes 
only assessment collected 
prior to the new therapy 
initiation and that confirmed PD 
to be identified as per separate 
rule than confirmed sCR-SD 
responses 
and avoid ambiguity 
 
7.7.2. Time to 
Event Parameters 
a) Footnotes to the Tables 2 
and 3 were added 
b) derivation formulae added 
for various parameters 
a) following sponsor’s 
request 
b) to improve 
comprehensibility and avoid 
ambiguity 
 
7.7.3. Efficacy  
Assessments 
Statement re replacement of 
missing central assessments 
with unscheduled local ones 
added  
To address updated eCRF 
design and data collection 
process 
 
7.8.1. Exposure to 
Study Treatment 
Dose delay due to COVID-19 
analysis added 
To assess the impact of 
COVID-19 on dose delay 
 
7.8.2. Local 
Reactions 
Clarification added that for the 
VIP Score there is an 
exception to the rule specified 
7.1 regarding the assignment 
of measurements to particular 
injection type happened just 
prior to the shift to the other 
injection type 
To avoid ambiguity 
 
7.8.3. Adverse 
Events 
a) the way of presentation 
changed to by sequence arms 
b) MedDRA version has been 
updated to 24 or higher 
c) the first and last dose refer 
to the earliest of 
dexamethasone and melflufen 
and the latest of 
dexamethasone and melflufen 
respectively, instead of 
referring to melflufen only 
d) Dexamethasone related 
summaries were added to the 
list 
e) the definition updated for 
Thrombocytopenia, 
Neutropenia, Anemia grouped 
adverse events categories. 
The new categories added: 
myelodysplastic syndrome, 
a), d), e) following sponsor’s 
request for consistency with 
the other studies 
 
b) To reflect the actual 
MedDRA version used 
 
c) to reflect the revised 
approach considering the 
combination of drugs rather 
than melflufen alone 
 
f) to improve 
comprehensibility and avoid 
ambiguity 


Statistical Analysis Plan: OP-109 
Review Status: Final 
 
Version: 2.2 
 
Version Date: 24 January 2022 
 
 
CONFIDENTAL 
Page 5 of 51 
 
second primary malignancies, 
infective pneumonia 
f) clarification added that for by 
cycle presentation maximum 
toxicity grade should be 
identified separately within 
each cycle 
 
7.8.4. Laboratory 
Data 
a) the way of presentation 
changed to by sequence arms 
b) clarification added that only 
local assessments are used for 
the summaries 
c) clarification added that for by 
cycle presentation the worst 
grade should be identified 
separately within each cycle 
d) eGFR added to the list of 
parameters for which toxicity 
grade should be presented  
a) following discussions with 
the sponsor regarding the 
most appropriate way of 
presentation, considering 
cross-over design 
b) and c) to improve 
comprehensibility and avoid 
ambiguity 
d) to reflect the data properly 
 
7.8.5. Vital Signs 
The way of presentation 
changed to by sequence arms 
following discussions with the 
sponsor regarding the most 
appropriate way of 
presentation, considering 
cross-over design 
 
7.8.7. 12-Lead 
Electrocardiogram 
(ECG) 
The way of presentation 
changed to by sequence arms 
following discussions with the 
sponsor regarding the most 
appropriate way of 
presentation, considering 
cross-over design 
 
7.9.2. Treatment 
Satisfaction and 
Quality of Life 
Clarifications regarding way of 
presentation were added 
following discussions with the 
sponsor regarding the most 
appropriate way of 
presentation, considering 
cross-over design 
 
7.10.2. ECOG 
Section updated  
For consistency with the 
other studies 
 
9. Deviations from 
Analysis as 
Described in the 
Protocol 
Deviations to the protocol 
regarding way of presentation 
by sequence arm added 
To document existing 
deviation to the protocol 
 
 
 
 
2.1 
7.8.3. Adverse 
Events 
The statement that only deaths 
occurred prior to the 
subsequent therapy are to be 
presented in the summary of 
The client decided to 
consider all deaths happened 
for summary of deaths and 
not only those happened 


Statistical Analysis Plan: OP-109 
Review Status: Final 
 
Version: 2.2 
 
Version Date: 24 January 2022 
 
 
CONFIDENTAL 
Page 6 of 51 
 
deaths was removed 
prior to subsequent therapy 
2.2 
Signature page 
The name of the OP Head of 
Clinical Pharmacology and the 
name of the OP study 
physician as well as the name 
of PSI Medical Writer were 
updated 
To reflect the changes in the 
study team on the OP and 
PSI sides 
 
7.5 Protocol 
Deviations 
Clarification added that for the 
Overall column all major 
protocol deviations are 
presented, regardless if they 
happened within treatment 
period or not 
To fix the way of presentation 
used for the interim analysis 
and provide a summarization 
of all available major protocol 
deviations data 
 
7.6.5. Prior and 
Concomitant 
Medications 
The word “Haemapoetic” was 
replaced with “Haematopoietic” 
To fix the spelling 
 
7.7.2 Time to 
Event Parameters 
Table 3 
Conventions for 
Censoring for 
TTP 
Death mentioning was 
removed from the first 
censoring rule  
Death is not treated as an 
event for the time to 
progression analysis 
 
7.7.3 Efficacy 
Assessments 
Serum and Urine 
immunofixation central lab data 
excluded from summaries 
presentation, will only be 
presented in the listings   
Removed from summaries 
presentation as only 
measured at screening and 
at some specific conditions 
 
7.7.3 Efficacy 
Assessments 
The part regarding 
replacement of missing central 
results with available local 
results was removed 
Myeloma specific laboratory 
data were supposed to be 
collected centrally as per the 
protocol. There was a very 
small amount of such data 
collected locally, which were 
collected as Unscheduled 
results and could not be 
presented within a summary 
by time points 


Statistical Analysis Plan: OP-109 
Review Status: Final 
 
Version: 2.2 
 
Version Date: 24 January 2022 
 
 
CONFIDENTAL 
Page 7 of 51 
 
APPROVAL SIGNATURES 
STUDY 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 
SAP Final 2.2, 24 January 2022 
 
PSI 
Author: 
       digitally signed and dated 
 
Peer-reviewer Statistician: 
          digitally signed and dated 
 
Project Manager: 
                                                 digitally signed and dated 
 
Associate Medical Writer: 
                                            digitally signed and dated 
 
Oncopeptides AB 
Study Statistician: 
                                              digitally signed and dated 
 
Study Physician: 
                                                          digitally signed and dated 
 
Head of Clinical Pharmacology: 
                              digitally signed and dated 
 


Statistical Analysis Plan: OP-109 
Review Status: Final 
 
Version: 2.2 
 
Version Date: 24 January 2022 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 10 
1. 
INTRODUCTION ......................................................................................................... 13 
2. 
STUDY OBJECTIVES ................................................................................................. 13 
2.1 
Primary Objectives ................................................................................................. 13 
2.2 
Secondary Objectives ............................................................................................. 13 
2.3 
Exploratory Objectives .......................................................................................... 14 
3. 
STUDY DESCRIPTION ............................................................................................... 14 
3.1 
Study Design .......................................................................................................... 14 
3.2 
Study Treatment ..................................................................................................... 15 
3.3 
Data and Safety Monitoring Committee ................................................................ 16 
4. 
SAMPLE SIZE AND POWER CALCULATION...................................................... 17 
5. 
ANALYSIS ENDPOINTS............................................................................................. 18 
5.1 
Primary Endpoints.................................................................................................. 18 
5.2 
Secondary Endpoints.............................................................................................. 18 
6. 
ANALYSIS POPULATIONS ....................................................................................... 19 
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS ....................................... 20 
7.1 
General Conventions and Statistical Considerations ............................................. 20 
7.2 
Definition of Baseline, Study Visits, and Visit Windows...................................... 21 
7.3 
Handling of Missing Data ...................................................................................... 22 
7.4 
Patient Disposition ................................................................................................. 23 
7.5 
Protocol Deviations ................................................................................................ 23 
7.6 
Patient Characteristics ............................................................................................ 24 
7.6.1 
Baseline and Demographic Characteristics ................................................ 24 
7.6.2 
Medical History and Current Medical Conditions ...................................... 24 
7.6.3 
Multiple Myeloma Disease History ............................................................. 24 
7.6.4 
Prior MM Therapies .................................................................................... 27 
7.6.5 
Prior and Concomitant Medication ............................................................. 29 
7.7 
Efficacy Endpoints and Analysis ........................................................................... 30 
7.7.1 
Response Rates ............................................................................................ 30 
7.7.2 
Time to Event Parameters ............................................................................ 31 
7.7.3 
Efficacy Assessments .................................................................................... 35 
7.8 
Safety Endpoints and Analysis .............................................................................. 35 
7.8.1 
Exposure to Study Treatment ....................................................................... 35 
7.8.2 
Local Reactions. Primary Safety Endpoint .................................................. 37 
7.8.3 
Adverse Events ............................................................................................. 37 
7.8.4 
Laboratory Data .......................................................................................... 41 
7.8.5 
Vital Signs .................................................................................................... 43 
7.8.6 
Physical Examination .................................................................................. 43 


