Clinical trial NCT02963493
Conditions: Multiple Myeloma
Keywords: relapsed refractory multiple myeloma
Sponsor: Oncopeptides AB
Start date: 2016-12-28; Completion date: 2021-11-16
Enrollment: 157 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle.

Detailed description:
Melphalan flufenamide (melflufen) is a peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. Peptidases are expressed in several cancers, including solid tumors and hematologic malignancies. Melphalan flufenamide is rapidly taken up by myeloma cells due to its high lipophilicity. Once inside the myeloma cell, the activity of melphalan flufenamide is determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are entrapped. Melphalan flufenamide is 50-fold more potent than melphalan in myeloma cells in vitro due to increased intracellular alkylator concentration. It rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells. Melphalan flufenamide displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, in vitro. Melphalan flufenamide also has demonstrated inhibition of angiogenesis and DNA damage with a lack of functional DNA repair in preclinical studies.

Arms: arm 1: Melphalan flufenamide (melflufen) 40 mg Day 1 and dexamethasone 40 mg (20 mg for patients 75 years or older) on Days 1, 8, 15 and 22 of each 28-day cycle.
Interventions: intervention 1: Melphalan flufenamide (Melflufen) intervention 2: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: IV dexamethasone may be substituted for oral dexamethasone in the US. Oral only in Europe.

Protocol documents:
SAP_002.pdf: 
Melflufen 
 
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Protocol OP-106 Statistical Analysis Plan 
 
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Statistical Analysis Plan   
Protocol OP-106 
 
 
A Single Arm, Open-Label, Phase 2 Study of Melflufen in Combination with 
Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma who are 
Refractory to Pomalidomide and/or an anti-CD38 Monoclonal Antibody 
 
 
 
Investigational Agent:  Melflufen 
 
Sponsor:  
 
Oncopeptides AB 
 
 
 
Västra Trädgårdsgatan 15 
 
 
 
SE-111 53 Stockholm, Sweden 
 
Version:   1  
20 September 2017 
 
       2  
19 July 2019 
 
       3  
7 January 2020 
 
       4  
26 February 2020 
 
       5  
18 October 2020 
 
Confidential Information 
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable laws and regulations.  In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential and may not be further 
disclosed by them.  These restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential. 
 
 


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PREPARED BY: 
 
Biostatistics 
Consultant 
Signed: 
 
Printed name: 
Tonya K Marmon, DrPH 
Precision for Medicine, Oncology and Rare 
Diseases 
Date: 
18-October-2020 
 
APPROVED BY: 
Director of 
Biostatistics 
Signed: 
 
Printed name: 
Pontus Larsson, MSc 
Oncopeptides AB 
Date: 
23-October-2020 
 
REVIEWED BY: 
 Study Physician Signed: 
 
Printed name: 
Johan Harmenberg, MD, PhD  
Oncopeptides AB 
Date: 
20-October-2020 
 
 


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DOCUMENT HISTORY 
Version 
Modified by 
Description of Changes 
Version 1.0 
20 Sep 2017 
J. Michael White 
Biostatistics Consultant, 
Precision for Medicine 
Initial version 
Version 2.0 
19 Jul 2019 
J. Michael White 
Biostatistics Consultant, 
Precision for Medicine 
Updates for protocol amendment 6, 
2019-03-04 
 
Triple-class refractory added as a 
subgroup of specific interest in all 
analyses. 
Version 3.0 
07 Jan 2020 
Pontus Larsson 
Sr Project Statistician, 
Oncopeptides AB 
General restructuring of document. 
 
Discussion on available therapies and 
expected treatment effect added. 
 
Clarification of objectives and endpoints 
in relation to scientific rationale for NDA 
submission. 
 
Clarification on use of triple-class 
refractory as main subgroup for 
analyses. EMD added as a subgroup of 
specific interest for some analyses.  
 
Clarification of analytical definitions. 
Version 4 
26 Feb 2020 
Pontus Larsson 
Director of Biostatistics, 
Oncopeptides AB 
Clarification of definitions for analysis 
populations.  
 
Clarification of threshold used for 
establishing efficacy. 
 
Clarification on scope for Clinical Study 
Report. 
Version 5 
18 Oct 2020 
Pontus Larsson 
Director of Biostatistics, 
Oncopeptides AB 
Other secondary endpoints of QLQ-C30 
and EQ-5D-3L clarified and added, for 
an appendix to the Clinical Study 
Report to be submitted to European 
Medicinal Agency. 
  
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
ADaM 
Analysis Data Model 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT (SGPT) 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase 
ATC 
Anatomical/Therapeutic/Chemical 
BSA 
body surface area 
C1D1 
Cycle 1 Day 1 
CBR 
clinical benefit rate 
CDISC 
Clinical Data Interchange Standards 
Consortium 
CM 
concomitant medication 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
dFLC 
difference in serum free light chains 
DOR 
duration of response 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMD 
extramedullary disease 
EORTC 
European Organisation for Research and 
Treatment of Cancer 
EQ-5D-3L 
EuroQol-5 Dimensions 3 Level 
EQ VAS 
visual analogue scale of the EQ-5D-3L 
FAS 
Full analysis set 


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Abbreviation or Term 
Definition 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
HRQoL 
health related quality of life 
IMiD 
immunomodulatory drug 
IMWG-URC 
International Myeloma Working Group-Uniform 
Response Criteria 
IRC 
independent review committee 
ISS 
international staging system 
ITT 
intention-to-treat 
kg 
kilogram(s) 
K-M 
Kaplan-Meier 
LDH 
lactase dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
min 
minute 
M-protein 
monoclonal protein spike 
MM 
multiple myeloma 
MR 
minimal response 
NCI 
National Cancer Institute 
NDA 
new drug application 
NE 
not evaluable 
OR 
overall response 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
PI 
proteasome inhibitor 
PR 
partial response 
PRO 
Patient Reported Outcome 
PT 
preferred term 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QoL 
quality of life 


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Abbreviation or Term 
Definition 
QT 
Interval of time from the start of the Q wave to 
the end of the T wave 
QTcF 
Fridericia's formula for the interval of time from 
the start of the Q wave to the end of the T 
wave, corrected for heart rate 
RR 
interval of time between QRS complexes 
RRMM 
relapsed and refractory multiple myeloma 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SD 
standard deviation; stable disease (depending 
on context) 
SDG 
(WHO DD) 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 
TEAE 
treatment emergent adverse event 
TTNT 
time to next treatment 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal range 
UPEP 
urine protein electrophoresis 
VAS 
visual analogue scale 
VGPR 
very good partial response 
WBC 
white blood cell count 
WHO 
World Health Organization 
 
 
 


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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................... 3 
LIST OF ABBREVIATIONS .............................................................................. 4 
TABLE OF CONTENTS .................................................................................... 7 
1 
INTRODUCTION ....................................................................................... 12 
2 
OVERVIEW OF STUDY DESIGN ............................................................. 12 
3 
AVAILABLE THERAPIES AND EXPECTED TREATMENT 
EFFECT ................................................................................... 13 
4 
STUDY OBJECTIVES AND ENDPOINTS ................................................ 13 
4.1 
Primary Objective .................................................................... 13 
4.1.1 
Primary Endpoint ..................................................................... 14 
4.2 
Key Secondary Objectives ....................................................... 14 
4.2.1 
Safety and Tolerability Endpoints ............................................ 14 
4.2.2 
Key Secondary Efficacy Endpoints .......................................... 14 
4.3 
Other Secondary Objectives .................................................... 14 
4.3.1 
Other Secondary Endpoints ..................................................... 15 
4.3.2 
Patient Reported Outcomes (PRO) endpoints ......................... 15 
5 
DETERMINATION OF SAMPLE SIZE ..................................................... 15 
6 
ANALYSIS POPULATIONS ..................................................................... 17 
6.1 
Analysis Sets ........................................................................... 17 
6.2 
Subgroups of Specific Interest ................................................. 17 
7 
DATA MANAGEMENT ............................................................................. 18 
7.1 
Data Cut-Off ............................................................................. 18 
7.2 
Data Validation and Database Lock ......................................... 18 
7.3 
Data Standards ........................................................................ 18 
8 
ANALYTIC DEFINITIONS ........................................................................ 18 
8.1 
General .................................................................................... 18 
8.1.1 
Study Day 1 ............................................................................. 18 
8.1.2 
Study Day ................................................................................ 19 


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8.1.3 
Baseline ................................................................................... 19 
8.1.4 
Unscheduled Visits .................................................................. 19 
8.1.5 
Duration ................................................................................... 20 
8.2 
Medical Coding ........................................................................ 21 
8.2.1 
MedDRA .................................................................................. 21 
8.2.2 
WHO Drug Dictionary .............................................................. 21 
8.3 
Patient Characteristics ............................................................. 21 
8.3.1 
Age .......................................................................................... 21 
8.3.1 
Geographic Region .................................................................. 21 
8.4 
Disease Characteristics ........................................................... 21 
8.4.1 
Time Since Initial Diagnosis ..................................................... 21 
8.4.2 
Prior and Concomitant Medications ......................................... 22 
8.4.1 
Therapeutic Drug Classes ....................................................... 22 
8.4.2 
Prior Regimens ........................................................................ 22 
8.4.3 
Refractory Status ..................................................................... 23 
8.4.4 
Transplants .............................................................................. 23 
8.4.5 
Cytogenetic Risk Groups ......................................................... 24 
8.4.6 
International Staging System (ISS) .......................................... 24 
8.4.7 
Monoclonal Protein Spike (M-protein) ...................................... 25 
8.4.8 
Plasma Cell Involvement ......................................................... 26 
8.4.9 
Presence of Bone Lesions and Extramedullary Disease (EMD)26 
8.5 
Myeloma and Safety Laboratory Assessments (Hematology, 
Coagulation, and Serum Chemistry) ............................................................ 26 
8.5.1 
Unit Conversion ....................................................................... 26 
8.5.2 
Derived Laboratory Parameters and Subgroups ...................... 29 
8.5.3 
Toxicity Grades ........................................................................ 30 
8.6 
Myeloma Response Parameters .............................................. 31 
8.6.1 
Response Rates ...................................................................... 31 
8.6.2 
Progression Free Survival (PFS) ............................................. 31 
8.6.3 
Duration of Response (DOR) ................................................... 32 


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8.6.4 
Time to Response (TTR) ......................................................... 32 
8.6.5 
Time to Progression (TTP) ....................................................... 33 
8.6.6 
Time to Next Treatment (TTNT) ............................................... 33 
8.6.7 
Duration of Stable Disease ...................................................... 33 
8.6.8 
Duration of Disease Stabilization ............................................. 33 
8.6.9 
Duration of Clinical Benefit ....................................................... 34 
8.6.10 
Overall Survival ........................................................................ 34 
8.6.11 
Assessments by Independent Review Committee (IRC) ......... 34 
8.6.12 
Long Term Follow-up for PFS and OS ..................................... 34 
8.7 
Functional Status and Well-being ............................................ 34 
8.7.1 
EQ-5D-3L ................................................................................. 34 
8.7.2 
EORTC QLQ-C30 .................................................................... 35 
8.7.3 
Evaluable HRQoL at Cycle 4 ................................................... 35 
8.8 
Exposure .................................................................................. 36 
8.8.1 
Overall Study Drug Exposure .................................................. 36 
8.8.2 
Melflufen Exposure .................................................................. 36 
8.8.3 
Dexamethasone Exposure....................................................... 36 
8.8.4 
Action Taken with Study Drug .................................................. 37 
8.9 
Safety Evaluation ..................................................................... 37 
8.9.1 
Adverse Events ........................................................................ 37 
8.9.2 
Dose Modifications due to Adverse Event ............................... 39 
8.9.3 
Adverse Events of Special Interest .......................................... 39 
8.9.4 
Deaths ..................................................................................... 39 
8.10 
Protocol Deviations .................................................................. 40 
9 
STATISTICAL METHODS ........................................................................ 40 
9.1 
General Considerations ........................................................... 40 
9.2 
Disposition of Patients ............................................................. 41 
9.3 
Protocol Deviations .................................................................. 41 
9.4 
Demographic, Baseline Characteristics, and Prior Therapy ..... 42 
9.4.1 
Demographic and Baseline Characteristics ............................. 42 


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9.4.2 
Medical History ........................................................................ 42 
9.4.3 
Disease Characteristics ........................................................... 42 
9.4.4 
Prior Myeloma Therapy............................................................ 43 
9.4.5 
Prior and Concomitant Medications ......................................... 44 
9.5 
Efficacy Analyses ..................................................................... 44 
9.5.1 
Response Rates ...................................................................... 44 
9.5.2 
Changes in M-protein .............................................................. 45 
9.5.3 
Progression Free Survival........................................................ 45 
9.5.4 
Duration of Response (DOR) ................................................... 45 
9.5.5 
Time to Response (TTR) ......................................................... 45 
9.5.6 
Time to Progression (TTP) ....................................................... 45 
9.5.7 
Time to Next Treatment (TTNT) ............................................... 46 
9.5.8 
Duration of Stable Disease ...................................................... 46 
9.5.9 
Duration of Disease Stabilization ............................................. 46 
9.5.10 
Duration of Clinical Benefit ....................................................... 46 
9.5.11 
Overall Survival (OS) ............................................................... 46 
9.5.12 
Analyses by Subgroups ........................................................... 46 
9.5.13 
Assessments by IRC ............................................................... 47 
9.5.14 
Functional Status and Well-being ............................................. 48 
9.6 
Safety Analysis ........................................................................ 48 
9.6.1 
Exposure .................................................................................. 49 
9.6.1.1 
Overall Study Drug Exposure ........................................................................... 49 
9.6.1.2 
Melflufen Exposure .......................................................................................... 49 
9.6.1.3 
Dexamethasone Exposure ............................................................................... 50 
9.6.2 
Adverse Events ........................................................................ 50 
9.6.3 
Adverse Events of Special Interest .......................................... 50 
9.6.4 
Deaths ..................................................................................... 51 
9.6.5 
Hematology, Serum Chemistry, and Coagulation .................... 51 
9.6.6 
Vital Signs ................................................................................ 51 


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9.6.7 
ECOG Performance Status ...................................................... 52 
9.6.8 
Physical Examination ............................................................... 52 
9.6.9 
12-Lead Electrocardiograms .................................................... 52 
9.6.10 
Analyses by Subgroups ........................................................... 52 
10 STATISTICAL/ANALYTICAL ISSUES ..................................................... 53 
10.1 
Handling of Dropouts or Missing Data ..................................... 53 
10.1.1 
Efficacy Assessments .............................................................. 53 
10.1.2 
Safety Assessments ................................................................ 53 
10.1.2.1 
Adverse Events ................................................................................................. 53 
10.1.2.2 
Laboratory Assessments .................................................................................. 53 
10.1.3 
Dates and Times ...................................................................... 54 
10.2 
Multiplicity ................................................................................ 54 
10.3 
Data Maturity ........................................................................... 55 
10.4 
Interim Analysis for Futility ....................................................... 55 
10.5 
Changes to Planned Analyses ................................................. 55 
10.5.1 
Protocol Amendments ............................................................. 55 
10.5.2 
Analysis Sets ........................................................................... 56 
10.5.3 
Subgroups of Specific Interest ................................................. 56 
10.5.4 
Objectives and Endpoints ........................................................ 57 
10.5.5 
Clinical Study Report ............................................................... 57 
11 REFERENCES .......................................................................................... 58 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) was prepared in accordance with version 7.0 
(amendment 6) of the protocol for study OP-106, dated 4 March 2019.  It 
specifies the main safety and efficacy analyses to be performed for the clinical 
study report (CSR).   
Any changes that are made to the planned analyses after the SAP is finalized, 
along with an explanation as to when and why they occurred, will be noted in the 
CSR produced for the study.  Any changes made to the planned analyses that 
are in the protocol are summarized in section 10.5 of this document. 
2 
OVERVIEW OF STUDY DESIGN  
This is a single arm, open-label, Phase 2 multicenter study which will enroll 
patients with relapsed and refractory multiple myeloma (RRMM) following at least 
2 lines of prior therapy, including a drug classified as an immunomodulatory drug 
(IMiD) and a drug classified as a proteasome inhibitor (PI), and who are 
refractory to pomalidomide and/or an Anti-CD38 Monoclonal Antibody.  
Refractory is defined in Section 8.4 of this SAP.  A total number of approximately 
150 patients are planned to be enrolled in the study, to achieve 130 patients 
evaluable for efficacy, and 50 patients evaluable for EQ-5D-3L.  
Patients will be treated with melflufen 40 mg on Day 1 and dexamethasone 40 
mg on Days 1, 8, 15 and 22 of each 28-day cycle.  Patients ≥ 75 years of age will 
have a reduction of the starting dose of dexamethasone from 40 mg to 20 mg on 
the same schedule. 
Patients may receive treatment until there is documented disease progression, 
unacceptable toxicity or the patient/treating physician determine it is not in the 
patient’s best interest to continue. 
Dose modifications and delays in therapy may be implemented based on patient 
tolerability as detailed in the protocol. 
The initial study design proposed to enroll patients refractory to pomalidomide 
and patients refractory to daratumumab (an anti-CD38 mAb) separately to 
evaluate clinical benefit in both groups, with a target enrollment of up to 
approximately 39 efficacy-evaluable (per protocol section 11.4.2.1, different from 
the definition in section 6.1) patients per group. However, the study was later 
amended (in protocol version 5, 31 May 2018) to assess the total population and 
expand the sample size to encompass approximately 150 patients. Based on 
regulatory considerations, a subgroup of specific interest was subsequently (in 
protocol version 7, 4 March 2019) identified, i.e., triple-class refractory patients 
defined as patient’s refractory to all 3 currently approved classes of drugs (IMiDs, 
PIs and anti-CD38 mAbs). This group was identified as having an unmet medical 


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need, potentially allowing FDA accelerated approval based on ORR and DOR in 
a single arm study. In addition, based on preliminary signals of efficacy in a 
population with poor prognosis, extramedullary disease (EMD) was also 
identified as a subgroup of specific interest. 
The study rationale is summarized in section 2.3 of the protocol. See sections 
10.4 and 10.5.3 of this document regarding the decision to increase the sample 
size and to focus on triple-class refractory as a subgroup of primary interest.    
3 
AVAILABLE THERAPIES AND EXPECTED TREATMENT EFFECT 
Currently, there are no treatments for patients with triple-class RRMM which 
have received FDA regular approval. Patients who are refractory to 5 drugs 
(penta-refractory) can receive selinexor, but a confirmatory trial and regular FDA 
approval are pending for this drug, and thus selinexor is not considered to be 
“available therapy”. Other options for these patients are clinical trials of 
experimental regimens, retreatment with agents belonging to drug classes to 
which their disease has already progressed (relapsed or refractory to the last 
treatment) or hospice/palliative care.  
The different treatment options after becoming refractory to anti-CD38 mAb were 
assessed in a retrospective study [Gandhi, 2019]. None of the 10 assessed 
treatment regimens provided a durable benefit to the patients after anti-CD38 
mAb-refractoriness.  
In a 2017 publication, an overall response rate (ORR) less than 15% was 
observed in RRMM patients who were re-treated with an IMiD or PI after 
becoming refractory to an IMiD and a PI. The ORR decreased as patients 
received more lines of treatment after becoming relapsed-refractory. [Kumar 
2017]. 
Patients who become refractory to the major classes of available anti-myeloma 
therapies have very poor outcomes. Therefore, there is an urgent need for new 
therapies for patients with RRMM who have exhausted available therapies. 
Accordingly, an ORR of at least 15% would represent a clinically relevant 
treatment effect.    
4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 Primary Objective 
The primary objective of this Phase 2 study is to evaluate the efficacy of 
melflufen treatment in RRMM patients.  


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4.1.1 Primary Endpoint   
• Overall response rate (ORR). 
4.2 Key Secondary Objectives 
The secondary objectives of this study are to evaluate the following aspects, 
listed below by order of relevance: 
• Safety and tolerability of melflufen, 
• Duration of response (DOR). 
4.2.1 Safety and Tolerability Endpoints  
• Frequency and grade of treatment emergent adverse events (TEAEs), 
• Frequency and grade of TEAEs of special interest, 
• Frequency of TEAEs leading to dose modifications,  
• Frequency of melflufen dose modifications based on study drug exposure,  
• Treatment duration of melflufen, 
4.2.2 Key Secondary Efficacy Endpoints   
• DOR.   
4.3 Other Secondary Objectives 
Other objectives of this study are to assess the following aspects, listed below by 
order of relevance: 
• Progression free survival (PFS), 
• Overall survival (OS), 
• Clinical benefit rate (CBR), 
• Distribution of response categories, 
• Time to response (TTR), 
• Time to progression (TTP), 
• Change in relevant laboratory parameters,  
• Functional status and well-being. 


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4.3.1 Other Secondary Endpoints   
• PFS, 
• OS, 
• Proportion of patients per categories of best response; i.e. stringent CR 
(sCR), complete response (CR), very good partial response (VGPR), 
partial response (PR) or minimal response (MR),  
• TTR, 
• TTP, 
• Duration of stable disease,  
• Duration of disease stabilization,  
• Duration of clinical benefit, 
• Change from baseline in levels of serum and urine monoclonal protein 
spike (M-protein),  
• Change from baseline in levels of platelet count and absolute neutrophil 
count (ANC),  
4.3.2 Patient Reported Outcomes (PRO) endpoints 
The following clarifications of other secondary endpoints related to PROs, i.e. 
European Organization for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 version 3.0 (QLQ-C30) and EuroQol-5 Dimensions 
3 Level (EQ-5D-3L), were added post hoc in an updated SAP after the primary 
endpoint was evaluated, see section 10.5.510.5.5  
• Change from baseline in QLQ-C30 (i.e. change from baseline in EORTC 
QLQ-C30 summary score, each domain of the EORTC QLQ-C30)   
 
• Change from baseline in EQ-5D-3L (i.e. change from baseline in EQ-5D-3L 
index score, each dimension of the EQ-5D-3L, and the visual analogue 
scale (VAS) of the EQ-5D-3L (EQ VAS)) 
The change from baseline in the symptom scales Fatigue and Pain, and Global 
QoL in QLQ-C30 at Cycle 4 are considered the key PRO endpoints.  
5 
DETERMINATION OF SAMPLE SIZE  
A total number of approximately 150 patients are planned to be enrolled in the 
study, to achieve 130 patients evaluable for efficacy, and 50 patients evaluable 
for EQ-5D-3L. The protocol hypothesizes an observed ORR of 30%, and an 


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exact 95% confidence interval from 22.3% to 38.7%, given a sample size of 130 
patients.   
The sample size assumes that an ORR of 15% to 30% should warrant a positive 
benefit-risk ratio in RRMM, in context of available treatment alternatives for 
these heavily pre-treated patients with a high unmet medical need. Such ORR 
have previously been evaluated for Accelerated Approval by FDA [FDA review of 
selinexor] [Chen, 2019].  
The targeted effect size along with a satisfactory DOR is expected to satisfy 
three regulatory goals needed for accelerated approval:   
1) demonstrating a clinically meaningful ORR and DOR,  
2) demonstrating an advantage over available therapy, and  
3) establishing the contribution of melflufen to the melflufen-dexamethasone 
combination.   
In this setting, an ORR of at least 15% and a strong DOR would represent a 
clinically meaningful treatment effect. Because there is currently no approved 
treatment meeting the regulatory standard of “available therapy” in this setting, 
and no established off-label use of drugs that could be regarded as standard of 
care, the targeted results would also demonstrate an advantage over available 
therapy.  Finally, an ORR of at least 15% would represent a statistically 
significant difference from ORR reported for treatment with dexamethasone 
alone (i.e. ORR 2% for 4 mg dose to 4% for 40 mg dose) [Spicka 2019] 
[POMALYST label] and thus establish the contribution of melflufen to the 
melflufen-dexamethasone combination.    
With a sample size of 110 to 150 patients and an observed ORR of 15%, 20%, 
25% or 30%, the corresponding exact 95% confidence interval (Clopper-Pearson 
method) [Fleiss, 1981] would be ± 7% to 10%, see Table 1.  
Table 1: Exact binomial confidence intervals for ORR per sample size  
Sample size 
n=110 
n=120 
n=130 
n=140 
n=150 
ORR=15% 
9% to 23% 
9% to 23% 
9% to 22% 
10% to 22% 
9% to 21% 
ORR=20% 
13% to 29% 
13% to 28% 
14% to 28% 
14% to 28% 
14% to 27% 
ORR=25% 
17% to 34% 
18% to 34% 
18% to 33% 
18% to 33% 
18% to 32% 
ORR=30% 
22% to 40% 
22% to 39% 
22% to 39% 
23% to 38% 
23% to 38% 
The sample size calculations cover a range of sample sizes that are applicable 
both for the total study population and the triple-class refractory population. The 


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expected number of triple-class refractory patients is approximately 2/3 to 3/4 of 
enrolled patients, i.e. approximately 105 to 120 patients. 
The primary endpoint will be considered met if the lower bound of the 95% 
confidence interval for actual ORR among triple-class refractory patients is higher 
than 15%.  
6 
ANALYSIS POPULATIONS   
6.1 Analysis Sets 
The Full analysis set (FAS) is defined as all patients who fulfil all eligibility criteria 
at screening and prior to initiation of therapy as per study protocol section 7.2, 
and according to intention-to-treat principle as per ICH E9. The FAS will be used 
for summaries of disposition and all analyses of efficacy. 
The Safety analysis set is defined as all subjects who received at least one dose 
of melflufen or dexamethasone. The Safety analysis set will be used for all 
analyses of safety. 
The Efficacy evaluable analysis set as defined in the protocol will not be used for 
any analyses.  
The Health Related Quality of Life (HRQoL) analysis set is defined as all patients 
who have completed at least one of the HRQoL questionnaires both at baseline 
and post-baseline (at least one completed post-baseline assessment). HRQoL 
assessments were added at the time of protocol version 5.0. Only participants 
who enroll on or after protocol version 5.0 will be included in the HRQoL analysis 
set.  
6.2 Subgroups of Specific Interest  
Patients that are triple-class refractory, as defined in section 8.4.3, will be the 
primary subgroup of interest. This subgroup constitutes the majority of patients 
and will be used for all analyses of efficacy and safety. Triple-class refractory is 
the proposed indication for the new drug application (NDA) for accelerated 
approval. 
An additional, secondary subgroup of specific interest specified in this SAP, 
based on preliminary signals of efficacy, are patients with extramedullary disease 
(EMD), as defined in section 8.4.9. This additional subgroup will be presented 
separately for selected analyses. 


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7 
DATA MANAGEMENT 
7.1 Data Cut-Off 
The data cut-off date for the Clinical Study Report (CSR) will be at least 3 months 
after first administration of melflufen to the last patient enrolled. 
Data pertaining to any assessments performed as part of a visit per that date, 
and any AE or CM starting or ending before or on that date will be included in the 
database for the CSR.  
7.2 Data Validation and Database Lock 
Following data cut-off for the CSR, the data will be validated and subject to 
database lock procedures according to the Data Management Plan (DMP). A 
final database lock will be performed after additional data pertaining to long term 
follow-up of QLQ-C30, EQ-5D-3L, PFS and OS has been collected.  
Prior to any analysis, the study data will be reviewed for any data inconsistencies 
and major protocol deviations. Any data inconsistencies remaining after review 
will be documented according to the DMP and Clinical Data Interchange 
Standards Consortium (CDISC) requirements. Any changes made regarding 
analysis sets or analytic definitions will be documented and referred to in the 
CSR.   
7.3 Data Standards 
Study datasets will be developed according to CDISC Study Data Tabulation 
Model (SDTM) Implementation Guide Version 3.2.  All datasets used for the 
analyses and presentations of summary results will be developed according to 
CDISC analysis data model (ADaM) Implementation Guide Version 1.1. The 
source data for all ADaM datasets will be SDTM datasets.  
8 
ANALYTIC DEFINITIONS    
Definitions of terms used for the calculation of derived variables and general 
terms used for the analyses are provided in this section.   
8.1 General 
8.1.1 Study Day 1  
Study Day 1 corresponds to the date of the first dose of any study drug. 


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8.1.2 Study Day  
Unless otherwise specified, the timing of all study-related events, assessments, 
and interventions will be calculated relative to Study Day 1.  For events, 
assessments, and interventions after Study Day 1, study day represents the 
elapsed number of days from Study Day 1, inclusive:   
Study Day n = (Date of assessment – Date of Study Day 1) + 1 day 
Study Day −1 will be the day before Study Day 1, and in general for assessments 
prior to Study Day 1, study day is defined as: 
Study Day n = (Date of assessment – Date of Study Day 1)  
For listings (such as for adverse events) that include the derivation of “days since 
last dose,” this is defined as event date – date of last dose.  Events that occur on 
the same day as the last dose of study drug will therefore be described as 
occurring zero days from the last dose of study drug. 
8.1.3 Baseline  
Unless otherwise specified, the baseline value is defined as the most recent 
assessment prior to administration of the first dose of study drug, melflufen or 
dexamethasone.   
8.1.4 Unscheduled Visits 
All results not taken at a scheduled timepoint are unscheduled. Unscheduled 
assessments are labelled as ‘Unscheduled’ in the listings and will include the 
study day from first dose of all dates. 
Because unscheduled assessments are not associated with any scheduled 
timepoint, they are excluded from all summaries by timepoint.  Unscheduled 
assessments will be considered when deriving myeloma response parameters as 
described in section 8.6. 
The study protocol accepts a time window of ± 3 days for scheduled visits and 
assessments (visit window). In the event multiple protocol-specified assessments 
are reported within the same visit window the value reported for the scheduled 
visit should be used in summaries by timepoint, and if this value is missing or 
unknown the earliest reported value of scheduled and unscheduled assessments 
within the visit window should be used. Derivations using multiple assessments 
should be based on assessments from the same visit.  


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8.1.5 HRQoL Visits 
Baseline value for a HRQoL assessment is defined as the most recent 
assessment prior to administration of the first dose of study drug, melflufen or 
dexamethasone.   
HRQoL assessments are to be administered prior to any other study procedures 
and dosing on Day 1 of each cycle while on treatment or at End of Treatment.  
The HRQoL visits will be derived as Cycle X Day 1, where X corresponds to 
Cycles 2, 4, 6, and 8. The latest HRQoL assessment prior to melflufen Cycle X 
Day 1 dose date will be used for analyses. 
The End of Treatment HRQoL assessment will be derived as the first 
assessment after the last dose of melflufen.   
HRQoL assessments are to be administered monthly after end of treatment with 
each PFS follow up visit.  The HRQoL PFS follow up assessments will be labeled 
as “QOL PFS FU Month X”, where X is derived as the HRQoL assessment date 
within ±7 days of (End of Treatment Date + (X × 30 days)).  For example, QOL 
PFS FU Month 2 will be the HRQoL PFS follow up assessment within 53 to 67 
days of End of Treatment Date. 
OS FUP visit will not be summarized as they are not consistently administered to 
patients, only as indicated. 
8.1.6 Duration  
Duration can be expressed in days, weeks, months, years, or minutes as 
appropriate. 
• Days – Duration expressed in days between one date (date1) and another 
later date (date2) are calculated using the following formula:  
duration in days = (date2- date1+1). 
• Weeks – Durations expressed in weeks between one date (date1) and 
another later date (date2) are calculated using the following formula:  
duration in weeks = (date2-date1+1)/7. 
• Months – Durations expressed in months between one date (date1) and 
another later date (date2) are calculated using the following formula:  
duration in months = (date2-date1+1)/30.4375. 
• Years – Durations expressed in years between one date (date1) and 
another later date (date2) are calculated using the following formula:  
duration in years = (date2-date1+1)/365.25. 