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7.8.7 
12-lead Electrocardiogram (ECG) .............................................................. 43 
7.9 
Exploratory Endpoints and Analysis...................................................................... 43 
7.9.1 
Biomarkers ................................................................................................... 43 
7.9.2 
Treatment satisfaction and quality of life (QOL) ......................................... 43 
7.10 Other Endpoints and Analysis ................................................................................ 45 
7.10.1 
Pharmacokinetics ......................................................................................... 45 
7.10.2 
ECOG ........................................................................................................... 49 
8. 
INTERIM ANALYSIS .................................................................................................. 49 
9. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE PROTOCOL ........ 50 
10. 
PROGRAMMING SPECIFICATIONS ...................................................................... 50 
11. 
REFERENCES .............................................................................................................. 50 
 
 
 


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Version: 2.2 
 
Version Date: 24 January 2022 
 
 
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LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under curve 
AUC(0-∞) 
area under the concentration-time profile from 0 hours to infinity 
AUC(0-t) 
area under the concentration-time profile from 0 hours to the last 
measurable concentration 
BMA 
bone marrow aspiration 
CBC 
complete blood count 
CBR 
clinical benefit rate 
COVID-19 
coronavirus disease of 2019 
CI 
confidence interval 
cm 
centimeters 
CR 
complete response 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
common terminology criteria for adverse events 
CV% 
coefficient of variation 
CVC 
central venous catheter 
DOCB 
duration of clinical benefit 
DOR 
duration of response 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EMD 
extramedullary disease 
EOT 
end of treatment 
FAS 
full analysis set 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 
GMR 
geometric mean ratio 
ICH 
International Council for Harmonisation 
IFE 
immunofixation  
Ig 
immunoglobulin 
IMiD 
immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 


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ISS 
International Staging System 
i.v.  
intravenous  
K-M 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
mAb 
monoclonal antibodies 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MR 
minimal response 
MRI 
magnetic resonance imaging 
NCA 
non-compartmental analysis 
NCI 
 
National Cancer Institute 
NRS 
numerical rating scale 
ORR 
overall response rate 
PD 
progressive disease 
PFS 
progression free survival 
PFS-FU 
progression free survival follow-up 
PI 
proteasome inhibitor 
PK 
pharmacokinetic(s) 
p.o. 
 
per os/by mouth/orally 
PR 
partial response 
PT 
preferred Term 
PVC 
peripheral venous catheter 
q.d. 
Quaque die/ one a day 
QOL 
quality of life 
R-ISS 
revised international staging system 
RRMM 
relapsed refractory multiple myeloma 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
S-Cr 
serum creatinine 
SD 
standard deviation; stable disease (depending on context)  
SDG 
standardized drug groupings 
SDTM 
study data tabulation model 
SFLC 
serum free light chain 
SMQ 
standardized MedDRA query 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
t½ 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of the normal range 


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UPEP 
urine protein electrophoresis 
US  
United States 
VAS 
visual analogue scale 
VGPR 
very good partial response 
VIP 
visual infusion phlebitis 
WBC 
white blood cells 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 


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1. 
INTRODUCTION 
 
This statistical analysis plan (SAP) describes the statistical analysis and reporting for the study 
protocol OP-109 v.2.2 (10 March 2021) entitled; A randomized, two-period, cross-over, phase 2 
study, comparing the pharmacokinetics, and assessing safety and tolerability of peripheral and 
central intravenous (i.v.) administration of melflufen in patients with relapsed and refractory 
multiple myeloma. The purpose of the plan is to outline the types of analyses and data presentations 
that will address the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry. If the protocol is amended, this SAP will be 
revised as required.  
The statistical principles applied in the design and planned analyses of this study are consistent 
with International Council for Harmonisation (ICH) guidelines E9 (Statistical Principles for 
Clinical Trials). 
This SAP does not include the description of biomarkers analysis. 
 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
 
• To evaluate and compare the pharmacokinetic (PK) variables maximum observed 
concentration (Cmax), area under the concentration-time profile from 0 hours to the last 
measurable concentration (AUC(0-t)) and area under the concentration-time profile from 0 
hours to infinity (AUC(0-∞)) of melphalan after central and peripheral i.v.  infusion of 
melflufen 
• To assess the local tolerability of peripheral i.v. administration of melflufen 
2.2 
SECONDARY OBJECTIVES 
 
• To evaluate and compare the PK variables Cmax, AUC(0-t) and AUC(0-∞) of melflufen and 
desethyl-melflufen, and to evaluate the elimination half-life (t½) for melflufen, melphalan 
and desethyl-melflufen after central and peripheral i.v. infusion of melflufen 
• To assess safety and general tolerability of melflufen 


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• To evaluate efficacy: 
- 
Best response during the study  
- 
Overall response rate (ORR)  
- 
Clinical benefit rate (CBR) 
- 
Duration of response (DOR) 
- 
Duration of Clinical Benefit (DOCB) 
- 
Time to response (TTR) 
- 
Time to progression (TTP) 
- 
Time to next treatment (TTNT) 
- 
Progression Free Survival (PFS) 
2.3 
EXPLORATORY OBJECTIVES 
 
• To assess translational biomarkers that might predict effects of the treatment, aid in 
monitoring of disease progression as well as improve understanding of mechanism of 
action 
• To assess and compare patient satisfaction and preference, nurse convenience and 
preference after central and peripheral i.v. administration of melflufen 
• To assess Quality of Life (QoL) based on Patient Reported Outcome (PRO) 
• To assess use of health services and days of hospitalization 
3. 
STUDY DESCRIPTION 
3.1 
STUDY DESIGN 
 
This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety, 
tolerability and efficacy of peripheral and central i.v. administration of melflufen in patients with 
relapsed and refractory multiple myeloma (RRMM). It is an international study, enrolling patients 
in the United States (US) and Europe. The study will enroll patients following at least 2 lines of 
prior therapy. 


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Patients will be randomized (1:1) to Arm A or Arm B (see Figure 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. 
 
Figure 1. Study Design 
 
3.2 
STUDY TREATMENT 
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 days 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 central venous 
catheter (CVC)*. 
• Dexamethasone will be given p.o. at the standard dose of 40 mg weekly, at days 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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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 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 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. 
3.3 
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 contract research organization 
(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), as well as efficacy and PK data will 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 peripheral infusion and 
one cycle via central infusion with adequate PK data, the DSMC will assess the safety and 
tolerability of received infusions. The DSMC may then allow continuation with the peripheral 
infusion in Cycle 3 onwards (in both Arm A and B) to further study local toxicity 
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 
the DSMC meeting.  


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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 progressive disease (PD) according to International Myeloma Working Group 
Uniform Response Criteria (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. 
 
4. 
SAMPLE SIZE AND POWER CALCULATION 
 
Evaluation of combined data for the melflufen studies O-12-M1, OP-103, OP-104 and OP-107 on 
patients with multiple myeloma (MM) has demonstrated a relationship between melphalan 
systemic exposure and the lowest (nadir) levels of neutrophils and thrombocytes in treatment cycle 
1. The incidence of grade 3 and grade 4 events increased in parallel with the melphalan AUC 
values. For melflufen and desethyl-melflufen no corresponding relationship has been found. 
Melphalan AUC has therefore been selected as the main PK parameter for which similarity 
between central and peripheral melflufen administration should be assessed.   
The within-patient variability in melphalan PK parameters after melflufen administration has been 
evaluated in study OP-103 from data for the first two treatment cycles in 59 patients. The within-
patient standard deviations (SD) in log scale were Cmax: 0.251, AUC: 0.248 and AUCinf: 0.217. 
Based on a geometric mean ratio peripheral vs. central of 0.95, a 90% confidence interval (CI) for 
the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, 
a sample size of 20 patients (10 per sequence) is required assuming a within-patient variability for 
period differences (in log scale) of 0.29.   
Approximately 25 patients will be enrolled to achieve 20 PK- and local tolerance-evaluable 
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5. 
ANALYSIS ENDPOINTS 
5.1 
PRIMARY ENDPOINTS 
 
PK: 
• Cmax of melphalan 
• AUC(0-t) of melphalan 
• AUC(0-∞) of melphalan 
Safety: 
• Frequency and severity of local reactions including phlebitis at infusion site after peripheral 
i.v. administration 
 
5.2 
SECONDARY ENDPOINTS 
 
PK: 
• Cmax of melflufen and desethyl-melflufen 
• AUC(0-t) of melflufen and desethyl-melflufen  
• AUC(0-∞) of melflufen and desethyl-melflufen 
• Elimination half-life t½ of melflufen, melphalan and desethyl-melflufen 
Safety: 
• Frequency and Grade of Treatment emergent Adverse Events (TEAEs) 
Efficacy: 
• Best Response (stringent complete response (sCR), complete response (CR), very good 
partial response (VGPR), partial response (PR), minimal response (MR), stable disease 
(SD) or PD  
• ORR (including CR/sCR, VGPR and PR) 
• CBR proportion of patients with ≥ MR as best response   
• DOR (time from the first confirmed response of sCR, CR, VGPR or PR to first confirmed 
disease progression, or death due to any cause) 
• DOCB (time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR 
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• TTR (time from randomization to the date of the first documented confirmed response in 
a patient that has responded with ≥ PR (sCR, CR, VCPR or PR)) 
• TTP (time from the date of randomization to the date of the first documented confirmed 
PD)  
• TTNT (time from randomization to the date of next anti-myeloma treatment) 
• PFS (time from the date of randomization to the date of first documentation of confirmed 
PD or death due to any cause) 
Exploratory: 
• DNA, RNA and protein-based drug response biomarkers including but not limited to 
aminopeptidases and esterases 
• Value in each scale assessed by patients 
• Value in each scale assessed by nurses 
• EQ-5D-5L: 
- 
Value and changes from baseline in Visual Analogue Scale (VAS) and EQ-index  
- 
Number of patients by category and dimension 
• Number of health services  
• Number and days of hospitalization  
6. 
ANALYSIS POPULATIONS 
Full analysis set  
All patients who are randomized.  Patients will be analyzed according to the treatment assigned at 
randomization. All efficacy endpoints will be performed using the full analysis set (FAS). 
Safety Set 
All patients randomly assigned to study treatment that receive at least a partial dose of study 
treatment (melflufen and/or dexamethasone). Patients will be analyzed according to the 
treatment/administration route (peripheral or central) they actually received. For the safety analysis 
by sequence arms the planned sequence arms as randomized will be used. All safety endpoints will 
be performed using the safety analysis set. 
PK Set 
All patients that have received at least two melflufen doses of 40 mg and have sufficient PK 
samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series 


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following peripheral administration and one PK sampling series following central administration. 
Patients with a dose reduction in Cycle 2 are not evaluable for PK. 
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS 
7.1 
GENERAL CONVENTIONS AND STATISTICAL CONSIDERATIONS 
 
All analyses will be performed using SAS statistical analysis software (SAS, SAS/GRAPH and 
SAS/STAT; version 9.4 or higher of SAS for Windows [SAS Institute Inc.; Cary, NC, USA]). 
Descriptive statistics for continuous variables will include the number of patients with non-missing 
data (n), arithmetic mean, SD, median, minimum and maximum. Summary statistics for 
categorical variables will contain count and percentage based on the number of patients in the 
selected analysis population. Percentages will be presented to one decimal, except for zero and 
one hundred percent, which will be presented as 0% and 100%.  
For descriptive statistics of continuous variables, the accuracy of the minimum and maximum 
should match the original data; for the mean and median one more decimal point in addition to the 
original data will be presented, and for SD two more decimal points in addition to the original data 
will be presented. For the derived variables (e.g. time since diagnosis) minimum and maximum 
will be presented with one decimal after point; mean, median and SD decimals will be applied 
following the rule above. 
Presented decimal places should however not be greater than 4. 
Denominators for percentages will be based on the number of patients with non-missing data in 
the population used in each column, for the summaries presented by time points the denominator 
will be the number of patients with non-missing data at each time-point. A “missing” category will 
be included for any parameter for which information is missing, without a percentage. 
Formal statistical analysis will only be conducted for selected PK endpoints. Other endpoints will 
primarily be presented using descriptive statistics.   
By default the data collected in the electronic case report form (eCRF) and by external vendors 
will be used for analysis unless it is specified that additional derivation is required. 
 
In general demographics, disposition, historical and efficacy summaries will be presented by 
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either by combined groups (i.e. administration route: PVC and CVC) and total or sequence groups 
and total as specified in the specific sections of this SAP below. 
 
For the presentation by combined groups the assessments that happen prior to the shift to the new 
injection type are all linked to the previous type of injection, including also the measurements that 
happen just prior to the injection at the day of the new injection, the exception is the analysis of 
visual infusion phlebitis (VIP) scores where both pre-infusion and post-infusion assessments are 
linked to PVC injection type at cycles where PVC infusion is performed.   
 
7.2 
DEFINITION OF BASELINE, STUDY VISITS, AND VISIT WINDOWS 
 
In general the baseline is the last available assessment prior to the first dose of study drug (the 
earliest of melflufen and dexamethasone start date). 
Where assessments are made on the day of first treatment and the time is available for comparison 
the time should be used to recognize whether the assessment was prior to the first treatment and 
thus should be used as a baseline or not.  If only date is in place and time is not available, for 
assessments on the day of first treatment that are per protocol scheduled to take place prior to 
treatment, it will be assumed that the assessment is pre-dose, and is a valid baseline assessment. 
Refer to the protocol for the study visit schedule.  
Note that for this study there is no study day 0, so the day immediately prior to study day 1 is study 
day -1. For any events occurring on or after the first dose of study drug, the study day is calculated 
as: event date – date of first administration of study treatment + 1. As such, the first dose date was 
study day 1.  
For any events before the first dose date, study day is calculated as: event date – date of first 
administration of study treatment. As such, one day before first dose date was study day -1.  
Because unscheduled assessments are not associated with any scheduled time point, they are 
excluded from all summaries by time point.  Unscheduled assessments will be considered when 
deriving myeloma response parameters as described in the Section 7.7. and for analysis of 
laboratory parameters by worst toxicity grade as specified in the Section 7.8.4. of this SAP. All 
unscheduled assessments will be presented in the respective listings. 
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will be applied. 
7.3 
HANDLING OF MISSING DATA 
 
If only a partial date is available and is required for a calculation (e.g., time since diagnosis, time 
since most recent relapse, determination of whether a medication is concomitant or an AE is 
treatment-emergent), the following standards will be applied: 
• Start dates (e.g., AE onset date or start date of medication, date of diagnosis, date of 
relapse). For missing start day only - day will be imputed as the first day of the month (i.e., 
1) with the following exception: if the partial date falls in the same month and year as the 
date being used in the calculation (e.g., first dose date, informed consent date), then the 
partial date will be imputed to equal the date being used for the calculation, unless there is 
a complete end date which is earlier. 
• For missing start day and month - day and month will be imputed as the first day of the 
year (i.e., 1 January) with the following exception: if the partial date falls in the same year 
as the date being used in the calculation (e.g., first dose date, informed consent date), then 
the partial date will be imputed to equal the date being used for the calculation, unless there 
is a complete end date which is earlier (or incomplete end date with month earlier than 
month of the date being used for calculation, when year is the same). 
• Stop dates (e.g., AE resolution date or stop date of medication). For missing stop day only 
- day will be imputed as the last day of the month (i.e., 28, 29, 30, or 31). 
 
• For missing stop day and month - day and month will be imputed as the last day of the year 
(i.e., 31 December). 
 
Any partial dates will be displayed in data listings without imputation of missing days and/or 
months (e.g., MAR2011, 2009).  
 
In case of incomplete date of relapse, for the purpose of calculation of the time since most recent 
relapse the rules mentioned above for the partial start date will be used. However, for the purpose 
of calculation of time since frontline transplant to relapse and derivation of refractory status the 
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of missing month and day will be used. 
If time is not available but is required for a calculation (e.g., timing of AE vs study drug 
administration) the most conservative approach should be used, i.e. assuming that the time of AE 
was after study drug administration or that the time of concomitant medication was after AE. 
AEs with missing relationship are considered related for purposes of summaries. In case of 
multiple cases the information regarding the number of imputed relationships will be provided in 
the footnote of the respective summaries. 
AEs with missing severity are considered severe (grade 3) for purposes of summaries. Imputed 
relationship and severity will not be included in the listings. 
The handling of dropouts and missing disease status assessments for the efficacy variables is 
described in their definitions in the relevant sections.   
7.4 
PATIENT DISPOSITION 
 
Disposition summary will be based on the FAS and presented by sequence treatment arms. 
The disposition of patients includes: 
• The number and percentage of treated patients  
• The number and percent of randomized but never treated patients  
• Number (%) of patients in Safety and PK sets 
• Number (%) of patients permanently discontinued from the treatment along with the 
primary reasons for permanent treatment discontinuation. The numbers above will also be 
presented separately for the type of administration (PVC or CVC) during which the 
discontinuation occurred 
• Number (%) of patients in PFS follow-up 
• Number (%) of patients discontinued from the study and reasons for study discontinuation  
 
Treatment discontinuations due to AE specific to coronavirus disease of 2019 (COVID-19) or 
other pandemic-related reasons will be presented separately. 
All patient disposition information will be presented in the respective listings.  
7.5 
 PROTOCOL DEVIATIONS 
 
Major protocol deviations will be summarized by deviation type and relationship to COVID-19 


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for the FAS by combined treatment arms and Overall. Overall column includes all the major 
protocol deviations, including those that happened on Screening and Follow-Up period, while 
combined treatment arm columns include only those that happened during the treatment period 
and could be linked to the particular administration type.  
 