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• Minutes – Durations expressed in minutes between one timepoint (time1) 
and another later timepoint (time2) are calculated using the following 
formula: duration in minutes = (time2-time1)/60. 
8.2 Medical Coding 
8.2.1 MedDRA 
Events recorded as medical history or adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 19.1. Preferred 
term (PT) and system organ class (SOC) will be summarized. 
8.2.2 WHO Drug Dictionary 
All prior systemic cancer therapies as recorded on the Multiple Myeloma History - 
Prior Systemic Cancer Drug Therapy CRF page and prior and concomitant 
medications as recorded on the Concomitant Medications CRF will be coded 
using WHO Drug Dictionary (WHO DD) Enhanced version December 2016 B2.  
Medications are coded to Anatomical/Therapeutic/Chemical (ATC) drug class 
level 4 and preferred drug names.  If ATC drug class level 4 coded is 
unavailable, level is used; if level 3 coding is unavailable, level 2 is used. 
8.3 Patient Characteristics 
8.3.1 Age 
Age is calculated as the integer duration from the date of birth to the date of 
informed consent, if age is not recorded in the electronic case report form 
(eCRF). Age will be categorized as <65, 65 - <75, and 75 (years). 
8.3.1 Geographic Region 
Geographic location of study site will be categorized as United States of America 
and Rest of World. Rest of World is defined as all other countries. 
8.4 Disease Characteristics 
8.4.1 Time Since Initial Diagnosis  
Time since initial diagnosis in years at study entry will be defined as duration 
from diagnosis to first dose of study.  Partial dates will be imputed according to 
section 10.1. 


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8.4.2 Prior and Concomitant Medications 
Concomitant medications are defined as medications with start date or end date 
on or after the date of first dose and start date before the date of the last dose + 
30 days or are ongoing at the time of first dose.  Prior medications are defined as 
medications with a stop date before the date of first dose of study drug.   
For the purpose of determining if a medication should be noted as a concomitant 
medication, the imputation rules stated in section 10.1 will be used.  Imputed 
dates will not be presented in the listings.   
Patients may have more than one medication per ATC level 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. 
Transfusions will be defined as WHO DD preferred names of “Platelets” or “Red 
blood cells”.  Growth factor agents will be defined as WHO DD Standardized 
Drug Groupings (SDG) “Colony stimulating factors”. 
8.4.1 Therapeutic Drug Classes 
PI is defined as WHO DD SDG “Antineoplastic proteasome inhibitors”. 
IMiD is defined as SDG “Antineoplastic thalidomide analogues”. 
Anti-CD38 mAb is defined as SDG “Antineoplastic CD38 antigen inhibitors”. 
Other mAb is defined as SDG “Monoclonal antibodies – antineoplastics” 
excluding SDG “Antineoplastic CD38 antigen inhibitors”. 
Alkylators is defined as SDG “Antineoplastic alkylating drugs”. 
Other antineoplastic drugs for the treatment of multiple myeloma will be referred 
to as ‘Other’.  
Any experimental or investigational drugs that are not covered by WHO DD will 
be reviewed manually and classified as one of the above therapeutic drug 
classes if applicable. Classifications will be documented as part of database lock 
procedures and further described in the CSR. 
8.4.2 Prior Regimens 
A prior regimen is defined as one or more cycles of a planned treatment program 
that is considered prior in accordance with exclusion criteria 11 study 
protocol. This may consist of one or more planned cycles of single-agent therapy 
or combination therapy, as well as a sequence of treatments administered in a 


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planned manner. For example, a planned treatment approach of induction 
therapy followed by autologous stem cell transplantation, followed by 
maintenance is considered one regimen. A new regimen starts when a planned 
course of therapy is modified to include other treatment agents (alone or in 
combination) as a result of disease progression, relapse, or toxicity. A new 
regimen also starts when a planned period of observation off therapy is 
interrupted by a need for additional treatment for the disease. [Rajkumar 2011] 
Number of prior regimens per patient will be the ‘Total Lines of Therapy’ as 
reported by investigator on the Multiple Myeloma History – Prior Systemic 
Cancer Therapy Summary CRF.  
8.4.3 Refractory Status  
A patient is defined as refractory to a drug within a prior regimen if the patient 
fulfills any of the following criteria [Rajkumar 2011]: 
1. Reason for termination was PD  
2. Best response was PD or SD  
3. Relapse or progression occurred within 60 days from last administration 
Double-class refractory is defined as refractory to at least one PI and at least one 
IMiD.   
Triple-class refractory is defined as refractory to at least one PI, at least one 
IMiD, and at least one Anti-CD38 mAb. A patient is defined as intolerant to a 
specific therapeutic drug class if the patient discontinued the drug due to toxicity, 
and did not receive a drug in the same therapeutic drug class again prior to 
entering the current study. 
Triple-class refractoriness and intolerance will undergo a manual review and 
reconciliation of available data reported of prior antimyeloma therapy, date of 
discontinuation, reason for discontinuation as progression or toxicity date of 
progression as reported on the Refractory History, Multiple Myeloma History - 
Prior Systemic Cancer Therapy, or Multiple Myeloma History - Prior Systemic 
Cancer Drug Therapy CRFs. Classifications will be documented as part of 
database lock procedures and further described in the CSR.  
8.4.4 Transplants 
A front-line transplant is defined as the transplant indicated for the first line of 
therapy. This can be single or tandem transplant. Planned tandem autologous or 
autologous-allogeneic are considered as one transplant. 


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A salvage transplant is defined as any transplant given following failure of front-
line therapy. Planned tandem autologous or autologous-allogeneic are 
considered as one transplant. 
Time from autologous transplant to relapse is the duration in years from date of 
transplant (or date of first transplant if given in tandem) to date of relapse. Time 
from autologous transplant to relapse will be categorized as <1 year, 1 - <1.5 
years, 1.5 – 2 years, >2 years. 
8.4.5 Cytogenetic Risk Groups 
Genetic subtypes from cytogenetics analysis by fluorescence in situ hybridization 
(FISH) will be categorized into risk groups as follows [Sonneveld 2016]: 
• High-risk group: consists of patients who have the genetic subtype t(4; 
14), t(14:16), deletion 17p, gain 1q (+1q), t(14,20).1 
• Standard-risk group: consists of patients who have a genetic subtype 
recorded but none of the genetic subtypes categorized as high-risk 
• Unknown: consists of patients for whom the FISH procedure was not done 
or unevaluable. 
8.4.6 International Staging System (ISS) 
ISS Stage and Revised ISS (R-ISS) Stage will be derived [Palumbo, 2015], see 
Table 2. 
ISS will be derived from serum β2 microglobulin and albumin. This derived ISS 
will in turn be used with serum lactase dehydrogenase (LDH) and high-risk 
cytogenetics as defined by the R-ISS guidelines to derive R-ISS.  
 
1 The addition of subtypes gain 1q (+1q), t(14,20) were added to the IMWG definition of high risk 
cytogenetics [Sonneveld 2016] as an update to initial IMWG guideline [Rajkumar 2011]. As this 
definition was changed during the study and the protocol did not require testing of the additional 
high-risk cytogenetic abnormalities, these additional subtypes may be underrepresented. 


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Table 2: 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 by 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  
Lactase 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  
ISS as reported in CRF will be referred to as ‘ISS’ {I, II, III, Unknown, Not Done};  
ISS as derived will be referred to as ‘Derived ISS’ {I, II, III, Unknown, Not Done};  
R-ISS as reported on the CRF will be referred to as ‘R-ISS’ {R-I, R-II, R-III, 
Unknown, Not Done}. 
R-ISS as derived will be referred to as ‘Derived R-ISS’ {R-I, R-II, R-III, Unknown, 
Not Done}. 
8.4.7 Monoclonal Protein Spike (M-protein) 
M-protein is assessed from serum and urine protein electrophoresis test 
(SPEP/UPEP), and/or serum free light chain (sFLC).   
Measurable M-protein at screening and baseline are defined as follows:  
• Measurable SPEP is defined as M-protein ≥ 0.5 g/dL.2  
 
2 IMWG defined measurable serum M-protein as ≥ 1.0 g/dL [Rajkumar 2011]. 


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• Measurable UPEP is defined as M-protein ≥ 200 mg/24 hr.  
• Measurable sFLC is defined as involved FLC ≥ 10 mg/dL with abnormal 
Kappa/Lambda ratio (defined as values outside 0.26-1.65).    
If the sFLC kappa/lambda ratio is >1.65, kappa is the involved sFLC, and lambda 
is the uninvolved sFLC. If the kappa/lambda ratio is <0.26, lambda is the involved 
sFLC, and kappa is the uninvolved sFLC. Difference in sFLCs (dFLC) is defined 
as (Involved sFLC – Uninvolved sFLC) and is used for response assessment 
according to IMWG [Rajkumar 2011]. 
Maximum percent decrease of M-protein or dFLC as summarized in waterfall 
plots is defined as maximum decrease from baseline to lowest level (nadir) per 
patient divided by baseline level, expressed as percent. Maximum percent 
decreases of less than -100% will be set to -100%.  
When estimating maximum percent decrease; If both SPEP and UPEP are 
measurable at baseline, SPEP will be used. If only SPEP is measurable, SPEP 
will be used. If only UPEP is measurable UPEP will be used. If neither SPEP and 
UPEP are measurable, FLC will be used.  
8.4.8 Plasma Cell Involvement 
Bone marrow plasma cell involvement (%) as assessed by aspiration and biopsy 
will use the higher value in cases of discrepancy and referred to as maximum 
plasma cell involvement. Maximum plasma cell involvement will be categorized 
as (<30%, 30 - <60%, ≥60%). 
8.4.9 Presence of Bone Lesions and Extramedullary Disease (EMD) 
Presence of bone lesions and/or EMD at baseline will be defined following a 
manual review and reconciliation of available data reported as investigator 
assessments of imaging and M-protein laboratory results. Classifications will be 
documented as part of database lock procedures and further described in the 
CSR.  
8.5 Myeloma and Safety Laboratory Assessments (Hematology, 
Coagulation, and Serum Chemistry) 
8.5.1 Unit Conversion 
Reported units will be converted to standard units according to CDISC controlled 
terminology using the conversion factors shown in Table 3.  


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Table 3. Conversion factors for laboratory units 
Analyte 
Original 
reported 
unit 
Standard 
unit 
Conversion 
factor  
Myeloma Laboratory Assessments 
Urine Monoclonal Protein 
Spike 
mg/24hrs 
mg/day 
1 
Serum Monoclonal 
Protein Spike 
g/dL 
g/dL 
1 
Kappa/Lambda Free Light 
Chain 
Ratio 
RATIO 
1 
Beta-2 Microglobulin 
mg/dL 
mg/L 
Multiplied by 10 
Immunoglobulins (A, D, E, 
G, M), Kappa Free Light 
Chain, Lambda Free Light 
Chain,  
mg/dL 
mg/dL 
1 
Hematology 
WBC differentials 
(Basophils, Eosinophils, 
Monocytes, Lymphocytes, 
Neutrophils) 
% 
% 
1 
Platelets, WBC and WBC 
differentials (Basophils, 
Eosinophils, Monocytes, 
Lymphocytes, 
Neutrophils) 
10^9/L, x10^9/L, 
K/µL, K/CUMM, 
x10^3/µL, K/mcL 
10^9/L 
1 
Platelets, WBC and WBC 
differentials (Basophils, 
Eosinophils, Monocytes, 
Lymphocytes, 
Neutrophils) 
/uL, cells/mm3, 
cells/µL, cells/uL 
10^9/L 
Divided by 1000 
RBC 
10^12/L, 
x10^12/L, M/µL, 
M/CUMM, 
MIL/CUMM, 
x10^6/µL, M/mcL 
10^12/L 
1 
RBC 
/uL, cells/mm3, 
cells/µL, cells/uL 
10^12/L 
Divided by 1000000 
Hematocrit 
% 
% 
1 


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Analyte 
Original 
reported 
unit 
Standard 
unit 
Conversion 
factor  
Hemoglobin 
g/L 
g/L 
1 
Hemoglobin 
g/dL 
g/L 
Multiplied by 10 
Serum Chemistry 
ALT, AST, ALP, LDH 
U/L, IU/L 
U/L 
1 
Albumin 
g/L 
g/L 
1 
Albumin 
g/dL 
g/L 
Multiplied by 10 
Bicarbonate/CO2, 
Chloride, Potassium, 
Sodium 
mmol/L 
mmol/L 
1 
Bicarbonate/CO2, 
Chloride, Potassium, 
Sodium 
mEq/L 
mmol/L 
1 
Total Bilirubin 
umol/L, µmol/L 
umol/L 
1 
Total Bilirubin 
mmol/L 
umol/L 
Multiplied by 1000 
Total Bilirubin 
mg/dL 
umol/L 
Multiplied by 17.1037 
Calcium 
mmol/L 
mmol/L 
1 
Calcium 
mg/dL 
mmol/L 
Multiplied by 0.2495 
Creatinine 
umol/L, µmol/L 
umol/L 
1 
Creatinine 
mg/dL 
umol/L 
Multiplied by 88.4017 
Creatinine 
mmol/L 
umol/L 
Multiplied by 1000 
Glucose 
mmol/L 
mmol/L 
1 
Glucose 
mg/dL 
mmol/L 
Multiplied by 0.05556 
Glucose 
g/L 
mmol/L 
Multiplied by 5.556 
Magnesium 
mmol/L 
mmol/L 
1 
Magnesium 
mEq/L 
mmol/L 
Multiplied by 0.5 
Magnesium 
mg/dL 
mmol/L 
Multiplied by 0.4114 
Phosphate 
mmol/L 
mmol/L 
1 
Phosphate 
mg/dL 
mmol/L 
Multiplied by 0.3226 
Total Protein 
g/L 
g/L 
1 


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Analyte 
Original 
reported 
unit 
Standard 
unit 
Conversion 
factor  
Total Protein 
g/dL 
g/L 
Multiplied by 10 
Uric Acid/Urate 
umol/L, µmol/L 
umol/L 
1 
Uric Acid/Urate 
mg/dL 
umol/L 
Multiplied by 59.4849 
Uric Acid/Urate 
mmol/L 
umol/L 
Multiplied by 1000 
Urea Nitrogen/Blood Urea 
Nitrogen (BUN) 
mmol/L 
mmol/L 
1 
Urea Nitrogen/Blood Urea 
Nitrogen (BUN) 
mg/dL 
mmol/L 
Multiplied by 0.3571 
Coagulation 
INR 
Ratio 
RATIO 
1 
Prothrombin Time 
s, sec 
sec 
1 
Prothrombin Time 
% 
-- 
No conversion 
8.5.2 Derived Laboratory Parameters and Subgroups 
Creatinine clearance (ml/min) will be derived using the following equation:  
CrCl = K × {140 - age × weight} / {72 × serum creatinine} 
where K is 1 for males and 0.85 for females, age is integer years, weight in kg, 
and serum creatinine in mg/dL [Cockroft 1976]. Age at the date of serum 
creatinine assessment will be used.  Weight at the assessment date or nominal 
visit as serum creatinine will be used. 
For hypocalcemia and hypercalcemia (as defined from laboratory ranges), serum 
calcium values and normal ranges will be corrected using the formula: 
Corrected calcium = Serum calcium mg/dL + 0.8 × (4 - serum albumin g/dL)  
β2 microglobulin (mg/L) will be categorized as < 3.5, 3.5 – 5.5 and > 5.5.  
Platelet count (10^9/L) will be categorized as <75, 75 – 100, >100 – 150, and 
>150. 
ANC (10^9/L) will be categorized as <1.0, 1.0 – 1.5, and >1.5. 
Hemoglobin (g/L) will be categorized as <80, 80 – 100, >100. 
Lactase dehydrogenase (LDH) will be categorized as <1.5xULN and ≥1.5xULN, 
where ULN=upper limit of normal range based on reference ranges provided 
from each site.  