All protocol deviations will also be provided in a listing. 
 
7.6 
PATIENT CHARACTERISTICS 
7.6.1 BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
 
The following demographic and baseline characteristics will be summarized descriptively for the 
FAS by sequence treatment arms: 
• Age (years) 
• Age categories (<65, ≥ 65 -≤75, >75) 
• Sex 
• Race 
• Ethnicity 
• Baseline fertility status 
• Baseline height (cm) 
• Baseline weight (kg) 
• Baseline Eastern Cooperative Oncology Group (ECOG) performance status 
A listing will be provided for patient’s demographic and baseline characteristics. 
Separate listings will be provided for patient childbearing potential and ECOG results.  
7.6.2 MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
 
Medical history will be summarized by Medical Dictionary of Regulatory Activities (MedDRA) 
(version 24.0 or higher), System Organ Class (SOC) and preferred term (PT) using number (n) and 
percentage (%) of patients having at least one occurrence of a disease for FAS by sequence 
treatment arms. A listing will be provided for patient medical history. 
7.6.3 MULTIPLE MYELOMA DISEASE HISTORY 
 
The following disease characteristics at diagnosis will be summarized descriptively for the FAS 
by sequence treatment arms: 


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• Stage of disease (international staging system (ISS) and revised international staging 
system (R-ISS)) 
• Heavy chain and light chain subtypes 
• Evidence of lytic bone disease 
• Evidence of extramedullary disease (EMD) 
 
The following disease characteristics at baseline/study entry will be summarized descriptively for 
the FAS by sequence treatment arms: 
• Stage of disease ( ISS and R-ISS) 
• Heavy chain and light chain subtypes 
• Evidence of lytic bone disease 
• Evidence of EMD 
• Time since diagnosis in years (calculated as [date of first dose of study drugs (the earliest 
of melflufen and dexamethasone first dose)   – date of diagnosis+1]/365.25). Partial dates 
will be imputed according to the section 7.3 of this SAP 
• Time since most recent relapse/progression in months (calculated as [date of first dose of 
study drugs (the earliest of melflufen and dexamethasone first dose)  – date of most 
recent relapse/progression+1]/30.4375) 
• Baseline serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), 
kappa/lambda values 
• Baseline maximum bone marrow plasma cells (%) as values and by categories (<30%, 30 
- <60%, ≥60%) (Note: The maximum bone marrow plasma cells involvement will be 
defined as the highest value amongst any of the available baseline test results from the 
following local bone marrow lab parameters: clonal plasma cells (%) (immature plasma 
cells/total cells) and plasma cells (%) (plasma cells ratio)). 
• Baseline laboratory assessments 
o β2 microglobulin (mg/L) as values and categories (< 3.5, 3.5 – 5.5 and > 5.5) 
o Platelet count (10^9/L)  as values and categories (<75, ≥75 - ≤ 100, >100 - ≤ 150, 
>150) 
o ANC (10^9/L)   as values and categories (<1.0, 1.0 – 1.5, and >1.5) 
o Hemoglobin (g/L) as values and categories (<80, 80 – 100, >100) 
o Lactate dehydrogenase (LDH) (u/L) as values and categories (<1.5xULN and 
≥1.5xULN) 
o Albumin (g/L) as values and categories (<35,  ≥35) 
o Creatinine 


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o estimated glomerular filtration rate (eGFR) (mL/min/1.73m2) and categories ( <45, 
≥45 - <60, ≥60 - <90, ≥90) 
o Corrected calcium 
 
 
In addition to the above ISS Stage and Revised ISS (R-ISS) Stage will be derived [Palumbo, 
2015], see Table 1. 
ISS will be derived from screening serum β2 microglobulin and albumin. This derived ISS will 
in turn be used with screening serum lactate dehydrogenase (LDH) and high-risk cytogenetics at 
study entry as defined by the R-ISS guidelines to derive R-ISS. Derived ISS and R-ISS will be 
referred as “Derived ISS” and “Derived R-ISS” respectively. 
 
Table 1: Standard Risk Factors for MM and the Revised ISS (R-ISS)  
Standard Risk Factors for MM and the Revised -ISS (R-ISS)  
Prognostic Factor  
Criteria  
ISS Stage  
Stage I  Serum B2-microglobulin < 3.5 mg/L, serum albumin ≥ 3.5 g/dL  
Stage II  Not ISS stage I or III  
Stage III  Serum B2-microglobulin ≥ 5.5 mg/L  
Chromosomal abnormalities (CA) by interphase florescent in situ hybridization (iFISH)  
High-Risk  Presence of del(17p) and/or translocation of t(4:14) and/or translocation of t(14:16)  
Standard-Risk  No high-risk CA  
Lactate Dehydrogenase (LDH) 
Normal  Serum LDH ≤ upper limit of normal (ULN)  
High  Serum LDH > ULN  
A new model for risk stratification of MM R-ISS  
Stage I  ISS stage I and standard-risk CA by iFISH and normal LDH  
Stage II  Not R-ISS stage I or III  
Stage III  ISS stage III and either high-risk CA by iFISH or LDH  
 
A separate summary dedicated to fluorescence in situ hybridization (FISH) cytogenetics 
investigations at diagnosis and study entry will be presented, including the number and percentage 
of patients having particular types of cytogenetic abnormalities. Cytogenetics abnormalities will 
also be pooled by risk level (high-risk, standard-risk and Unknown).  


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High-risk is defined in case the following abnormalities were found: deletion (17p), gain 1q (+1q), 
gain (1q21); t (4;14), t(4;14) (p16;q32), t (14;16), t (14;16) (q32;q23), t(14;20), t(14;20) (q32;q11).  
Standard-risk consists of patients who have a genetic subtype recorded but none of the genetic 
subtypes categorized as high-risk. Standard-risk category will only be presented at diagnosis. 
Unknown: consists of patients for whom the FISH procedure was not done or unevaluable. 
Bone lesion assessments at screening will be analyzed descriptively with the number and percent 
of patients, including number and percent of patients for whom skeletal X-Ray or low dose CT 
scan was performed, method of skeletal survey, result of exam (in case multiple results are 
available patients are counted only for the result of exam based on the most severity case in the 
order of ‘Abnormal – clinically significant’, ‘Abnormal – not clinically significant’, ‘Normal’), 
bone lesions locations, the same information will be presented for the other imaging procedures. 
Listings will be provided for MM history. 
 
7.6.4 PRIOR MM THERAPIES 
 
The following information related to prior MM therapies will be summarized for the FAS by 
sequence treatment arms: 
• Number and percentage of patients who had a transplant  
• Number of patients who had a salvage transplant (defined as any transplant where the 
patient has already had 1 or more transplants in earlier lines). Planned tandem autologous 
or autologous-allogeneic are considered as one transplant 
• Frontline transplant type (allogeneic or autologous). Frontline transplant is the first 
transplant per patient irrespective in which therapy line it was applied. The number and 
percentage of patients having frontline transplant per prior therapy line will be presented 
• Number and percentage of patients with the tandem transplant 
• Number and percentage of patients with at least one prior autologous transplant, and 
number and percentage of patients with at least two prior autologous transplants 
• Number of prior autologous transplants 
• Time from frontline transplant to relapse (the earliest relapse following frontline transplant, 
not necessarily after the prior therapy line when frontline transplant occurred)  in years (as 


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continuous variable as well as per categories < 1 year, ≥1 year – <1.5 years, ≥1.5 years – 
≤2 years, >2 years) . Calculated as [date of relapse – date of frontline transplant+1]/365.25)  
• Number of prior systemic therapy lines 
• Best response to the last prior line of therapy 
• Refractory status to last prior line of therapy 
• Number and percentage of patients with any prior therapy lines (as well as during the last 
therapy) including: immunomodulatory drugs (IMiD’s), proteasome inhibitors (PI’s), 
alkylators,  anti-CD38 monoclonal antibodies (mAb), other mAb and others 
• The number and percentage of patients refractory to at least one prior line of therapy (as 
well as to last prior therapy line) mentioned in the point above 
• Number and percentage of patients who received an IMiD and PI (double-class)  in any of 
the prior therapy lines 
• Number and percentage of patients who received an IMiD, PI, and anti-CD38 mAb (triple-
class) in any of the prior therapy lines 
• Number and percentage of patients that are double class refractory (refractory to at least 
one PI and one IMiD happened in any of the prior therapy lines and not necessarily in one 
therapy line) 
• Number and percentage of patients that are triple-class refractory (refractory to at least one 
PI, at least one IMiD and at least one Anti-CD38 mAb happened in any of the prior therapy 
lines and not necessarily in one therapy line) or triple intolerant (if the patient discontinued 
at least one PI, at least one IMiD and at least one Anti-CD38 mAb due to toxicity in any 
of the prior therapy lines and not necessarily in one therapy line , and did not receive a drug 
in the same therapeutic drug class again prior to entering the current study) 
• Number and percentage of patients with prior radiotherapy. 
The next lists of drugs are associated with each drug class: 
• IMiD is defined as World Health Organization Drug Dictionary (WHODD) Standardized 
Drug Groupings (SDG) “Antineoplastic thalidomide analogues”.  
• PI is defined as SDG “Antineoplastic proteasome inhibitors”. 
• Alkylators is defined as SDG “Antineoplastic alkylating drugs”. 
• Anti-CD38 mAb is defined as SDG “Antineoplastic CD38 antigen inhibitors”. 


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• Other mAb is defined as SDG “Monoclonal antibodies – antineoplastics” excluding SDG 
“Antineoplastic CD38 antigen inhibitors”. 
• Other antineoplastic drugs for the treatment of MM will be referred to as ‘Other”. Will be 
identified by manual review of the drugs not included into the categories above. 
Refractory is defined as non-response disease (achieving SD or PD as the best response) while on 
therapy, or reason for termination was PD, or relapse/progression within 60 days after stop date of 
treatment.  
Patient considered refractory to the therapy line if refractory to any of the prior therapies within 
the prior therapy line, whereas a patient is deemed as non-refractory to a therapy line in case of 
non-refractory to all of agents in the therapy line. Otherwise, a patient’s refractory status to the 
therapy line will be considered unknown. 
All patient details of prior MM therapies will be presented in the respective listings. 
 
 
7.6.5 PRIOR AND CONCOMITANT MEDICATION 
 
All concomitant medications will be coded using the WHODD dated 01 March 2021 or higher.   
A medication is considered prior if stopped before the date of the first therapy (the earliest of 
melflufen and dexamethasone start date) dose. Concomitant medications are defined as 
medications with start date or end date on or after the date of first therapy dose and start date before 
the date of the last therapy dose (the latest of melflufen and dexamethasone end date) + 30 days or 
are ongoing at the time of first dose.   
The number and percentage of patients with at least one concomitant medication will be 
summarized by the Anatomical Therapeutic Chemical (ATC) class (ATC 2 and ATC 4) and 
preferred name. Summaries will be presented by FAS by sequence treatment arms. Patients may 
have more than one medication per ATC class and preferred name.  At each level of patient 
summarization, a patient is counted once if he/she reported one or more medications at that level.  
The summaries will be ordered by descending frequency of ATC class and preferred name within 
each ATC class in the total group. Prior medications will be presented separately in the same way.  
Concomitant medication is assigned to the particular cycle if taken between the date of the study 
drugs (the earliest of melflufen/dexamethasone) administration at particular cycle and date of study 
drugs administration in subsequent cycle. If patient discontinued somewhere in between the cycles 


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concomitant medication is assigned to the cycle in which the discontinuation has happened. 
Separate summaries will be provided for the number and percentage of patients with the following 
medication categories: “Haematopoietic growth factors” (WHODD SDG “Colony stimulating 
factors”) and “Transfusions” (including next PTs: “Platelets”, “Erythrocytes”, “Red blood cells”). 
A listing of prior and concomitant medications will be provided. 
 
7.7 
EFFICACY ENDPOINTS AND ANALYSIS 
 
All efficacy analyses will be produced on the FAS and Safety analysis set by sequence treatment 
arms. 
All tumor response and progression-depended objectives are assessed by investigators according 
to the IMWG-URC (Kumar et al.2016). 
 
7.7.1 RESPONSE RATES 
 
For analysis of response rates, all percentage calculations will be based on the respective analysis 
set. For analysis of the best confirmed response rates, a category of ‘Not available’ will be added 
and included in the percentage calculation for patients who cannot be categorized for the best 
confirmed response (as described below). For analysis of the best unconfirmed response rates, the 
same approach will be used.   
 
Best Overall Confirmed Response  
Best overall confirmed response during the study, including follow-up tumor response 
assessments, collected prior to the new therapy initiation, (sCR, CR, VGPR, PR, MR, SD or PD) 
assessed by the investigator according to IMWG-URC, will be summarized descriptively. 
 
Confirmed response: Two consecutive assessments with the same response result made at any 
time. In case at the second consecutive assessment (made at any time) the response is higher than 
the previous one then confirmed response (linked to the first assessment visit) will be the first one 
(e.g., PR – VGPR consecutive pair will lead to a PR confirmed response at the first visit). In case 
the second consecutive response is lower than the first one then confirmed response (linked to the 
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confirmed response at the first visit). 
This rule for confirmed response above is only applicable to sCR-SD responses; confirmed PD is 
treated separately as two consecutive PD assessments.  
 
Best Unconfirmed Response 
Defined as the best response achieved on study, i.e. a response may not be confirmed by a 
consecutive assessment.   
 
ORR 
 
The ORR will be estimated as the proportion of patients who achieve a confirmed response of 
sCR, CR, VGPR, or PR as their best response, as assessed by the investigator. The denominator is 
the number of patients in the analysis population for particular sequence treatment arm.   The exact 
binomial two-sided 95% CI for ORR will be calculated.   
 
CBR 
CBR is the proportion of patients who achieve a confirmed minimal response or better (sCR, CR, 
VGPR, PR and MR).  CBR will be summarized using the same method as for ORR. 
 
All the details of myeloma response assessment will be presented in a listing. 
7.7.2 TIME TO EVENT PARAMETERS 
 
PFS 
PFS is defined as the time from the date of randomization to the date of first documentation of 
confirmed PD or death due to any cause, whichever occurs first. PFS time, in months, is calculated 
as (PFS date – date of randomization +1)/30.4375. 
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DOCB 
DOCB will be calculated as time in months 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 censored and summarized using the same method as for PFS. 
 
DOCB will be derived as (DOCB date – date of first documented confirmed response (≥MR) + 
1)/30.4375. 
 
TTR 
TTR will be calculated as time in months 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. Will be derived as (date of first documented confirmed response (≥PR) 
– date of randomization + 1)/30.4375. 
 
TTP 
TTP is defined as time in months from randomization to the date of the first documented confirmed 
progression. TTP will be censored and summarized using the same method as for PFS, but not 
considering death in the censoring rules, see Table 3 below.  
TTP will be derived as (TTP date – randomization date +1)/30.4375. 




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TTNT 
TTNT in months will be calculated as time in months from the date of randomization to the start 
of next line of therapy (excluding radiotherapy). Patients who have no post study myeloma therapy 
will be censored at the earlier of date of death and date of last contact. TTNT will be summarized 
using the Kaplan-Meier (K-M) method.   
 
TTNT will be derived as (TTNT date – randomization date +1)/30.4375. 
 
An alternative definition will also be used: 
TTNT in months will be calculated from the date of randomization to the start of next line of 
therapy (excluding radiotherapy) or death. Patients who have no post study myeloma therapy and 
do not have a date of death will be censored at the date of last contact. 
 
7.7.3 EFFICACY ASSESSMENTS 
 
Myeloma specific laboratory tests results, including SPEP, UPEP, and serum free light chain 
(SFLC) will be summarized descriptively by assessment visit.  
 
Central laboratory myeloma specific assessment to be used for the summaries. 
 
All the myeloma specific laboratory tests results and other efficacy assessments (i.e. 
extramedullary plasmacytoma assessment) will be presented in the listings. A separate listing for 
bone marrow aspirate will be presented. 
 
 
7.8 
SAFETY ENDPOINTS AND ANALYSIS 
 
All analyses of safety will be based on the Safety analysis set.   
 
7.8.1 EXPOSURE TO STUDY TREATMENT 
 
Exposure analysis will be based on the Safety analysis set by sequence treatment arms.   
 


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Duration of melflufen treatment in weeks is defined as (date of last dose – date of first dose + 29 
days) divided by 7. 
If a patient discontinued from treatment and the end of treatment (EOT) visit happened prior to 29 
days after last dose, then the duration of melflufen is defined as (date of EOT – date of first dose 
+1) divided by 7. 
If a patient died prior to 29 days after last dose, then the duration of melflufen is defined as (date 
of death – date of first dose +1) divided by 7. 
Duration of dexamethasone treatment in weeks is defined as (date of last dose – date of first 
dose + 1) divided by 7. 
Overall duration of treatment with study drug in weeks is defined as the longest duration of 
dexamethasone and melflufen treatment. 
 
The duration of study treatment exposure will be summarized descriptively and presented for 
overall treatment duration and  also separately for melflufen and dexamethasone and will include: 
treatment duration in weeks, number of cycles received (and also additionally number of doses for 
dexamethasone),  cumulative dose (in mg) of study drug received per patient, average dose of 
study drug (mg/week for melflufen and mg/week for dexamethasone), the total number and % of 
patients receiving a dose per cycle (for overall treatment and melflufen), average duration of 
infusion (min) for melflufen. Patients who received only a partial dose of melflufen for a given 
cycle will be considered as having received treatment for that cycle. 
Average dose of melflufen in mg/week is defined as the cumulative dose divided by the duration 
of melflufen treatment, the same for dexamethasone.  
 