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Albumin (g/dL) will be categorized as <3.5, and ≥3.5. 
Creatinine clearance (ml/min) will be categorized as <45, ≥45 - <60, ≥60 - <90, ≥ 
90. 
8.5.3 Toxicity Grades 
The following laboratory test results will be assigned toxicity grades using 
CTCAE 4.03: 
• Hematology 
o Hemoglobin (decrease) 
o Platelets (decrease) 
o WBC (increase, decrease) 
o ANC (decrease) 
o Lymphocyte Count (increase, decrease) 
• Serum Chemistry 
o Alanine transaminase (ALT) (increase) 
o Aspartate transaminase (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 (decrease) 
o Potassium (increase, decrease) 
For ANC and platelet count, the time to onset of grade 3 or 4 toxicity by cycle and 
overall will be derived. Time to onset of grade 3 or 4 toxicity by cycle is defined 
as the duration in days from day 1 of the cycle to day of grade 3 or 4 toxicity, 
whichever occurs first. Time to onset of grade 3 or 4 toxicity overall is defined as 


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the duration in days from treatment start to day of grade 3 or 4 toxicity, whichever 
occurs first. 
8.6 Myeloma Response Parameters 
All tumor response and progression-depended endpoints will be assessed using 
the International Myeloma Working Group Uniform Response Criteria (IMWG-
URC) [Rajkumar 2011]. 
8.6.1 Response Rates  
The overall response rate (ORR) is defined as the proportion of patients for 
whom the best overall confirmed response is stringent complete response (sCR), 
complete response (CR), very good partial response (VGPR), or partial response 
(PR).  
The clinical benefit rate (CBR) will be defined as the proportion of patients with 
the best overall confirmed response of minimal response (MR) or better.  
Stable disease (SD) will be defined as the proportion of patients with the best 
overall confirmed response of SD.  
Disease stabilization will be defined as the proportion of patients with the best 
overall confirmed response of SD or better.  
‘Best overall confirmed response’ is the best response achieved on study based 
on two consecutive assessments according to IMWG-URC.   
‘Best unconfirmed response’ defined as the best response achieved on study, i.e. 
a response may not be confirmed by a consecutive assessment.   
Responses of not evaluable (NE) will be determined if no measurable disease at 
baseline or no post-baseline response assessment.  No post-baseline response 
will be presented separately for patients still on study at the time of the data cut 
or if patient has withdrawn from study. 
8.6.2 Progression Free Survival (PFS) 
PFS is defined as the duration in months from start of treatment until first 
evidence of confirmed disease progression. Disease progression is defined 
according to IMWG-URC as PD or death due to any cause, whichever occurs 
first. PFS will be right-censored according to the conventions described in Table 
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Table 4: Conventions for Censoring of PFS 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline response 
assessments 
Date of first dose 
Censored 
Non-protocol systemic anticancer 
therapy started before 
documentation of PD or death 
Date of last response assessment 
prior to start of new anticancer 
therapy 
Censored 
Death or PD after more than 1 
consecutively missed response 
assessment  
Date of last response assessment 
without documentation of PD that is 
before the first missed visit 
Censored 
Unconfirmed PD as the final 
response assessment 
Date of latest PD assessment 
Progressed 
Alive and without PD documentation  Date of last response assessment 
Censored 
Death or PD between scheduled 
response assessments 
Date of death or preceding 
response assessment showing PD, 
whichever occurs first 
Progressed 
Death before first response 
assessment 
Date of death 
Progressed 
These conventions are adapted from the December 2018 FDA Guidance for 
Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics’, and on the April 2015 FDA Guidance for Industry ‘Clinical Trial 
Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics’.   
Event-free rates will be defined using K-M product-limits and categorized by 
consecutive periods of 3 months from treatment start. 
End of treatment as used for swim lane plots (section 9.5.3) is defined as the End 
of Treatment visit.  
8.6.3 Duration of Response (DOR) 
DOR will be estimated for patients who achieve a PR or better. DOR is defined 
as the duration in months from first documentation of a confirmed response to 
first evidence of confirmed disease progression or death due to any cause.  
Disease progression, and dates of progression and censoring, will be determined 
as described for the analysis of PFS (section 8.6.2). 
8.6.4 Time to Response (TTR)  
TTR will be estimated for patients with confirmed responses of PR or better. TTR 
is defined as the duration in months from the study treatment start to the first 
occurrence of a response of PR or better.   


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8.6.5 Time to Progression (TTP)  
TTP will be estimated for patients with confirmed PD. TTP is defined as the 
duration in months from treatment start to first evidence of disease progression.  
Disease progression, and dates of progression and censoring, will be determined 
as described for the analysis of PFS (section 8.6.2), with the exception that 
patients who die will be censored as of the last response assessment prior to 
death. 
8.6.6 Time to Next Treatment (TTNT) 
Analyses of TTNT will use two alternative definitions, referred to as TTNTA and 
TTNTB. 
TTNTA: Duration will be time (months) from the study treatment start to the start 
of first post study myeloma 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.  
TTNTB: Duration will be time (months) from the study treatment start to the start 
of the first post study myeloma 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. 
8.6.7 Duration of Stable Disease  
Duration of SD will be estimated for patients whose best response is SD 
confirmed by two consecutive post-baseline myeloma response assessments. 
The duration is defined as the time in months from the study treatment start to 
disease progression or death due to any cause.  
Disease progression, and dates of progression and censoring, will be determined 
as described for the analysis of PFS (section 8.6.2).  
8.6.8 Duration of Disease Stabilization 
Duration of disease stabilization will be estimated for patients whose best 
response is SD confirmed by two consecutive post-baseline myeloma response 
assessments or better. The duration is defined as the time in months from the 
study treatment start to disease progression or death due to any cause.  
Disease progression, and dates of progression and censoring, will be determined 
as described for the analysis of PFS (section 8.6.2). 


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8.6.9 Duration of Clinical Benefit  
Duration of clinical benefit will be estimated for patients whose best confirmed 
response is MR or better. Duration is defined as the time in months from first 
post-baseline documentation of a confirmed MR or better to disease progression 
or death due to any cause.  
Disease progression, and dates of progression and censoring, will be determined 
as described for the analysis of PFS (section 8.6.2). 
8.6.10 Overall Survival 
OS is defined as the time in months from the date of the first dose of study drug 
to date of death due to any cause. Patients who are alive will be censored at the 
last follow up visit or data cut-off date for patients still on-study. 
8.6.11 Assessments by Independent Review Committee (IRC) 
Response, confirmed response, and confirmed progression are also determined 
according to IMWG-URC by an IRC. This parallel set of data will be appended to the 
database and analyzed as a sensitivity analysis.  
8.6.12 Long Term Follow-up for PFS and OS 
According to the study protocol, patients who discontinue therapy for reasons 
other than disease progression should continue to have monthly disease 
assessments done until confirmed progression or initiation of subsequent 
therapy.  
Following confirmed disease progression or initiation of subsequent therapy, 
follow-up for overall survival status, second primary malignancies and 
subsequent therapy will take place every three months +/- 7 days for 24 months.  
8.7 Functional Status and Well-being  
PRO assessments of functional status and well-being (HRQoL) were added at 
the time of protocol version 5.0. Analyses of HRQoL will use the HRQoL analysis 
set. Additional analyses of HRQoL, including utility scores from the EQ5D-3L for 
the purpose of inclusion to health economic modelling, will be evaluated 
separately from this SAP.  
8.7.1 EQ-5D-3L 
EQ-5D-3L is a generic measure of health status. The EQ-5D-3L questionnaire 
[EuroQoL Research Foundation] converts 5 dimensions (Mobility, Self-Care, 
Usual Activities, Pain/Discomfort, and Anxiety/Depression) of patient-reported, 
current-day health status into a “health utility” score.  For the EQ-5D-3L 


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questionnaire, each dimension is scored on an ordinal scale with 3 available 
levels of response and scores ranging from 1 to 3, “no problems,” “some 
problems,” and “extreme problems,” respectively. EQ-5D-3L scoring and health 
utility values will be mapped in accordance with scoring manual [EuroQol 
Research Foundation. EQ-5D-3L User Guide 2018] and using United Kingdom 
as value set [Dolan 1997]. The EQ VAS scores rates “health today” with anchors 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health 
state). For the purposes of this SAP no imputation of missing items or composite 
scores will be done for EQ-5D-3L. 
8.7.2 EORTC QLQ-C30 
 
EORTC QLQ-C30 is an instrument assessing HRQOL of cancer patients 
participating in international clinical trials. EORTC QLQ-C30, includes 30 items   
resulting in 5 functional scales: 1 Global Health Status scale, 3 symptom scales, 
and 6 single items. The recall period is 1 week (the past week).  
The scoring for the EORTC QLQ-C30 will be done according to the procedures 
described in the Scoring Manual [Fayers 2001].  
EORTC QLQ-C30 raw scores will be transformed into a range from 0 to 100. For 
EORTC QLQ-C30 Global Health Status and functional domains (Physical 
Functioning, Role Functioning, Emotional Functioning, Cognitive Functioning, 
Social Functioning), a higher score indicates better function. For symptom 
domains (Fatigue, Nausea & vomiting, Pain, Dyspnea, Insomnia, Appetite loss, 
Constipation, Diarrhea, Financial Difficulty), a lower score indicates fewer 
symptoms.  
The EORTC QLQ-C30 Summary Score is calculated from the mean of 13 of the 
15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact 
scale are not included). Prior to calculating the mean, the symptom scales need 
to be reversed to obtain a uniform direction of all scales. The summary score 
should only be calculated if all of the required 13 scale scores are available 
(using scale scores based on the completed items), provided that at least 50% of 
the items in that scale have been completed. If at least 50% of the items from the 
scale have been answered, the missing items will be assumed to have values 
equal to the average of those items which are present for that respondent. No 
assessment will be carried forward from a prior assessment. 
8.7.3 Evaluable HRQoL at Cycle 4 
Having evaluable HRQoL at Cycle 4 will defined as patients; 
A. who have received a dose of melflufen at Cycle 3,  


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B. do not have an AE starting prior to Cycle 4 due to which melflufen was 
permanently withdrawn, and  
C. have a Cycle 4 assessment of EQ-5D-3L or EORTC QLQ-C30 
respectively. 
8.8 Exposure 
The study drugs for this study are melflufen and dexamethasone.   
8.8.1 Overall Study Drug Exposure 
Duration of treatment with study drug in weeks is defined as the longer of (date of 
last dose + 28 days – date of first dose + 1 for melflufen) or (date of last dose – 
date of first dose + 1 for dexamethasone) divided by 7. 
8.8.2 Melflufen Exposure 
Duration of melflufen treatment in weeks is defined as (date of last dose + 28 
days – date of first dose + 1) divided by 7. 
Melflufen treatment cycle is defined as cycle during which at least one dose of 
melflufen was administered. A treatment cycle starts on the date of melflufen 
administration. 
Cumulative dose of melflufen in mg is the sum of all melflufen doses 
administered.  
Average dose of melflufen in mg/week is defined as the cumulative dose divided 
by the duration of melflufen treatment. 
The dose intensity of melflufen is defined as the ratio of the average dose of 
melflufen to the prescribed dose, where prescribed dose is 40 mg per 4 weeks = 
10 mg/week, and expressed as a percent.   
A dose delay is defined as a consecutive dose of melflufen administered on day 
32 or later following a preceding dose of melflufen. Dose delays will be 
categorized as delays in weeks as 1 (day 32 to 38), 2 (day 39 to 45), 3 (day 46 to 
52), 4 (day 53 to 59), and >4 weeks (day 59 or later) for each cycle.  
A dose reduction is defined as a consecutive dose of melflufen lower than a 
preceding dose of melflufen. 
8.8.3 Dexamethasone Exposure 
Duration of dexamethasone treatment in weeks is defined as (date of last dose – 
date of first dose + 1) divided by 7. 


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Cumulative dose of dexamethasone in mg is the sum of all dexamethasone 
doses administered  
The dose intensity of dexamethasone is defined as the ratio of (cumulative dose 
divided by the Duration of dexamethasone treatment) to the prescribed dose, 
where prescribed dose is 160 mg per 4 weeks = 40 mg/week for patients with 
age <75 years, or 80 mg per 4 weeks = 20 mg/weeks for patients with age ≥75 
years, and expressed as a percent.   
A dose delay is defined as a dose of dexamethasone administered on day 4 or 
later following the planned dosing days 1, 8, 15 and 22 respectively, and before 
the day of a planned subsequent dose. A missed dose of dexamethasone is a 
planned dose that is not given before the day of a planned subsequent dose (e.g. 
if planned dose on day 8 is not given before day 15).  
A dose reduction is defined as a consecutive dose of dexamethasone lower than 
a preceding dose of dexamethasone. 
8.8.4 Action Taken with Study Drug 
The protocol and eCRF use the terms dose held and dose delay.  A dose held is 
the same as a dose delay.  The term dose delay is used herein and will be used 
for the CSR. 
Dose delays or dose reductions in summaries of scheduled study drug 
administration will be analyzed using the derived continuous variables described 
in sections 8.8.2 and 8.8.3 and not as reported in the CRF. The ‘Dose 
adjustment’ as reported in CRF {NO ACTION TAKEN, DOSE HELD, DOSE 
REDUCED, and DRUG PREMANENTLY DISCONTINUED} and dose adjustment 
according to CDISC Controlled terminology (CT) {DOSE NOT CHANGED, DOSE 
REDUCED, DRUG INTERRUPTED, and DRUG WITHDRAWN} will be included 
in listings. CRF entry ‘DOSE HELD’ correspond to CT ‘DRUG INTERRUPTED’, 
and CRF entry ‘DRUG PERMANENTLY DISCONTINUED’ correspond to CT 
‘DRUG WITHDRAWN’. 
8.9 Safety Evaluation 
8.9.1 Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a study patient 
administered an investigational product and that does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable 
and unintended sign (including laboratory finding), symptom, or disease 
temporally associated with participation in an investigational study, whether or 
not considered drug-related.  In addition to new events, any increase in the 


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severity or frequency of a pre-existing condition that occurs after the patient 
begins study is considered an AE. This includes any adverse reactions, injury, 
toxicity, or sensitivity reaction. 
Further details for the definition of SAE is provided in study protocol section 
9.1.1. 
A serious adverse event (SAE) is defined as any AE, occurring at any dose that 
meets any one or more of the following criteria:  
• Is fatal or immediately life-threatening  
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the 
patient or may require medical or surgical intervention to prevent one of 
the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization (AEs requiring hospitalization of less than 24 hours, will not 
be reported as SAEs unless another seriousness criteria are fulfilled) 
Further details for the definition of SAE is provided in study protocol section 
9.2.1.  
A treatment-emergent adverse event (TEAE) is an AE with an onset or 
increase in severity level after the initial dose of study drug and no later than day 
30 after the last dose of study drug or initiation of new multiple myeloma therapy, 
whichever is sooner. 
A treatment-related adverse event is an AE that is recorded by the investigator 
as possibly or probably related to either or both of melflufen and dexamethasone.  
A melflufen related AE is an AE that is noted as possibly or probably related to 
melflufen independently of relationship with dexamethasone, and a 
dexamethasone related AE is an AE that is noted as possibly or probably related 
to dexamethasone independently of relationship with melflufen. 
Patients may have more than one adverse event per SOC and preferred term. At 
each level of patient summarization, a patient is counted once if he/she reported 
one or more adverse events at that level. For such cases, the maximum CTCAE 


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toxicity grade and strongest causal relationship to study drug will be used in the 
incidence calculations. 
8.9.2 Dose Modifications due to Adverse Event 
Dose delays or dose reductions in summaries of ‘Action taken with study drug’ 
due to AE will be analyzed as reported in the CRF {NO ACTION TAKEN, DOSE 
HELD, DOSE REDUCED, DRUG INTERRUPTED, and DRUG PREMANENTLY 
DISCONTINUED}. Listings will include Action taken as reported on CRF and 
Action taken as mapped according to CDISC Controlled terminology (CT) {DOSE 
NOT CHANGED, DOSE REDUCED, DRUG INTERRUPTED, and DRUG 
WITHDRAWN}.  
8.9.3 Adverse Events of Special Interest 
AEs of special interest (AESIs) are TEAEs defined as follows: 
• Neutropenia: Standardized MedDRA Query (SMQ) {“Haematopoietic 
leukopenia”}  
• Thrombocytopenia: SMQ {“Haematopoietic thrombocytopenia”}   
• Anemia: SMQ {“Haematopoietic erythropenia”}   
• Febrile neutropenia: PT {“Febrile neutropenia”}3 
• Infections: SOC {“Infections and infestations”}  
• Hemorrhage: SMQ {“Haemorrhage terms, excluding laboratory 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. 
• 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. 
8.9.4 Deaths 
Deaths will be categorized as occurring within 30 days of the last dose of study 
drug or more than 30 days after the last dose respectively. Deaths related study 
drug occurring more than 30 days after the last dose will also be categorized. 
Early deaths will be defined as occurring within 60 days of first dose of study 
drug. 
 
3 PT “Febrile neutropenia” is listed as an individual PT and is also included in the SMQ 
“Haematopoietic leukopenia”. Hence, that PT will be counted in the 2 separate AESIs. 


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8.10 Protocol Deviations 
Major protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a patient’s rights, safety, or well-being.  Protocol deviations will 
be identified and classified prior to any database snapshot or database lock.   
9 
STATISTICAL METHODS  
9.1 General Considerations 
All statistical summaries and analyses will be performed in SAS® version 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA). 
In general, summaries of all data will be presented for the total group and for the 
triple-class refractory subgroup in each analysis set. Data from the EMD 
subgroup will be presented separately for selected analyses.  
Statistical analyses will be reported using summary tables, figures, and data 
listings.  No inferential statistical comparisons using p-values will be performed.   
For continuous variables, the number of patients with non-missing data (n), 
mean, standard deviation (SD), median, minimum, and maximum will be 
presented.   
For discrete data, the frequency and percent distribution will be presented.  
Unless otherwise indicated, percentages will be calculated based upon the 
number of patients in the FAS in each study group as the denominator.  
Graphical methods will be used, as appropriate, to illustrate study endpoints. 
Confidence intervals, when presented, will be constructed at the 95% level and 
will be provided for the triple-class refractory subgroup and for the total group.  
For binomial variables, exact distribution methods will be employed.  The 
distribution of time-to-event endpoints will be summarized by the Kaplan-Meier 
(K-M) method.  Quartiles including median will be estimated by K-M method 
along with their 95% confidence intervals based on a log(-log(survival)) 
distribution.  
Assuming raw or derived variables are recorded to “x” decimal places; range and 
quartiles will be presented to x decimal places, mean and median to x+1, and SD 
and confidence intervaIs to x+2 decimal places. Presented decimal places should 
however not be greater than 4.  
Percentages will be presented to 1 decimal place, with the exception of 0, which 
will be presented without percent, and 100, which will be presented without 
decimal places. Categorization of percentages will be done before rounding. 


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Tables that summarize categorical data will present data as “0”, if the number of 
events is zero. Denominators for percentages will be based on the number of 
patients with non-missing data in the population used in each column. A 
“missing” category will be included for any parameter for which information is 
missing, without a percentage. 
Individual patient data recorded on the electronic case report forms (eCRFs) and 
any derived data will be presented by study group and by patient in data listings. 
9.2 Disposition of Patients 
The following patient disposition information will be summarized for the FAS and 
HRQoL analysis set: 
• Number of treated patients 
o Number that are daratumumab refractory 
o Number that are pomalidomide refractory 
o Number that are refractory to both pomalidomide and 
daratumumab. 
• Number (%) of treated patients by geographic region (United States of 
America and Rest of World), country and site. 
• Number (%) of treated patients who are on treatment 
• Number (%) of treated patients who discontinued treatment 
• Primary reason for treatment discontinuation 
• Number (%) of treated patients in long-term PFS follow-up 
• Number (%) of treated patients in long-term OS follow-up 
• Number (%) of treated patients who discontinued the study 
• Primary reason for study discontinuation  
9.3 Protocol Deviations 
Major protocol deviations will be summarized by deviation type for the FAS. All 
protocol deviations will also be provided in a listing. 


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9.4 Demographic, Baseline Characteristics, and Prior Therapy   
9.4.1 Demographic and Baseline Characteristics   
The following demographic and baseline characteristics will be summarized for 
the FAS and HRQoL analysis set.  
• Age (years) and age categories 
• Sex 
• Race 
• Ethnicity 
• Baseline ECOG performance status 
• Baseline fertility status 
• Baseline weight (kg) 
9.4.2 Medical History 
The number (%) of patients who experienced a prior disease or disorder will be 
summarized by SOC and PT for the FAS.   
9.4.3 Disease Characteristics 
The following disease characteristics at diagnosis will be summarized for the 
FAS and HRQoL analysis set based on data recorded on the Multiple Myeloma 
History at Diagnosis CRF: 
• Stage of disease (ISS and R-ISS) 
• Heavy chain and light chain status, heavy chain and light chain 
combinations (e.g., IgG-lambda, IgG-kappa) 
• Presence of bone lesions 
• Presence of extramedullary disease 
• Cytogenetic risk groups 
The following disease characteristics at baseline/study entry will be summarized 
for the FAS and HRQoL analysis set: 
• Stage of disease (ISS, Derived ISS, R-ISS, Derived R-ISS) 
• Time from diagnosis to first dose of study drug in years 
• Type of measurable disease 


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• SPEP, UPEP, Kappa/Lambda values 
• Heavy chain and light chain status, heavy chain and light chain 
combinations 
• Maximum plasma cell involvement (%)  
• Presence of bone lesions 
• Presence of extramedullary disease 
• Cytogenetic risk groups 
• Laboratory Assessments 
o 2 microglobulin as values and categories 
o Platelet count as values and categories 
o ANC as values and categories 
o Hemoglobin as values and categories 
o LDH as values and categories  
o Albumin as values and categories 
o Creatinine 
o Creatinine clearance (ml/min) as values and categories 
o Corrected calcium 
9.4.4 Prior Myeloma Therapy 
The following information related to prior myeloma therapy will be summarized 
for the FAS and HRQoL analysis set: 
• Number of regimens of prior treatment for multiple myeloma   
• Number (%) of patients with at least one prior regimen including a 
therapeutic drug class, i.e. IMiD, PI, Alkylators, anti-CD38 mAb, Other 
mAb, and Other. 
• Number (%) of patients who are refractory to a prior regimen including a 
therapeutic drug class. 
• Number (%) of patients who received an IMiD and PI (double-class)   
• Number (%) of patients who received an IMiD, PI, and anti-CD38 mAb 
(triple-class)  
• Number (%) of patients who are double-class refractory (IMiD and PI) 
• Number (%) of patients who are refractory to most recent prior regimen 


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• Best response to most recent prior regimen 
• Number (%) of patients per last prior therapeutic class. 
• Number (%) of patients refractory to any agent per last prior therapeutic 
class. 
• Number (%) of patients who are refractory to IMiD, PI, Alkylators, anti-
CD38 mAb, Other mAb, or Other per the most recent prior regimen by 
therapeutic classes. 
• Number (%) of patients with at least one prior autologous transplant, and 
number (%) of patients with at least two prior autologous transplants 
• Number of prior autologous transplants 
• Time (years) from front line transplant to relapse 
• Number (%) of patients with prior radiotherapy 
 
9.4.5 Prior and Concomitant Medications 
Concomitant medications will be summarized for the FAS and HRQoL analysis 
set by ATC class and preferred name using as counts and percentages. 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 listed 
without summary.  
A separate summary table will summarize the number and percentage patients 
with transfusions and taking growth factor agents. 
9.5 Efficacy Analyses 
The primary population for all efficacy analyses will be the FAS. All tumor 
response and progression-depended endpoints will be assessed using the 
International Myeloma Working Group Uniform Response Criteria (IMWG-URC) 
[Rajkumar 2011].   
The efficacy analyses will also be performed for the HRQoL analysis set. 
9.5.1 Response Rates 
The primary endpoint, ORR will be summarized with the corresponding two-sided 
95% exact binomial confidence interval (Clopper-Pearson method [Fleiss, 1981]).   
CBR and disease stabilization, and best confirmed responses (sCR, CR, VGPR, 
PR, MR, SD, PD, or not evaluable (NE)) will be summarized. In addition, best 
unconfirmed response will be summarized. 


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9.5.2 Changes in M-protein 
“Waterfall” plots will display the maximum percent decrease in the M-protein 
being used to determine response for all patients. Bars will be stacked per best 
responses.  
9.5.3 Progression Free Survival   
K-M product-limits will be used to estimate the distribution of PFS. Quartiles 
including the median and the two-sided 95% confidence intervals based on the 
log(-log(survival)) distribution will be presented. The number of patients 
censored, and types of events and censoring events will be summarized. Event 
free rates (with 95 % confidence intervals) will be presented based on the K-M 
curve. A K-M plot showing the estimated PFS distribution will be provided. These 
analyses will be provided for the FAS and HRQoL analysis set. 
Potential follow-up for PFS will be summarized for the FAS using the reverse K-
M method where the censoring variable is inverted [Schemper and Smith, 1996]. 
The median potential follow-up time will be summarized.   
“Swim lane” plots based on PFS will be provided for the FAS and HRQoL 
analysis set.  The plots will be stacked by day of first documentation of the 
different response levels (SD, MR, PR, VGPR, CR, sCR) on study.  
9.5.4 Duration of Response (DOR)  
The distribution of DOR will be estimated and summarized using the same 
method as for PFS. 
DOR will be summarized for patients in FAS whose best overall confirmed 
response is sCR, CR, VGPR, or PR.  
9.5.5 Time to Response (TTR)  
TTR will be summarized as a continuous variable using descriptive statistics.  A 
K-M plot showing the estimated time to response distribution will be provided.  
TTR will be summarized for the FAS and HRQoL analysis set. 
9.5.6 Time to Progression (TTP) 
The distribution of TTP will be estimated and summarized using the same 
method as for PFS.  
TTP will be summarized for the FAS.  


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9.5.7 Time to Next Treatment (TTNT) 
The distribution of TTNTA and TTNTB will be estimated and summarized using 
the same method as for PFS.  
TTNTA and TTNTB will be summarized for the FAS and HRQoL analysis set. 
9.5.8 Duration of Stable Disease 
Duration of SD will be estimated and summarized using the same method as for 
PFS. 
Duration of SD will be summarized for the FAS. 
9.5.9 Duration of Disease Stabilization 
Duration of disease stabilization will be estimated and summarized using the 
same method as for PFS.  
Duration of disease stabilization will be summarized for the FAS and HRQoL 
analysis set. 
9.5.10 Duration of Clinical Benefit  
Duration of clinical benefit will be estimated and summarized using the same 
method as for PFS. 
Duration of clinical benefit will be summarized for the FAS and HRQoL analysis 
set. 
9.5.11 Overall Survival (OS) 
OS will be estimated and summarized using the same method as for PFS, 
including median potential follow-up time.  
OS will be summarized for the FAS and HRQoL analysis set.  
9.5.12 Analyses by Subgroups 
EMD presence at baseline is a subgroup of specific interest (section 6.2).  
Summary tables for ORR, CBR, disease stabilization rate, best confirmed 
response, PFS, DOR, and OS will be presented for patients with EMD at 
baseline. 
ORR, CBR, disease stabilization rate, and best confirmed response will also be 
summarized for the following subgroups.  
In addition, forest plots presenting the K-M median estimate and 95% confidence 
interval for efficacy endpoints PFS, DOR, TTR, TTP, duration of SD, duration of 


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clinical benefit, and OS will be provided for the following subgroups.  The 
summaries will be based on the FAS.  
• Age (<65, 65 - <75, ≥75 years) 
• Sex (male, female) 
• Race (White, All Other Races) 
• Geographic region (United States of America, Rest of World) 
• Presence of Extramedullary Disease at Baseline (Derived per section 
8.4.9; yes, no) 
• Prior autologous stem cell transplant (yes, no) 
• Number of prior regimens (<4, 4 - 5, ≥6) 
• Maximum plasma cell involvement (%) at baseline, as assessed with bone 
marrow assessment (<30, 30 - <60, ≥60) 
• Baseline creatinine clearance (ml/min) (<45, 45 - < 60, 60 - < 90, ≥90) 
• Baseline LDH (<1.5×ULN, ≥1.5×ULN) 
• Baseline albumin (g/L) (<35, ≥35) 
• R-ISS at baseline (Derived per section 8.4.6; R-I, R-II, R-III, unknown) 
• ISS at baseline (Derived per section 8.4.6; I, II, III, unknown) 
• Cytogenetic risk groups (standard risk, high risk, unknown) 
• Refractory status: 
o Refractory to an alkylator (yes, no) 
o Refractory to an anti CD38 mAb (yes, no) 
o Refractory to a PI and IMiD but not to an anti CD38 mAb (yes, no) 
9.5.13 Assessments by IRC 
Summaries of ORR, CBR, best confirmed response, disease stabilization rate, 
PFS, DOR, duration of stable disease, TTR and TTP will be repeated for the 
assessments performed by IRC. These summaries will be provided for the FAS.   
Summaries of ORR, CBR, PFS and DOR by subgroups of disease 
characteristics (section 9.5.12) will be repeated for the assessments performed 
by IRC and provided for the FAS. 


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9.5.14 Functional Status and Well-being 
Results and change from baseline by cycle for the EQ-5D-3L index score, each 
of the 5 dimensions, and the EQ VAS will be summarized with descriptive 
statistics.  
Results and change from baseline by cycle for the EORTC QLQ-C30 summary 
score, global health status, functional domains, and symptom scales will be 
summarized with descriptive statistics.   
The above descriptive summaries will also be presented by subgroups of 
patients having sCR, CR, VGPR or PR as best overall confirmed response and 
patients not having this as best overall confirmed response.    
The change from baseline in the symptom scales Fatigue and Pain, and Global 
QoL in QLQ-C30 for evaluable HRQoL at Cycle 4 will be analyzed by calculating 
95% confidence intervals around the mean change based on the t-distribution. If 
the upper confidence limit for change in Pain are below 24 units (i.e. upper 
Minimal Important Difference (MID) limit for deterioration) the symptom will be 
considered as stable or improved. For change in Fatigue, the symptom will be 
considered as stable or improved if the upper confidence limit for Fatigue falls 
below 15. If the lower confidence limit for change in Global QoL is above -18 the 
Global QoL will be considered as stable or improved [Kvam 2010].   
If 0 is not included in the confidence intervals for the change from baseline this is 
equivalent to a statistically significant change. Based on MIDs, this change can 
be judged as important or not [Kvam 2010]. 
As a sensitivity analysis the change from baseline to Cycle 4 in the symptom 
scales Fatigue and Pain, and Global QoL in QLQ-C30 will be performed where 
patients who have an AE starting after Cycle 3 due to which melflufen was 
permanently withdrawn, and have an assessment of EORTC QLQ-C30 at a 
subsequent Cycle 4 or End of Treatment visit after Cycle 3, are included. 
All HRQoL assessments will be listed by cycle and date, including repeat 
assessments or assessments performed at cycles other than Cycle 1, 2, 4, 6, 8 
and EoT respectively. 
9.6 Safety Analysis 
All analyses of safety will be based on the Safety analysis set.   
The following analyses will also be performed for the HRQoL analysis set: 
• Study Drug Exposure 
• Exposure to Melflufen 


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• Melflufen Dose by Cycle 
• Melflufen Dose Modifications  
• Melflufen Dose Modifications by Cycle  
• Overview of TEAE 
• TEAE by SOC, PT and Severity 
• Treatment-related AE by SOC, PT and Severity 
• Melflufen-related AE by SOC, PT and Severity 
• Serious TEAE by SOC, PT and Severity 
• Serious Treatment-related AE by SOC, PT and Severity 
• TEAE resulting in dose modifications 
• Overview of AESI 
• Summary of Deaths 
• Listing of Fatal Adverse Events 
9.6.1 Exposure 
9.6.1.1 Overall Study Drug Exposure  
Duration of treatment will be summarized as a continuous variable using 
descriptive statistics. 
Treatment cycles and patients dosed by cycle will be summarized as counts 
and percentages, and as a continuous variable using descriptive statistics. 
9.6.1.2 Melflufen Exposure 
Duration of treatment, treatment cycles, cumulative dose, infusion time, 
average dose, and dose intensity will be summarized as continuous variables 
using descriptive statistics. 
Number of patients dosed, treatment cycles (overall and per dose), patients 
with dose modifications, cycles with dose modifications, cycles with dose 
reduction after dose delay of 3 weeks or longer, reason for dose reduction, 
patients with dose delay by cycle and categories of delay, and patients with 
dose reductions by cycle, will be summarized as counts and percentages. 