Dose modification information will be summarized descriptively for any drug and then also 
separately for melflufen and dexamethasone. The number of patients with drug modifications due 
to AEs will be presented based on the AE eCRF page and the number of patients with each action 
by frequency will be presented based on the melflufen/dexamethasone administration eCRF page. 
The number of patients with any drug modification will also be presented by cycle. 
A dose delay is defined as a consecutive dose of melflufen administered on day 33 or later 
following a preceding dose of melflufen (day at the moment of melflufen administration is defined 
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categorized as delays in weeks as 1 (day 33 to 39), 2 (day 40 to 46), 3 (day 47 to 53), 4 (day 54 to 
60), and >4 weeks (day 61 or later) for each cycle.  
A separate table will present the number and percentage of patients with delayed completed cycles 
(those with day 33 and later at the moment of melflufen administration following a preceding dose 
of melflufen) as well as the number of delayed cycles by delay categories (1 week, 2 weeks, 3 
weeks, 4 weeks and >4 weeks).  
Number of patients with a melflufen dose delay due to COVID-19 pandemic will be summarized. 
All melflufen and dexamethasone administration details will be presented in the respective listings.  
 
7.8.2 LOCAL REACTIONS. PRIMARY SAFETY ENDPOINT 
 
Peripheral infusion related reactions summaries will be presented based on the Safety analysis 
set by combined PVC treatment arm overall and by cycle.   
 
The number and percentage of patients experiencing at least one local infusion related reaction 
after peripheral i.v. administration will be presented. Local infusion related reactions will be 
presented by SOC and PT and also separately by SOC, PT and maximum toxicity grade overall 
and by cycle. The same rules for analysis as specified in section 7.8.3. Adverse Events section are 
applicable here. 
Local infusion related reactions will be identified from all infusion related reactions using the list 
of applicable preferred terms (PT), based on selected PTs of the High Level Term (HLT) “Infusion 
site reactions” and also standardized MedDRA queries (SMQ) “Hypersensitivity” and 
"Extravasation events (injections, infusions and implants)", the list will be finalized prior to the 
database lock following manual review of the respective data. 
A separate summary will present the number and percentage of patients with particular VIP scores 
by visit and time point. For VIP scores analysis both pre-infusion and post-infusion assessments 
are linked to PVC injection type at cycles where PVC infusion is performed. 
A listing showing all the infusion related reactions details will be presented. A separate listing will 
be presented for the VIP Scores. 
7.8.3 ADVERSE EVENTS 
 
All AE summaries will be presented based on the Safety analysis set by sequence treatment arms 


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and total, overall and by cycle unless otherwise specified.   
 
All AEs will be coded using the MedDRA (version 24.0 or higher), for toxicity assessment the 
National Cancer Institute Common Toxicity Criteria (NCI CTCAE) version 5.0 AE will be used.  
The summaries of AEs will be based on TEAEs.  
TEAEs are defined as AEs that start on or after the first day of study treatment administration (the 
earliest of melflufen and dexamethasone start date) and within 30 days of the last administration 
of study treatment (the latest of melflufen and dexamethasone end date), or before start of 
subsequent anticancer treatment (whichever occurs first).    
An overall summary of TEAEs will be presented. It will include the number and percentage of 
patients (as well as total event count) with at least one TEAE, patients with at least one grade 3, 
grade 4 and grade 3/4 TEAE, patients with at least one serious TEAE, and patients with TEAEs 
leading to death.  
The overall summary will include the treatment related TEAEs analyzed separately in three ways: 
treatment related TEAEs (melflufen and/or dexamethasone related, melflufen related TEAEs, and 
dexamethasone related TEAEs).  It will include the number and percentage of patients (as well as 
total event count) with related TEAEs; patients with related grade 3, grade 4 and grade 3/4 TEAEs; 
patients with related serious TEAEs; and patients with related TEAEs leading to death. In addition 
the number and percentage of patients with TEAEs leading to dose reduction, dose delay and dose 
discontinuation will be presented separately for overall treatment (melflufen and/or 
dexamethasone), melflufen and dexamethasone.  
 
The number and percentage of patients experiencing TEAEs, as well as total event count (except 
for summaries by toxicity grade), will be summarized by MedDRA SOC and PT for:  
• TEAEs 
• Non-serious TEAEs 
• Treatment related (related to melflufen and/or dexamethasone) TEAEs 
• Melflufen related TEAEs 
• Dexamethasone related TEAEs 
• Serious TEAEs 
• Treatment related serious TEAEs 


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• Melflufen related serious TEAEs 
• Dexamethasone related serious TEAEs  
• TEAEs by CTCAE toxicity grade 
• Treatment related (related to melflufen and/or dexamethasone) TEAEs by CTCAE toxicity 
grade 
• Melflufen related TEAEs by CTCAE toxicity grade 
• Dexamethasone related TEAEs by CTCAE toxicity grade 
• Serious TEAEs by CTCAE toxicity grade 
• Treatment related serious TEAEs by CTCAE toxicity grade 
• Melflufen related serious TEAEs by CTCAE toxicity grade 
• Dexamethasone related serious TEAEs by CTCAE toxicity grade 
• TEAEs resulting in any treatment modification (hold, reduction, delay, interruption and 
discontinuation) for any study drug and also separately for melflufen and dexamethasone 
 
The number and percentage of patients with grouped AEs – TEAEs defined as follows: 
• Thrombocytopenia (SMQ “Haematopoietic thrombocytopenia” – Broad scope) 
• Neutropenia (PTs: “Neutropenia”, “Neutrophil count decreased”, “Febrile neutropenia”, 
“Neutropenic sepsis”, “Neutropenic infection”, “Cyclic neutropenia”, “Band neutrophil 
count decreased”, “Band neutrophil percentage decreased”, “Neutrophil percentage 
decreased”, “Agranulocytosis”, “Granulocyte count decreased”, “Granulocytopenia)  
• Anemia ( SMQ “Haematopoietic erythropenia” – Broad Scope) 
• Myelodysplastic syndrome (PTs: “5q minus syndrome”, “Chronic myelomonocytic 
leukemia”, “Myelodysplastic syndrome”, “Myelodysplastic syndrome transformation”, 
“Myelodysplastic syndrome unclassifiable”, “Refractory anemia with an excess of blasts”, 
“Refractory anemia with ringed sideroblasts”,”Refractory cytopenia with multilineage 
dysplasia”, “Refractory cytopenia with unilineage dysplasia”, “Sideroblastic anemia”) 
• Second primary malignancies ((SMQ “Malignant or unspecified tumours” and HLT 
“Myelodysplastic syndromes”), excluding HLGT “Plasma cell neoplasms”) 
• Febrile neutropenia (PT “Febrile neutropenia”) 
• Infections ( SOC “Infections and infestations”) 


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• Infective pneumonia – broad scope (SMQ “Infective pneumonia”) 
• Infective pneumonia – narrow scope (SMQ “Infective pneumonia” – Narrow terms) 
• Hemorrhage (SMQ “Haemorrhages” – Narrow terms) 
• Thrombocytopenia concomitant to hemorrhage: Hemorrhage with an onset date within ± 7 
days of the onset and/or resolution date of a grade 3 or 4 thrombocytopenia. Grade 3/4 
thrombocytopenia resolution date is to be identified based on the laboratory data as a first 
day when thrombocytopenia assessment is grade 2 or lower (grade ≤ 2 for toxicity “Platelet 
count decreased”). 
• Neutropenia concomitant to infection: Infection with an onset date within ± 7 days of the 
onset and/or resolution date of a grade 3 or 4 neutropenia. Grade 3/4 neutropenia resolution 
date is to be identified based on the laboratory data as a first day when neutropenia 
assessment is grade 2 or lower (grade ≤ 2 for toxicity “Neutrophil count decreased”).  
 
The groups above will be summarized as a separate summaries for TEAEs by SOC, PT and TEAEs 
by SOC, PT, CTCAE toxicity grade analyses.  
For by-cycle reporting, an AE is assigned to particular cycle if started at or after the date and time 
of the study treatment (earliest of melflufen and dexamethasone administration at particular cycle) 
administration at particular cycle and prior to the date and time of treatment administration in a 
subsequent cycle. If a patient discontinued somewhere in between the cycles, the AE is assigned 
to the cycle in which the discontinuation has happened. 
A patient reporting the same TEAE more than once will only be counted once when calculating 
incidence:  
1) within a given SOC 
2) within a given SOC and PT combination or MedDRA SMQ 
The maximum CTCAE toxicity grade and strongest causal relationship to study treatment for the 
event will be used in the incidence calculations. For by cycle presentation the maximum toxicity 
grade will be identified separately within each cycle.  
TEAEs reported with a causality assessment of “Probably Related” and “Possibly Related” are to 
be considered as “Related” for the analysis purposes. AEs having both onset and end dates missing 
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considered a TEAE unless the end date is prior to the date of the first dose of study drug (the 
earliest of melflufen and dexamethasone start date). 
A separate summary by sequence arms will present the number and percentage of patients who 
died during the study treatment period (between the first dose of melflufen/dexamethasone up to 
30 days after last dose of melflufen/dexamethasone) and on follow-up (more than 30 days after 
last melflufen/dexamethasone dose) along with the reason for deaths as well as the number of 
patients died within 60 days after first melflufen/dexamethasone dose.  
 