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9.6.1.3 Dexamethasone Exposure 
Duration of treatment, number of doses, cumulative dose, and dose intensity 
will be summarized as continuous variables using descriptive statistics. 
Dose modifications and reasons for permanent discontinuation will be 
summarized as counts and percentages. 
9.6.2 Adverse Events  
Number and percentage of patients with TEAEs will be summarized by 
categories of maximum severity, relationship with study drug (either, melflufen, 
and dexamethasone), seriousness and dose modifications of study drug (either, 
melflufen, and dexamethasone). 
Number and percentage of TEAEs will be summarized by SOC and PT by 
categories of severity, relationship with study drug, seriousness and dose 
modifications of study drug. Summaries that are displayed by SOC and PT will 
be ordered by descending order of incidence per SOC and PT within each SOC 
for the total group.  
Number and percentage of patients with TEAEs, SAEs, fatal TEAEs, and AEs 
leading to study drug discontinuation, by SOC and PT will also be summarized 
by subgroups listed in section 9.6.10. 
Separate listings of serious AEs, AEs leading to dose modification of melflufen, 
AEs leading to discontinuation of melflufen, AEs leading to dose modification of 
dexamethasone, or AEs leading to discontinuation of dexamethasone will be 
provided.  A separate listing will be provided for the SOC of “neoplasms benign, 
malignant and unspecified”. AEs that are not treatment-emergent will be provided 
in listings. 
9.6.3 Adverse Events of Special Interest 
AESI neutropenia will be summarized as counts and percentages, overall and 
per severity grade.  
AESI neutropenia concomitant to infection will be summarized as counts and 
percentages. 
AESI febrile neutropenia will be summarized as counts and percentages, overall 
and per severity grade. 
AESI infection will be summarized as counts and percentages, overall and per 
severity grade.  
AESI thrombocytopenia will be summarized as counts and percentages, overall 
and per severity grade.  


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AESI thrombocytopenia concomitant to hemorrhage will be summarized as 
counts and percentages. 
For the AESIs of neutropenia, thrombocytopenia, anemia, infection, and 
hemorrhage, the maximum toxicity grade during each cycle and at the End of 
Treatment visit will be summarized respectively. These tables will be presented 
for three subsets of cycles during which the AESI’s starts: 1) excluding last cycle 
per patient; 2) including the last cycle per patient; and 3) only the last cycle per 
patient. 
9.6.4 Deaths  
Number of deaths and the cause of death, as collected on the Patient Death 
CRF, will be summarized as counts and percentages, overall, and as 
categorized.  All deaths which occur on study are recorded on the Patient Death 
CRF, i.e. on treatment and off treatment.  The total number of deaths will not be 
equivalent to the number of fatal TEAEs. 
A listing of all deaths will be provided.   
9.6.5 Hematology, Serum Chemistry, and Coagulation 
Results and change from baseline at each scheduled visit for all hematology, 
serum chemistry, and coagulation parameters will be summarized with 
descriptive statistics. 
Toxicity grade of applicable parameters will be summarized as counts and 
percentages in shift tables of baseline versus worst toxicity grade through the 
End of Treatment visit.  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.   
For hemoglobin, ANC and platelet count, the maximum toxicity grade recorded 
during each cycle and at the End of Treatment visit will be summarized 
separately.   
 
For ANC and platelet count, results and change from the Day 1 pre-infusion 
value at Days 8, 15, and 22 during each cycle will be summarized as descriptive 
statistics. Corresponding line series plots of average values will also be provided.  
For ANC and platelet count, the time to onset (days) of grade 3 or 4 toxicity will 
be summarized by cycle and overall.  
9.6.6 Vital Signs 
Results and change from baseline for blood pressure, pulse, respiratory rate and 
temperature will be summarized by visit.  Results and change from pre-infusion 


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to post-infusion for blood pressure, pulse, respiratory rate and temperature will 
be summarized by cycle.  The nominal pre and post infusion timepoints on the 
CRF will be used as vital signs assessment time is not collected.  
9.6.7 ECOG Performance Status  
ECOG performance status will be summarized as counts and percentages using 
shift tables of baseline versus worst performance status during study.  The 
number of patients with improvement 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.  
9.6.8 Physical Examination 
Physical examination results will be listed without summary.   
9.6.9 12-Lead Electrocardiograms 
QTc-Fridericia (QTcF) interval results and changes from baseline will be 
summarized with descriptive statistics at baseline and End of Treatment visit.  
QTcF is calculated in the database as QTcF = QT / (RR)1/3 assuming units of 
milliseconds.  
9.6.10 Analyses by Subgroups 
The following safety endpoints will be provided for the EMD subgroup, based on 
the FAS: 
• Frequency of TEAEs, SAEs, fatal TEAEs, TEAEs leading to 
discontinuation, and TEAEs leading to dose modifications 
• Maximum severity grade of TEAEs 
• Frequency and grade of AESIs, 
• Frequency of melflufen dose modifications based on study drug exposure,  
• Treatment duration of melflufen 
Analysis of TEAEs, AESIs, SAEs, fatal TEAEs, TEAEs leading to discontinuation, 
and TEAEs leading to dose modifications will be provided by the following 
subgroups:  
• Age (<65, 65 - <75, ≥75 years) 
• Sex (male, female) 
• Race (White, All Other Races) 
• Geographic region (United States of America, Rest of World) 


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10 STATISTICAL/ANALYTICAL ISSUES 
10.1 Handling of Dropouts or Missing Data 
10.1.1 Efficacy Assessments 
The handling of dropouts and missing disease status assessments for the 
efficacy variables is described in their definitions.  Table 4: Conventions for 
Censoring of PFS describes how dropouts and missing data impact the 
calculation of the time to event variables. Missing data will not be estimated or 
carried forward for any of the other summaries. For partially completed PRO 
instruments see Sections 8.7.1 and 8.7.2 respectively. 
10.1.2 Safety Assessments 
10.1.2.1 
Adverse Events 
Adverse events with missing relationship are considered related for purposes of 
summaries. Imputed relationship will not be included in the listings.  
Adverse events with missing severity are considered severe (grade 3) for 
purposes of summaries.  Imputed severity will not be included in the listings. 
Adverse events with missing action taken with study drug are excluded from 
analyses. 
10.1.2.2 
Laboratory Assessments 
The following imputations will be made for missing reported units: 
• Creatinine clearance: ml/min 
• ALT: U/L 
• Albumin values less than 10: g/dL 
• INR: RATIO 
• Prothrombin Time (PT): seconds (sec) 
• Hematocrit values greater than 1: % 
• Hemoglobin values less than 20: g/dL  
• RBC: 10^12/L. 
• WBC and WBC differential counts with values less than 10: 10^9/L.  
Prothrombin times reported as %, which will not be imputed, will be omitted from 
summaries. 


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10.1.3 Dates and Times 
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. 
 
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. 
• 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).   
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. 
10.2 Multiplicity 
No inferential statistical comparisons using p-values are planned as part of this 
SAP. Confidence intervals will be provided for descriptive purposes, and the 
increasing probability of type I error by number of statistical conclusions should 
be considered when interpreting the results. The efficacy endpoints are listed by 
order of relevance and this hierarchy should be considered in summary 
conclusions. 


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10.3 Data Maturity 
The data cut-off date for the CSR will be at least 3 months after first 
administration of melflufen to the last patient enrolled. With a data cut-off of at 
least 3 months after first administration of melflufen in the last patient enrolled, at 
least 24 weeks follow-up (up to 6 cycles) would be accrued for more than 90% of 
all patients. This would represent an adequate amount of follow-up time for 
assessment of ORR and evaluation of safety, and a limited risk of having too few 
patients remaining at risk in secondary time-to-event efficacy endpoints.  
10.4 Interim Analysis for Futility 
In the initial study design one group of approximately 39 efficacy evaluable 
patients that were refractory to pomalidomide and one group of approximately 39 
efficacy-evaluable patients that were refractory to daratumumab were planned to 
be enrolled. Patients refractory to both drugs were assigned to both groups.   
A Simon two-stage optimal design [Simon 1989] was used for each group 
separately to determine whether study drug had sufficient activity to warrant 
further development in each group.  For each group, using Simon’s optimal two-
stage design (with significance level 10% and power of 80%), a true ORR of 15% 
or less was considered unacceptable (null hypothesis) whereas a true ORR of at 
least 30% (alternative hypothesis) would merit further study. In the first stage, 19 
efficacy evaluable patients were to be accrued.  If there were 3 or fewer 
responses observed, then the results were to be further reviewed by the Data 
Safety Monitoring Committee (DSMC) in order to determine if the second stage 
for the specific group would continue.  An interim analysis for futility was 
conducted after 19 patients had been enrolled in each group and were evaluable 
for response.  The response rates were 5/19 in the pomalidomide refractory 
group and 3/19 in the daratumumab refractory group.  The DSMC assessed the 
benefit/risk balance and found the balance to be positive in both of the groups as 
well as for the total study population.  Due to the overall positive benefit/risk 
balance, the DSMC recommended that the study recruitment proceed without 
changes or limitations. 
10.5 Changes to Planned Analyses 
10.5.1 Protocol Amendments 
The following protocol amendments have had implications on planned analyses:  
In protocol version 3.0, 19 Dec 2016, the following was added; 
1. Response assessments were to be evaluated by IRC. 
In protocol version 5.0, 31 May2018, the following was added; 


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1. Expansion of the study sample size 
2. Population considered one group, since majority of patients were 
refractory to both pomalidomide and daratumumab (patients refractory to 
pomalidomide and patients refractory to daratumumab are no longer 
evaluated separately) 
3. Addition of the objective to assess functional status and well-being  
4. Addition of the possibility to follow patients for OS for more than 24 
months" 
In protocol version 7.0, 04 Mar 2019, the following was added; 
1. Expand the drug class of anti-CD38 monoclonal antibodies (mAbs) from 
being limited to daratumumab only to include all anti-CD38 mAbs, i.e. 
accepting patients refractory to e.g. isatuximab (currently in phase 3 
clinical trials) as eligible.   
2. Adding transparency of a targeted sub-group of special interest, consisting 
of patients who are triple-class refractory (i.e. refractory to an 
immunomodulatory drug (IMiD), a proteasome inhibitor (PI) and an anti-
CD38 mAb). 
3. Addition of the assessment of functional status and well-being at follow up 
visits 
10.5.2 Analysis Sets 
The Efficacy evaluable analysis set will not be used for any analyses. The 
protocol defines this analysis set as all patients who receive at least 2 doses of 
melflufen, have a baseline disease assessment and at least 1 post-baseline 
disease assessment.  The definition has been modified to include all patients 
who receive at least 1 dose and have a baseline and at least 1 post-baseline 
response assessment, or who discontinued treatment due to progressive disease 
or death prior to the first post-baseline response assessment.  
Instead, it was decided to define the Full analysis set (FAS) as all patients who 
fulfil all eligibility criteria at screening and prior to initiation of therapy as per study 
protocol section 7.2, to be consistent with the intention-to-treat principle as per 
ICH E9. The FAS will be used for all analyses of efficacy. 
10.5.3 Subgroups of Specific Interest 
The decision to expand enrollment to 150 patients and to focus on analyses 
combining the patients that are refractory to pomalidomide and the patients that 
are refractory to daratumumab is described in section 11.3 of amendment 6 of 
the protocol (version 7, 4 March 2019).  It was also decided to introduce a 


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subgroup of specific interest and to provide summaries and analyses for patients 
who are triple-class refractory, as defined in section 8.4 of this SAP. This 
subgroup was identified as having an unmet medical need, potentially allowing 
FDA accelerated approval based on ORR and DOR in a single arm study.  
In addition, based on preliminary signals of efficacy, EMD was also identified as 
a subgroup of specific interest due to the poor prognosis of these patients. Data 
from the EMD subgroup will be presented separately for selected analyses. 
10.5.4 Objectives and Endpoints 
The purpose of the SAP update to version 3 was to clarify objectives and 
endpoints in relation to scientific rationale for NDA submission for accelerated 
approval, as was advised by FDA at a pre-NDA meeting on December 3rd 2019. 
The primary objective in this SAP relates to evaluation of efficacy, and the 
primary endpoint is ORR. DOR is considered the most relevant secondary 
efficacy endpoint. The evaluation of safety and tolerability is specified as a 
secondary endpoint. The ordering of endpoints is changed to reflect relevance 
and analytical hierarchy. It is clarified that patients with triple-class refractory 
RRMM is the subgroup of primary interest for these objectives.   
10.5.5 Clinical Study Report  
As a clarification to section 12.5 of the study protocol, the CSR was based on a 
data cut-off occurring at least 3 months after first administration of melflufen in 
the last patient enrolled, i.e. January 14, 2020. A future CSR addendum will be 
written based on data pertaining to long term follow-up of PFS and OS, at least 
12 months after first administration of melflufen in the last patient enrolled unless 
all patients have discontinued from the study before that.  
Analyses of HRQoL data as per January 14, 2020 will be performed based on an 
update of this SAP to version 5 and summarized in an appendix to the CSR to be 
submitted to European Medicinal Agency. HRQoL data was not part of main 
analyses for submission to FDA as per SAP version 4.   
 
 
 


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11 REFERENCES 
Chen EY, Raghunathan V, Prasad V. An Overview of Cancer Drugs 
Approved by the US Food and Drug Administration Based on the Surrogate 
End Point of Response Rate. JAMA Intern Med. 2019;179(7):915-921. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16(1):31-41. 
EuroQoL Research Foundation. EQ-5D-3L User Guide, version 6.0, 
December 2018. Available from: https://euroqol.org/publications/user-guides. 
Dolan, P. Modeling valuations for EuroQol health states. Med Care. 1997 
Nov;35(11):1095-108. 
Fayers PM, et al, on behalf of the EORTC Quality of Life Group. EORTC 
QLQ-C30 Scoring Manual (3rd edition). Brussels: EORTC, 2001. ISBN: 2-
9300 64-22-6. 
FDA Guidance for Industry on Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics  
FDA Guidance for Industry on Clinical Trial Endpoints for the Approval of 
Non-Small Cell Lung Cancer Drugs and Biologics  
FDA review of selinexor. XPOVIO (Selinexor) MULTI-DISCIPLINE REVIEW 
– FDA.  
Fleiss, J.L. Statistical Methods for Rates and Proportions, Second Edition, 
1981, New York: John Wiley & Sons, Inc. 
Gandhi UH, et al. Outcomes of Patients with Multiple Myeloma Refractory to 
CD38-Targeted Monoclonal Antibody Therapy. Leukemia. 2019 September; 
33(9): 2266–2275. 
ICH E9 Statistical Principles for Clinical Trials  
Kaplan, E. L. and P. Meier (1958). "Nonparametric estimation from 
incomplete observations." Journal of the American Statistical Association 53: 
457-485. 
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. 
Kvam A K, Fayers P, Wisloff F. What changes in health-related quality of life 
matter to multiple myeloma patients? A prospective study. Eur J Haematol. 
2010 Apr;84(4):345-53.  
Rajkumar SV, Harousseau JL, Durie BGM, Anderson KC, Dimopoulos M, 
Kyle R et al.  Consensus recommendations for the uniform reporting of 


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clinical trials: report of the International Myeloma Workshop Consensus 
Panel 1.  Blood 2011; 117: 4691-4695. 
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. 
POMALYST label. POMALYST (pomalidomide) capsules - FDA. 
NDA204026, NDC 59572-503-21.  
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure 
time. Controlled Clinical Trials 1996; 17:343–346. 
Simon, R. (1989). Optimal two-stage designs for phase II clinical trials. 
Control Clin Trials 10(1): 1-10. 
Sonneveld P, et al. Treatment of multiple myeloma with high-risk 
cytogenetics: a consensus of the International Myeloma Working Group. 
Blood. 2016 Jun 16; 127(24): 2955–2962. 
Spicka, I, et al. Randomized phase III study (ADMYRE) of plitidepsin in 
combination with dexamethasone vs. dexamethasone alone in patients with 
relapsed/refractory multiple myeloma. Ann Hematol (2019) 98:2139–2150. 
The National Cancer Institute. Common Terminology Criteria for Adverse 
Events (CTCAE 4.03) June 14, 2010  
 
 
 
 

Prot_000.pdf: 
Confidential 
Page 1 
Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Clinical Development Protocol 
HORIZON TRIAL 
A Single Arm, Open-Label, Phase 2 Study of Melflufen in Combination with Dexamethasone in 
Patients with Relapsed Refractory Multiple Myeloma who are Refractory to Pomalidomide 
and/or an anti-CD38 Monoclonal Antibody 
Investigational Product 
Study Sponsor 
Protocol Number 
EUDRACT Number 
Investigational New Drug Number 
Clinical Research Organization 
Development phase 
Document status 
Melflufen 
Oncopeptides AB 
Västra Trädgårdsgatan 15 
SE-111 53 Stockholm, Sweden 
OP-106; NCT02963493 
2016-000965-21 
116362 
Precision Oncology 
200 Route 31 North 
Suite 102 
Flemington, NJ 08822 
USA 
Phase 2 
Version 1.0: May 4, 2016 
Version 2.0, Amendment 1: October 13, 2016 
Version 3.0, Amendment 2: December 19, 2016  
Version 4.0, Amendment 3: July 12, 2017 
Version 5.0, Amendment 4: May 31, 2018 
Version 6.0, Amendment 5: November 27, 2018 
Version 7.0, Amendment 6: March 4, 2019 
Version 7.1, Amendment 7: March 20, 2020 
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. 