Listings will be provided for patients experiencing AEs, SAEs, AEs resulting in drug withdrawal 
and events with fatal outcome. 
 
7.8.4 LABORATORY DATA 
 
Laboratory data will be summarized for Safety analysis set by sequence treatment arms.  
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units on Study Data Tabulation Model (SDTM) level. Only local 
laboratory data will be used for the summaries, however both local and central results will be 
presented in the listings.  
Hematology and chemistry parameters will be summarized descriptively and changes from 
baseline to post-baseline visits for each parameter will be presented. Urinalysis results will only 
be listed.  
All the data from both scheduled and unscheduled time points will be included in the CTCAE 
grade shift tables. 
Shift tables for the change in CTCAE grade (with separate parts for decreased and increased 
grades) will be constructed for hematology and chemistry laboratory parameters, which have 
corresponding CTCAE grades to tabulate changes in NCI CTCAE (version 5.0) from baseline to 
worst post-baseline on study (up to and including EOT visit) CTCAE grade. Number of patients 
with grade 3 or higher toxicity will be summarized as counts and percentages by cycle.  A separate 
listing of all laboratory results corresponding to grade 3 or 4 will be provided.   
The following list of parameters that will be presented in the toxicity grades laboratory tables: 
•  Hematology 


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o Hemoglobin (increase , decrease) 
o Platelets (decrease) 
o White blood cells (WBC) (increase, decrease) 
o Absolute neutrophil count (ANC) (decrease) 
o Lymphocyte count (increase, decrease) 
• Serum Chemistry 
o Alanine aminotransferase (ALT) (increase) 
o Aspartate aminotransferase (AST) (increase) 
o Alkaline phosphatase (increase) 
o Total bilirubin (increase) 
o Creatinine (increase) 
o Calcium (increase, decrease) 
o Glucose (increase, decrease) 
o Albumin (decrease) 
o Uric Acid/Urate (increase) 
o Magnesium (increase, decrease) 
o Phosphorus/Phosphate (increase , decrease) 
o Potassium (increase, decrease) 
o Sodium (increase, decrease) 
o eGFR (decrease) 
 
For hemoglobin, ANC and platelet counts, CTCAE grade shift tables will also be additionally 
presented by cycles. For by cycle presentation the worst grade is calculated within each cycle. 
Time from the date of the melflufen dose until the date of grade 3, grade 4 and grade 3/4 onset in 
particular cycle will be presented for each cycle for ANC and platelets. Time to onset of grade 3, 
grade 4 and grade 3/4 for ANC and platelets will also be presented overall (duration in days from 
the treatment start until the date of grade 3, grade 4 and grade 3/4 respectively). 
For laboratory results reported with a prefix, for example "<" or ">", the value derived from the 
reported results without a prefix will be analyzed. 
All laboratory data will be listed, including toxicity grades and normal ranges. A listing will be 
provided for urine pregnancy tests as well. 


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7.8.5 VITAL SIGNS  
 
Vital signs will be summarized for the Safety analysis set by sequence treatment arms. 
Results and change from baseline to post-baseline time-points for weight, blood pressure, pulse, 
respiratory rate and temperature will be presented. 
 
7.8.6 
PHYSICAL EXAMINATION 
 
Physical examination will only be listed without a summary. 
 
 
ECG data will be summarized for Safety analysis set by sequence treatment arms. 
ECG data (heart rate, PR interval, QRS interval, QT interval, QTc-Fridericia (QTcF) interval, RR 
interval) will be summarized using descriptive statistics, changes from baseline to EOT visit will 
also be evaluated.  
Shift tables from baseline (Normal/Abnormal-clinically significant/Abnormal – not clinically 
significant) to each visit will be summarized for ECG interpretation data.   
All ECG data collected will be presented in the listing. 
7.9 
EXPLORATORY ENDPOINTS AND ANALYSIS 
7.9.1 BIOMARKERS 
 
DNA and RNA-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) 
and will be managed by the sponsor. 
7.9.2 TREATMENT SATISFACTION AND QUALITY OF LIFE (QOL) 
 
Treatment satisfaction and QOL will be analyzed for Safety analysis either by sequence or 
combined treatment arms as specified in this section below. 
Patient satisfaction and preference, nurse convenience and preference  
 
An 11-point numerical rating scale (NRS) will be used to measure patient treatment satisfaction 
after central and peripheral i.v. administration of melflufen. The scale ranges from 0-10, 
7.8.7 
12-LEAD ELECTROCARDIOGRAM (ECG)


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where “0” represents no satisfaction, and “10” represents very satisfied. For patient satisfaction 
and preference scales, the number and percentage of patients having particular score assigned to a 
particular question will be presented by combined treatment arms by cycle. The results will also 
be analyzed by means of numeric descriptive statistics (n, mean, SD, median and etc.). 
 
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. For nurse convenience and preference scales, the number and 
percentage of nurses having particular score assigned to a particular question will be presented by 
combined treatment arms by cycle. The results will also be analyzed by means of numeric 
descriptive statistics (n, mean, SD, median and etc.). 
 
A separate summary by sequence group and overall will present the number and percentage of 
patients and nurses who preferred PVC or CVC route of administration. Also a cross-tabulation 
summary presenting the number and percentage of nurses and patients who had the same or 
different preferences will be created. 
 
EQ-5D-5L 
 
EQ-5D-5L questionnaire consists of two parts – the EQ-5D-5L descriptive system and the EQ 
VAS and will be presented by sequence treatment arms.  
For EQ-5D-5L descriptive system the number and percentage of patients for each score within the 
dimension will be presented. Shift table from baseline to post-baseline assessments will be used 
for analysis of results changes. 
EQ VAS will be analyzed by means of descriptive statistics and change from baseline.  
In addition, the EQ Index will be identified at each time point comparing health state to US value 
set and analyzed the same as EQ VAS. 
 
Use of health services and hospitalization 
 
The number of health services used and the number of days of hospitalization will be summarized 
by means of descriptive statistics by sequence treatment arms. 


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7.10 OTHER ENDPOINTS AND ANALYSIS 
7.10.1 PHARMACOKINETICS 
 
PK parameters will be calculated and provided by the Sponsor using Non-Compartmental Analysis 
(NCA) and the software Phoenix WinNonlin® version 8.2 or later (Pharsight Corporation, 
U.S.A.). The following PK parameters will be assessed for melflufen, desethyl-melflufen and 
melphalan: 
 
• Cmax 
 
Cmax is defined as the maximum observed drug concentration observed in plasma over all PK 
sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. 
If there is no measurable concentration in the subject’s PK profile, then Cmax will be missing 
for that subject. Cmax will be reported in units of ng/mL. 
 
• Time of maximum concentration (Tmax) 
 
Time of maximum plasma concentration (Tmax) is defined as the time at which the Cmax occurs. 
It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable 
Cmax in the subject’s PK profile, then Tmax will be missing for that subject. Tmax will be reported 
in minutes. 
 
• AUC(0-t)  
 
AUC(0-t) is defined as the area under the concentration-time curve from dosing (time 0) to the 
time of the last measured concentration. AUC(0-t) will be estimated using the Linear Up Log 
Down calculation method and obtained from the AUClast parameter calculated by 
WinNonlin®. 
  
• AUC(0-∞) 
 
AUC(0-∞) is defined as the total area under the concentration-time curve from start of infusion 
(time 0) to the limit as the end time becomes arbitrarily large. AUC(0-∞) will be obtained from 
the AUCINF_obs parameter calculated by WinNonlin®. 
 