Oncopeptides AB 
Confidential 
Signature Page 
Protocol Number: OP-106: HORIZON TRIAL 
Page2 
Protocol No. OP-106 
Protocol Title: 
A Single Arm, Open-Label, Phase 2 Study ofMelflufen in Combination with 
Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma who 
are Refractory to Pomalidomide and/or an anti-CD38 Monoclonal Antibody 
Date of Original Protocol: Version 1.0: May 4, 2016 
Version 2.0, Amendment 1: October 13, 2016 
Version 3.0, Amendment 2: December 19, 2016 
Version 4.0, Amendment 3: July 12, 2017 
Version 5.0, Amendment 4: May 31, 2018 
Version 6.0, Amendment 5: November 27, 2018 
Version 7.0, Amendment 6: March 4, 2019 
Version 7.1, Amendment 7: March 20, 2020 
Approved By: 
Study Physician 
Global Lead Investigator 
Head of Clinical Development 
Date 
Date 
Date 
Protocol OP-106. Version 7.1, Amendment 7: 04Mar2020 


 
 
Confidential 
Page 3 
Oncopeptides AB 
 
Protocol No. OP-106  
 
 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
 
Protocol Acceptance Page 
 
 
Protocol Number:  OP-106   HORIZON TRIAL 
 
Protocol Title:   
A Single Arm, Open-Label, Phase 2 Study of Melflufen in Combination with 
Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma who 
are Refractory to Pomalidomide and/or an anti-CD38 monoclonal antibody 
 
 
Protocol Date:  
Version 1.0: May 4, 2016 
Version 2.0: 
Amendment 1: October 13, 2016 
Version 3.0:  Amendment 2: December 19, 2016 
Version 4.0:  Amendment 3: July 12, 2017 
Version 5.0:  Amendment 4: May 31, 2018 
Version 6.0:  Amendment 5: November 27, 2018 
Version 7.0:  Amendment 6: March 4, 2019 
Version 7.1: 
Amendment 7: March 20, 2020 
 
 
By signing this protocol acceptance page, I confirm I have read, understood, and agree to conduct 
the study in accordance with the current protocol.  
 
 
__________________________________________ 
Principal Investigator Name (Printed) 
 
__________________________________________ 
____________ 
Principal Investigator Signature 
 
 
 
Date 
 
 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations Title 
21), and with the ethical principles laid down in the Declaration of Helsinki. 
 
The study protocol and any amendments are to be reviewed by an Independent Ethics Committee 
(IEC) or Institutional Review Board (IRB) before implementation. 
 
Confidential information contained in this document will not be used for any purpose other than 
the evaluation or conduct of the clinical investigation without the prior written consent of 
Oncopeptides AB. 


 
 
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Oncopeptides AB 
 
Protocol No. OP-106  
 
 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
 
TABLE OF CONTENTS 
Table of Contents .............................................................................................................. 4 
List of Figures ................................................................................................................... 6 
List of Tables ..................................................................................................................... 6 
Protocol Synopsis: ............................................................................................................. 7 
1 
BACKGROUND ............................................................................................ 25 
1.1 
Overview of Multiple Myeloma ..................................................................... 25 
1.2 
Overview of Melflufen ................................................................................... 27 
2 
STUDY RATIONALE ................................................................................... 33 
2.1 
Rationale for the selected patient population .................................................. 33 
2.2 
Rationale for Dose Selection .......................................................................... 34 
2.3 
Rationale for study expansion ......................................................................... 34 
3 
OBJECTIVES AND ENDPOINTS ................................................................ 35 
3.1 
Primary Objective ........................................................................................... 35 
3.2 
Primary Endpoint ............................................................................................ 36 
4 
STUDY DESIGN............................................................................................ 36 
4.1 
Description of Study Design ........................................................................... 36 
5 
PATIENT POPULATION .............................................................................. 37 
5.1 
Patient Screening ............................................................................................ 37 
5.2 
Patient Eligibility ............................................................................................ 37 
5.3 
Inclusion Criteria ............................................................................................ 37 
5.4 
Exclusion Criteria ........................................................................................... 39 
6 
PATIENT ENROLLMENT ............................................................................ 40 
6.1 
Enrollment Procedure ..................................................................................... 40 
6.2 
Patient Numbering .......................................................................................... 40 
6.3 
Replacement Policy ........................................................................................ 40 
7 
TREATMENT ................................................................................................ 40 
7.1 
Study Treatment .............................................................................................. 40 
7.2 
Initiation of Therapy ....................................................................................... 41 
7.3 
Melflufen......................................................................................................... 42 
7.4 
Dexamethasone ............................................................................................... 43 
7.5 
Study Drug Compliance and Accountability .................................................. 44 
7.6 
Concomitant Therapy...................................................................................... 44 
7.7 
Dose Modifications ......................................................................................... 46 
8 
VISIT SCHEDULE AND ASSESSMENTS .................................................. 52 
8.1 
Schedule of Events .......................................................................................... 52 


 
 
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Oncopeptides AB 
 
Protocol No. OP-106  
 
 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
 
8.2 
Study Assessments .......................................................................................... 58 
9 
SAFETY MONITORING AND REPORTING.............................................. 63 
9.1 
Adverse Events ............................................................................................... 63 
9.2 
Serious Adverse Events .................................................................................. 66 
9.3 
Pregnancy ........................................................................................................ 68 
9.4 
Data Safety Monitoring Committee ................................................................ 69 
10 
DATA COLLECTION AND MANAGEMENT ............................................ 69 
10.1 
Data Confidentiality ........................................................................................ 69 
10.2 
Site Monitoring ............................................................................................... 69 
10.3 
Data Collection ............................................................................................... 70 
10.4 
Database Management and Quality Control ................................................... 70 
11 
STATISTICAL METHODS AND DATA ANALYSIS ................................ 70 
11.1 
Study Endpoints .............................................................................................. 70 
11.2 
Sample Size Calculation ................................................................................. 71 
11.3 
Sub-group Of Specific Interest ....................................................................... 72 
11.4 
Statistical Methods .......................................................................................... 72 
11.5 
Handling of Drop-Outs and Missing Data ...................................................... 76 
12 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES76 
12.1 
Regulatory and Ethical Compliance ............................................................... 76 
12.2 
Responsibilities of the Investigator and IRB/IEC ........................................... 76 
12.3 
Informed Consent Procedures ......................................................................... 76 
12.4 
Discontinuation of the Study .......................................................................... 77 
12.5 
Publication of Study Protocol and Results...................................................... 77 
12.6 
Study Documentation, Record Keeping and Retention of Documents........... 77 
12.7 
Confidentiality of Study Documents and Patient Records ............................. 78 
12.8 
Audits and Inspections .................................................................................... 78 
12.9 
Financial Disclosures ...................................................................................... 78 
12.10 
Protocol Adherence ......................................................................................... 78 
12.11 
Amendments to the Protocol ........................................................................... 78 
13 
REFERENCES ............................................................................................... 80 
14 
APPENDICES ................................................................................................ 83 
APPENDIX A.  ECOG PERFORMANCE SCALE ................................................................. 83 
APPENDIX B.  NCI CTCAE VERSION 4.03 ......................................................................... 84 
APPENDIX C.  IMWG RESPONSE CRITERIA .................................................................... 85 
APPENDIX D.  LINE OF THERAPY DEFINITION.............................................................. 87 
APPENDIX E.  DEFINITION OF RELAPSED REFRACTORY DISEASE ......................... 88 
APPENDIX F.  DECLARATION OF HELSINKI................................................................... 88 


 
 
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Oncopeptides AB 
 
Protocol No. OP-106  
 
 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
 
APPENDIX G.  RENAL FUNCTION CALCULATIONS ...................................................... 89 
APPENDIX H.  QTC FRIDERICIA FORMULA..................................................................... 89 
APPENDIX I.   ISS AND R-ISS SCORE ................................................................................ 90 
APPENDIX J.   QLQ-C30 ........................................................................................................ 91 
APPENDIX K. EQ-5D-3L........................................................................................................ 93 
 
LIST OF FIGURES 
Figure 1-1:  Structure of Melflufen ........................................................................................... 27 
 
LIST OF TABLES 
Table 1-1   Summary of Melflufen Treatment Related Grade 3 or 4 AE in ≥ 5% of 40 Patients 
Dosed with 40 mg Melflufen in Clinical Trial O-12-M1 ......................................................... 30 
Table 7-2    Dose Reduction Steps for Melflufen ..................................................................... 46 
Table 7-3    Dose Modifications of Melflufen for Hematologic Toxicity: ............................... 47 
Table 7-4    Dose Reduction Steps for Dexamethasone ............................................................ 49 
Table 7-5    Dose Modifications for Toxicity Related to Dexamethasone ............................... 51 
Table 8-1   Schedule of Events ................................................................................................. 53 
Table 9-1    Adverse Event Severity ......................................................................................... 64 
Table 11-1  Conventions for Censoring for PFS ...................................................................... 74 
 
 
 
 


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
PROTOCOL SYNOPSIS: 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
Chemical Name 
 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-
phenylalanine ethyl ester hydrochloride 
Study Protocol 
Title 
A Single Arm, Open-Label, Phase 2 Study of Melflufen in 
Combination with Dexamethasone in Patients with Relapsed 
Refractory Multiple Myeloma who are Refractory to Pomalidomide 
and/or an Anti-CD38 Monoclonal Antibody 
Study Sponsor 
Oncopeptides AB 
Global Lead 
Investigator 
Sites 
Approximately 15-20 sites in Europe and the USA 
Study Period 
First patient in December 2016 with approximately 32 months of 
recruitment. Treatment may continue until disease progression or 
unacceptable toxicity, thereafter follow-up for overall survival. 
Background and 
Rational 
Melflufen is a peptidase-potentiated therapy designed for targeted 
delivery of alkylating moieties to tumor cells. In contrast to other 
alkylating agents that are hydrophilic, the lipophilicity of melflufen 
leads to rapid and extensive distribution into tissues and cells.  Inside 
cells, melflufen may directly bind deoxyribonucleic acid (DNA) or 
is readily metabolized by intracellular peptidases into the well-
known antitumor compound melphalan, or by esterases into des-
ethylmelflufen, which also has alkylating properties.  Due to the high 
activity of peptidases and esterases in human tumor cells, the 
formation of melflufen’s metabolites is rapid in these cells with 
subsequent inflow of more melflufen (Gullbo et al. 2003c, 
Wickstrom et al. 2010). Since des-ethylmelflufen and melphalan are 
relatively hydrophilic, there is a possibility for intracellular trapping 
of these alkylators.  This can be explained by a more efficient 
transport of melflufen into these cells, an efficient conversion into 
other alkylating molecules (i.e. melphalan and desethyl-melflufen) 
inside the cells and a less rapid disappearance of these molecules 
from the cells. 
The addition of melflufen to panels of primary cultures of human 
tumor cells, including multiple myeloma (MM), results in a similar 
pattern of activity as that of melphalan, but with 50 to 100-fold higher 
efficacy (Wickstrom et al. 2008), which is explained by the 50-fold 


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
higher intracellular exposure in MM cells of alkylating agents 
compared to that observed after an equimolar dose of melphalan 
(Chauhan et al. 2013a).  Mechanistically oriented studies have shown 
that melflufen-induced apoptosis is associated with (i) activation of 
caspases and poly ADP ribose polymerase (PARP) cleavage; (ii) 
reactive oxygen species generation; (iii) mitochondrial dysfunction 
and release of cytochrome c; and (iv) induction of DNA damage 
(Chauhan et al. 2013a).  Moreover, melflufen inhibits MM cell 
migration and tumor associated angiogenesis.  Importantly, in vitro 
studies in MM cell lines resistant to dexamethasone, bortezomib and 
melphalan have shown cytotoxic activities of melflufen at 
concentrations similar to those observed in the parental, non-resistant 
cell lines. In efficacy studies conducted in mice and rats carrying 
different human tumors, including MM, superior antitumor activity 
of melflufen over equimolar dosage of melphalan was observed at 
seemingly comparable toxicity (Gullbo et al. 2004, Wickstrom et al. 
2007, Chauhan et al. 2013a). 
Melflufen is currently being evaluated in combination with low dose 
dexamethasone and as single agent in a Phase 1/2a clinical trial (O-
12-M1) in relapsed refractory MM (RRMM).  The Phase 1 part of
the clinical trial, completed in September 2014, established the
maximum tolerated dose (MTD) at 40 mg of melflufen every 21 days
combined with 40 mg dexamethasone weekly (Paba-Prada et al.
2014). The schedule was later changed to 28 days in a Phase 2
amendment. The dose limiting toxicities consisted of dose-dependent
neutropenia and thrombocytopenia manageable with dose delays and
appropriate treatment, including dose reductions in subsequent
cycles.
A preliminary assessment of data from clinical trial O-12-M1 was 
performed on patients who were evaluable for efficacy by 11 Feb 
2016. Of the 30 efficacy evaluable patients treated with 40 mg 
melflufen in combination with dexamethasone, 19 patients (63%) 
have reported a best response of minimal response (MR) or better 
and 12 patients (40%) have reported partial response (PR) or better. 
These 30 patients had a median of 4 prior lines of therapy, including 
immunomodulatory drugs (IMiD)s, proteasome inhibitors (PI)s and 
alkylators. The median progression free survival (PFS) was 4.5 
months at the time of data-cut based on 30 events in 40 patients with 
≥1 cycle. Median number of cycles is 3.5 (range 1 – 14). 


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
The safety profile of melflufen suggested by preclinical studies is 
supported by clinical data from 45 patients with solid tumors and 
from a total of 57 patients with RRMM in the Phase 1/2a clinical trial 
O-12-M1 [40 patients dosed at the maximum tolerated dose (MTD)
of 40 mg of melflufen and 17 patients dosed at other doses in Phase
1 of the trial].
Taken together, clinical and preclinical data support that melflufen 
provides peptidase-potentiated delivery of alkylating moieties to 
tumor cells (such as MM cells) and thereby exerts a higher anti-tumor 
activity compared with equimolar administration of melphalan but 
with a seemingly similar safety profile. The efficacy seems to be 
consistent across MM populations including patients who are double-
refractory to IMiDs and PIs and refractory to alkylators. 
The present Phase 2 study will explore the use of melflufen plus 
dexamethasone in patients with pomalidomide and/or an anti-CD38 
monoclonal antibody (mAb) refractory disease. In this population, 
there is a clear lack of treatment alternatives and a high unmet 
medical need. 
As of 22 October 2018, a total of 83 patients had been enrolled in the 
study: the population characteristics include a median number of 5 
prior lines, with 60% of patients being refractory to pomalidomide 
and daratumumab, and 60% refractory to an IMiD, a PI and an anti-
CD38 mAb. The preliminary ORR for the whole population (N=83) 
was 33%. (ASH 2018 oral presentation). 
The safety profile is acceptable, with primary adverse events being 
thrombocytopenia, neutropenia and anemia, and few grade 3/4 non-
hematological adverse reactions. (ASH 2018 oral presentation, IB 
edition 8.0). 
As the study suggests a positive benefit-risk ratio for heavily pre-
treated patients receiving melflufen, the sponsor expanded the study 
cohort for further collection of safety and efficacy data. Expansion of 
the study also allows for collection of functional status and well-
being information. 
Study Design 
This is a single arm, open-label, Phase 2 multicenter study which will 
enroll patients with RRMM following at least 2 lines of prior therapy 
(Appendix D), including an IMiD and a PI, and who are refractory to 
pomalidomide and/or an anti-CD38 mAb defined as patients who 
relapse while on therapy or within 60 days of last dose. 