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Table 5. PK parameters to be calculated 
Phoenix WinNonLin ID 
Unit 
Parameter code 
CDISC submission value 
Rsq 
R2 
R Squared 
Rsq_adjusted 
R2ADJ 
R Squared Adjusted 
Corr_XY 
CORRXY 
Correlation Between TimeX and Log ConcY 
No_points_lambda_z 
LAMZNPT 
Number of Points for Lambda z 
Lambda_z 
min 
LAMZ 
Lambda z 
Lambda_z_int 
ng/mL 
LAMZINT 
Lambda z Intercept  
Lambda_z_lower 
min 
LAMZLL 
Lambda z Lower Limit 
Lambda_z_upper 
min 
LAMZUL 
Lambda z Upper Limit 
Lambda_z_span 
min 
LAMZSPN 
Lambda z Span  
*HL_Lambda_z 
min 
LAMZHL 
Half-Life Lambda z 
*Tmax 
min 
TMAX 
Time of CMAX 
*Cmax 
ng/mL 
CMAX 
Max Conc 
Cmax_D 
ng/mL/mg 
CMAXD 
Max Conc Norm by Dose 
Tlast 
min 
TLST 
Time of Last Nonzero Conc 
Clast 
ng/mL 
CLST 
Last Nonzero Conc 
Clast_pred 
ng/mL 
CLSTP 
Last Nonzero Conc Pred  
*AUClast 
min*ng/mL 
AUCLST 
AUC to Last Nonzero Conc 
AUClast_D 
min*ng/mL 
AUCLSTD 
AUC to Last Nonzero Conc Norm by Dose  
AUCall 
min*ng/mL 
AUCALL 
AUC All 
*AUCINF_obs 
min*ng/mL 
AUCIFO 
AUC Infinity Obs 
AUCINF_D_obs 
min*ng/mL/mg 
AUCIFOD 
AUC Infinity Obs Norm by Dose 
AUC_%Extrap_obs 
% 
AUCPEO 
AUC %Extrapolation Obs 
Vss_obs 
L 
VSSO 
Vol Dist Steady State Obs  
Vz_obs 
L 
VZO 
Vz Obs  
Cl_obs 
L/min 
CLO 
Total CL Obs 
AUCINF_pred 
min*ng/mL 
AUCIFP 
AUC Infinity Pred 
AUCINF_D_pred 
min*ng/mL/mg 
AUCIFPD 
AUC Infinity Pred Norm by Dose 
AUC_%Extrap_pred 
% 
AUCPEP 
AUC %Extrapolation Pred 
Vss_pred 
L 
VSSP 
Vol Dist Steady State Pred  
Vz_pred 
L 
VZP 
Vz Pred  
Cl_pred 
L/min 
CLP 
Total CL Pred 
AUMClast 
min*min*ng/mL 
AUMCLST 
AUMC to Last Nonzero Conc 
AUMCINF_obs 
min*min*ng/mL 
AUMCIFO 
AUMC Infinity Obs 
AUMC_%Extrap_obs 
% 
AUMCPEO 
AUMC % Extrapolation Obs 


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AUMCINF_pred 
min*min*ng/mL 
AUMCIFP 
AUMC Infinity Pred 
AUMC_%Extrap_pred 
% 
AUMCPEP 
AUMC % Extrapolation Pred 
MRTlast 
min 
MRTIVLST 
MRT Intravasc to Last Nonzero Conc 
MRTINF_obs 
min 
MRTIVIFO 
MRT Intravasc Infinity Obs 
 MRTINF_pred 
min 
MRTIVIFP 
MRT Intravasc Infinity Pred 
* Summarized with descriptive statistics as continuous variables and with the geometric mean and geometric coefficient of 
variation. 
 
Cmax and Tmax will be presented with the same number of decimals as the concentration 
measurements and time points, while the derived PK variables will be presented with an 
appropriate number of significant digits based on the general practice.  
 
It may be necessary to exclude individual PK profiles because they are erroneous or abnormal, e.g. 
protocol violation, documented sample handling errors etc. Such data will not be used for analysis 
and any excluded data should be flagged in the listings and the reason for exclusion should be 
documented. 
 
Statistical methods 
 
Descriptive statistics for drug concentrations by time point and PK variables will be provided for 
melflufen, melphalan and desethyl-melflufen by route of administration. For Cmax, Tmax, 
AUC(0-t), AUC(0-∞),  and t½ arithmetic mean ± SD, geometric mean with coefficient of variation 
(CV%), median with minimum and maximum will be given by route of administration. Other PK 
parameters will be provided in a listing. 
 
Geometric mean and geometric CV% will be calculated as follows: 
𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚= GeoMean =  𝑒𝑒𝑒𝑒𝑒𝑒[{𝑙𝑙𝑙𝑙(𝑦𝑦1) + ⋯+ 𝑙𝑙𝑙𝑙(𝑦𝑦𝑛𝑛)} 𝑛𝑛
⁄ ] , 
𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑= 𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺=  𝑒𝑒𝑒𝑒𝑒𝑒[𝑆𝑆𝑆𝑆{𝑙𝑙𝑙𝑙(𝑦𝑦1), … , 𝑙𝑙𝑙𝑙(𝑦𝑦𝑛𝑛)}] , and 
𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐶𝐶𝐶𝐶 (%) = 𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺=  100 × ඥ𝑒𝑒𝑒𝑒𝑒𝑒{𝑙𝑙𝑙𝑙(𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺)}2 −1 , 
 
where SD is the arithmetic standard deviation. 
A mean value graph (with arithmetic means) by administration route will be generated for 
melflufen, melphalan and desethyl-melflufen concentrations in plasma from all subjects based on 
planned time (min) relative to start of melflufen infusion. Individual line plots for concentrations 
will also be created.  
Formal statistical analysis will for each compound be performed on the PK parameters AUC (0-t), 


Statistical Analysis Plan: OP-109 
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AUC(0-∞) 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 site of infusion (administration route: PVC or CVC) as 
fixed effects and subject nested within sequence as a random effect. Adjusted geometric mean 
ratios (GMRs) and 90% CIs for the adjusted GMRs for the comparisons between central and 
peripheral administration will be provided. 
The following SAS code will be used for the analyses (variable names to be updated accordingly): 
 
proc mixed data= datasetname;  
      class sequence period trt subject;  
      model logAVAL=sequence period trt /   ddfm=kenwardroger;  
      random subject(sequence); 
      estimate 'CVC vs PVC' trt 1 -1 / cl alpha=0.1;  
      ods output estimates=est; 
     run; 
      
 where trt refers to administration route (PVC or CVC). 
GMR with 90% CI is calculated as the exp(estimate of trt comparison in log scale). 
A 90% CI of the GMR outside 0.8-1.25 is assessed to be a clinically meaningful difference for 
melphalan Cmax and AUC. No corresponding criteria will be applied for melflufen or desethyl-
melflufen as data from clinical studies show no relationship between their PK parameters and 
indicators of bone marrow toxicity.  
7.10.2 ECOG 
 
ECOG performance status will be summarized by sequence arms as counts and percentages using 
shift tables of baseline versus worst performance status (largest ECOG value) during the study.  
Also, the number of patients with decrease of ≥1 unit and ≥2 units respectively at the last available 
visit and at the End of Treatment visit will be summarized as counts and percentages to reflect the 
level of improvement in ECOG values. 
 
8. 
INTERIM ANALYSIS 
 
When the PK and peripheral safety study are completed, an interim CSR will be written. The 
interim analyses will include at least 20 patients who have received two melflufen doses of 40 mg, 
have an observation period of 28 days after the second dose and at least one peripheral i.v. infusion. 


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The objective of the interim CSR will be to evaluate if a peripheral i.v. infusion of melflufen can 
be introduced in other trials, as an alternative to central i.v. infusion. The interim analysis will 
include PK analysis described in the Section 7.10.1 of this SAP and safety analysis described in 
the Section 7.8 of this SAP. Due to the short duration of treatment, efficacy endpoints will not be 
included in the interim CSR.  
 
9. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE 
PROTOCOL 
 
 
As per the protocol all safety analyses are supposed to be presented by administration group. 
However during SAP development discussions presentation by sequence arms was found more 
relevant for most of the safety analyses as providing sufficient information and avoiding confusion 
in analysis and interpretation due to treatment shifts.   
 
10. PROGRAMMING SPECIFICATIONS 
 
All outputs will be produced using SAS version 9.4 or a later version. 
The margins should be at least 1.50 inches for the binding edge and 1.0 inches for all others.  
In the top left portion of each table/listing, the protocol number will be presented. On the next line 
a table/listing number followed by the title of the table/listing and population information will be 
displayed. Horizontal lines will appear after the column heading of the table/listing. Footnotes will 
be put under the main body of text at the bottom of the page. The source listing number will be 
displayed for all tables. The SAS program name will appear bottom left in a string and the page 
number will appear on the bottom right corner of each table/listing. The date and time of creation 
of table/listing will appear bottom left under to the SAS program name line.  
Courier New 8-point bold font will be used for all tables and listings. Usually, a landscape layout 
is suggested for both tables and listings, but it is not mandatory. Any date information in the listing 
will use the date9. format, for example, 07MAY2002. 
Shells for unique tables and listings are provided in a separate Mock-Up TFLs document. 
11. 
REFERENCES 
 


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Brookmeyer R, Crowley J. A Confidence interval for the median survival time. Biometrics; 
1982; 38: 29-41. 
 
Kumar SK, et al. Natural history of relapsed myeloma, refractory to immunomodulatory 
drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia (2017) 31, 2443–
2448. 
 
Palumbo A, et al. Revised International Staging System for Multiple Myeloma: A Report 
from International Myeloma Working Group. Journal of Oncology 2015. 33:26, 2863-2869.