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
Patients will be treated with melflufen 40 mg on Day 1 and 
dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.  
Patients ≥ 75 years of age will have a reduction of the starting dose 
of dexamethasone from 40 mg to 20 mg on the same schedule.  In 
the event of cycle delay, in the absence of dexamethasone toxicity, it 
is recommended that dexamethasone continue weekly. 
Patients may receive treatment until there is documented disease 
progression, unacceptable toxicity or the patient/treating physician 
determine it is not in the patient’s best interest to continue.   
Dose modifications and delays in therapy may be implemented based 
on patient tolerability as detailed in the protocol. 
A Schedule of Events for the study is outlined in Table 8-1 of the 
protocol. 
Objectives  
Primary Objective 
•
To assess overall response rate (ORR), i.e. proportion of patients
with ≥ partial response (PR) [stringent CR (sCR), complete
response (CR), very good partial response (VGPR), and PR] as
best response in efficacy evaluable patients as assessed by the
investigator according to IMWG Uniform Response Criteria
(Rajkumar et al. 2011) (Appendix C).
Key Secondary Objectives 
•
To assess PFS according to IMWG Criteria (Rajkumar et al.
2011),
•
To assess duration of response (DOR) in efficacy evaluable
patients with ≥ PR (sCR, CR, VGPR, PR) as best response
according to IMWG Uniform Response Criteria (Rajkumar et al.
2011).
•
To assess overall survival (OS).
Other Secondary Objectives
•
To assess clinical benefit rate (CBR, i.e. proportion of patients
with ≥ MR) as best response in efficacy evaluable patients
•
Time to response (TTR)
•
Time to progression (TTP)
•
To assess the safety and tolerability
•
To assess functional status and well-being


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
Endpoints 
Primary Endpoint: 
•
Best response of PR or better, as assessed by the investigator
according to IMWG-URC, from which ORR is calculated.
Secondary Endpoints 
•
PFS
•
DOR
•
OS
•
Best response of MR or better, from which CBR is calculated
•
TTR
•
TTP
•
Duration of SD
•
Frequency and grade of adverse events
•
Change from baseline in QLQ-C30 assessment
Change from baseline in EQ-5D-3L assessment 
All tumor response and progression-depended endpoints are as 
assessed by the investigator assessment of response according to the 
International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) (Rajkumar et al. 2011, Appendix C).  
Inclusion Criteria 
Patients will be considered for inclusion in this study if they meet 
all of the following criteria: 
1. Male or female, age 18 years or older
2. A prior diagnosis of multiple myeloma with documented
disease progression in need of treatment at time of screening.
3. Measurable disease defined as any of the following:
•
Serum monoclonal protein ≥ 0.5 g/dL (≥ 5g/L) by protein
electrophoresis (SPEP)
•
≥ 200 mg/24 hours of monoclonal protein in the urine on
24-hour urine electrophoresis (UPEP)
•
Serum immunoglobulin free light chain ≥10 mg/dL (≥100
mg/L) AND abnormal serum immunoglobulin kappa to
lambda free light chain ratio
4. A minimum of 2 prior lines of therapy including an IMiD and
a PI and is refractory to pomalidomide and/or an anti-CD38
mAb (Refractory is defined as patients who relapse while on
therapy or within 60 days of last dose of pomalidomide and/or
an anti-CD38 mAb in any line, regardless of response).


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
5. Life expectancy of ≥ 6 months;
6. Eastern Cooperative Oncology Group (ECOG) performance
status ≤ 2. (Patients with worse performance status based
solely on bone pain secondary to multiple myeloma may be
eligible following consultation and approval of the medical
monitor)
7. Female of child bearing potential (FCBP)* and non-
vasectomized male agree to practice appropriate methods of
birth control (Section 7.6.1)
8. Ability to understand the purpose and risks of the study and
provide signed and dated informed consent and authorization
to use protected health information
9. 12-lead electrocardiogram (ECG) with QTc interval
calculated by Fridericia Formula QTcF interval of ≤ 470
msec (Appendix H)
10. The following laboratory results must be met during
screening (within 21 days) and also prior to study drug
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
prior to initiation of therapy)
•
Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without
transfusions during 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); or
higher value in patients diagnosed with Gilberts
syndrome after review and approval by the medical
monitor.
•
Aspartate transaminase (AST) and alanine transaminase
(ALT) ≤ 3.0 x ULN
•
Renal function: Estimated creatinine clearance by
Cockcroft-Gault formula ≥ 45 mL/min. For women ≤
155cm in height and with normal BMI (18.5 – 24.9
kg/m2) the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) method for calculation of
glomerular filtration may be used (Appendix G). Cases
with borderline values of creatinine clearance based on


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
the Cockcroft-Gault formula may be discussed with the 
medical monitor. 
11. Must have, or accept to have, an acceptable central catheter
for infusion of melflufen prior to the first dose. (Port a cath,
peripherally inserted central catheter (PICC) line, or central
venous catheter)
*(FCBP) is any sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (not having menstrual cycles due to cancer therapy 
does not rule out childbearing potential) for at least 24 consecutive 
months. 
Exclusion Criteria 
Patients will be ineligible for this study if they meet any one of 
the following criteria: 
1. Evidence of mucosal or internal bleeding and/or is platelet
transfusion refractory (i.e. platelet count fails to increase
by > 10,000 cells/mm3 after a transfusion of an appropriate
dose of platelets).
2. 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 conduction system
abnormalities, 
uncontrolled 
hypertension, ≥ grade 
3
thromboembolic event in the last 6 months).
3. Active infection, treated with parenteral anti-infectives
within 14 days, or oral anti-infectives within 7 days, prior to
initiation of treatment (exceptions may be considered after
review and approval by the medical monitor).
4. Primary refractory disease (i.e. never responded (≥ MR) to
any prior therapy).
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, and very-low and low risk prostate
cancer patients in active surveillance as defined in NCCN
version 3.2016.
6. Pregnant or breast-feeding females


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
7. Serious psychiatric illness, active alcoholism, or drug
addiction that may hinder or confuse compliance or follow-
up evaluation
8. Known HIV or active hepatitis B or C viral infection
9. Concurrent symptomatic amyloidosis or plasma cell
leukemia
10. POEMS 
syndrome 
[plasma 
cell 
dyscrasia 
with
polyneuropathy, organomegaly, endocrinopathy, monoclonal
protein (M-protein) and skin changes]
11. Previous 
cytotoxic 
therapies, 
including 
cytotoxic
investigational agents, for multiple myeloma within 3 weeks
(6 weeks for nitrosoureas) prior to initiation of therapy.
IMiDs, PIs and/or corticosteroids within 2 weeks prior to
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
investigational therapies and monoclonal antibodies or live
vaccines within 4 weeks of initiation of therapy (other
washout times may be considered following consultation
with the medical monitor).
12. Residual side effects to previous therapy > grade 1 prior to
initiation of therapy (Alopecia any grade and/or neuropathy
grade 2 without pain are permitted)
13. Prior autologous or allogeneic stem cell transplant within 12
weeks of initiation of therapy
14. Prior allogeneic stem cell transplant with active graft-versus-
host- disease (GVHD).
15. Prior major surgical procedure or radiation therapy within 4
weeks of the first dose of study treatment (this does not
include limited course of radiation used for management of
bone pain within 7 days of initiation of therapy).
16. Known intolerance to steroid therapy
 Study 
Treatment(s) 
Treatment will be given in cycles in an outpatient treatment setting.  
Planned cycle length is 28 days. 
Melflufen 40 mg will be administered as a 30-minutes intravenous 
(iv) infusion on Day 1 of every 28-day cycle via acceptable central
catheter.


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
Dexamethasone 40 mg should be administered orally on Days 1, 8, 
15 and 22 of each 28-day cycle.  Dexamethasone starting dose will 
be reduced to 20 mg on the same schedule for patients ≥ 75 years of 
age.  
Dose 
modifications 
and 
delays 
for 
both 
melflufen 
and 
dexamethasone may be implemented based on patient tolerance as 
detailed in Section 7.7. In the event of cycle delays, in the absence of 
dexamethasone toxicity, it is recommended that dexamethasone 
continue weekly. 
Duration of 
treatment 
Patients will receive treatment until there is documented progressive 
disease (PD) (PD to be confirmed on two consecutive assessments), 
unacceptable toxicity, or the patient/treating physician determines it 
is not in the patient’s best interest to continue.  
Duration of 
follow-up 
Follow up for progression free survival (PFS-FU): Patients who 
discontinue treatment for reasons other than disease progression will 
continue to be followed for disease response monthly until disease 
progression (PD to be confirmed on two consecutive assessments) or 
initiation of subsequent therapy, whichever comes first.   
Follow up for overall survival (OS-FU): Following disease 
progression or initiation of subsequent therapy, patients should be 
followed every three months, for 24 months for overall survival 
including recordings of first subsequent therapy and secondary 
malignancies. In the event that Oncopeptides AB would like to 
determine the OS status of patients following 24 months, future 
inquiries about their health status may be conducted.  
Concomitant 
Drug/Therapy 
All blood products and concomitant medications received within 21 
days of the initiation of therapy until the end of study visit should be 
recorded.  Refer to Section 7.6 for a complete list of required, 
recommended and prohibited concomitant medications and 
therapies.  Antibacterial, antifungal and antiviral prophylaxis should 
be given according to National Comprehensive Cancer Network 
(NCCN 2015) or institutional guidelines ( See Section 7.6).  
Number of Patients A total number of approximately 150 patients are planned to be 
enrolled in the study, to achieve 130 patients evaluable for efficacy, 
including 50 patients evaluable for EQ-5D-3L.  


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Oncopeptides AB 
Protocol No. OP-106 
Protocol OP-106. Version 7.1, Amendment 7: 20Mar2020 
Compound Name 
Melflufen 
Protocol Name 
OP-106 
The study initially evaluated patients refractory to pomalidomide and 
patients refractory to daratumumab (an anti-CD38 mAb) separately 
to evaluate clinical benefit in both groups, with a target enrollment 
of approximately 39 efficacy evaluable patients per group. This 
original sample size was expanded in protocol amendment 4. Instead 
of calculating the sample size on the power to show superiority on 
ORR versus a fixed value, the sample size is now based on the 
precision of the estimates. As for the ORR, given a sample size of 
130 evaluable patients and an observed ORR of 30%, the exact 95 % 
confidence interval would range from 22.3 % to 38.7 %.  
Sub-group of 
specific interest 
Patients that are refractory to all three currently approved classes of 
drugs (IMiDs, PIs and anti-CD38 mAbs) have emerged as a sub-
group of particular interest. 
All efficacy and safety analyses performed for the total population 
will be repeated in a similar way for this sub-population. In 
a retrospectively analysis as of 06 February 2019, this triple-class 
refractory sub-group represented 70% of the total population (67 of 
95 patients). All triple-class refractory patients that are enrolled in 
the study on or after the date of the retrospective analysis will be 
followed prospectively. The ORR for patients of this sub-group 
accrued retrospectively before 06 February 2019 will be reported as 
well as patients prospectively enrolled after this date. If there is no 
substantial difference in ORR, the results will be presented for the 
total sub-group.  Assuming a similar (or slightly higher) proportion 
of patients within the remaining approximately 55 patients, about 40 
patients of the sub-group of specific interest can be followed 
prospectively. 
Assessments 
A complete list of study assessments and time lines can be found in 
Table 8-1, Schedule of Events.  
Screening Disease Assessments 
• M-protein determination using the following procedures:
- Serum protein electrophoresis (SPEP) and serum protein
immunofixation (IFE) with quantitative immunoglobulins
(Ig); and
- Urine protein electrophoresis (UPEP) and urine protein
immunofixation (all using the same 24-hour urine collection)
- Serum free light chains (SFLC) and SFLC ratio


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Compound Name 
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Protocol Name 
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•
Bone marrow to quantify percent myeloma cell involvement
•
Extramedullary plasmacytoma evaluation (by physical
examination (PE) and/or imaging technique)
•
Skeletal survey or low dose computerized tomography (CT)
scan.
•
Beta2 microglobulin
•
Lactate dehydrogenase (LDH)
•
Cytogenetics by fluorescence in situ hybridization (FISH)
•
International staging system (ISS) staging score and Revised-
ISS (R-ISS) (Appendix I)
Efficacy Assessments: 
• M-protein determination using the following procedures:
- SPEP and serum protein IFE with quantitative Ig
(quantitative Ig required only for patients with IgA and IgD
myeloma); and
- UPEP and urine protein IFE (all using the same 24-hour urine
collection)
- SFLC and SFLC ratio
• Bone marrow to quantify percent myeloma cell involvement
• Extramedullary plasmacytoma evaluation
• Skeletal x-rays or low dose CT scan (same technique used at
screening and each evaluation).
• Serum calcium (corrected calcium)
M protein disease status (assessed by M-protein quantitation, IFE 
and free light chain from serum and 24-hour urine collection) 
should be assessed at screening and Cycle 1 Day 1. Starting with 
Cycle 2, M protein response to treatment should be assessed every 
cycle.  Disease status, including skeletal x-rays or CT scan of 
bones and imaging assessment (i.e. CT, positron emission 
tomography (PET), magnetic resonance imaging [MRI] scan) of 
known or suspected extramedullary plasmacytomas will be 
performed at screening and if indicated according to the IMWG 
response criteria to evaluate response and/or progression. Bone 
marrow aspirate will be performed at screening and to confirm 


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Protocol Name 
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suspected CR in patients who have achieved a negative IFE. 
Additional skeletal x-rays and/or imaging assessments may be 
performed, at the investigator’s discretion, at screening to further 
evaluate plasmacytomas. All imaging assessments should be 
documented in the eCRF. Repeat assessments if the patient has 
symptoms suggestive of progression of lesion(s) documented at 
screening or new lesions. If extramedullary plasmacytomas are 
present and measurable on physical examination, they will be 
assessed at every cycle.  Extramedullary plasmacytomas 
documented and measurable only by imaging assessments will be 
assessed by the consistent relevant modality to confirm response 
or progression according to the IMWG response criteria. 
• Functional status and well-being
Two different PROs will be used to evaluate functional status
and well-being in the study; the EORTC QLQ-C30 and the EQ-
5D-3L.
- EORTC QLQ-C30, which includes 30 items resulting in 5
functional scales, 1 Global Health Status scale, 3 symptom
scales, and 6 single items. The recall period is 1 week (the
past week). The EORTC QLQ-C30 has been widely used
among cancer patients. Scores are transformed to a 0 to 100
scale. Administration time is approximately 11 minutes.
QLQ-C30 domain scores will be summarized at each time
point and change from baseline will be derived. The
relationship between clinical response and change in domain
scores will be explored.
- EQ-5D-3L, a generic measure of health status. For the
purpose of this study the EQ-5D-3L will be used to generate
utility scores for use in cost-effectiveness analyses. The EQ-
5D-3L is a 5-item questionnaire that assesses 5 domains
including 
mobility, 
self-care, 
usual 
activities,
pain/discomfort and anxiety/depression plus a visual analog
scale (EQ VAS) rating “health today” with anchors ranging
from 0 (worst imaginable health state) to 100 (best
imaginable health state). The scores for the 5 separate


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Protocol Name 
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questions are categorical and cannot be analyzed as cardinal 
numbers. However, the scores for the 5 dimensions are used 
to compute a single utility score ranging from zero (0.0) to 1 
(1.0) representing the general health status of the individual. 
The 5 domains of EQ-5D-3L and the EQ VAS will be 
summarized at each time point and change from baseline will 
be derived. 
Safety Assessments: 
• Assessment and grading of adverse events
• Physical examinations with vital signs, neurologic assessment
and assessment of performance status
• Routine safety laboratory tests (Complete blood count (CBC)
with differential and platelets; serum chemistry and coagulation
tests) with calculation of creatinine clearance by Cockcroft-
Gault formula. For women ≤ 155cm in height and with normal
BMI (18.5 – 24.9 kg/m2) the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) method for calculation
of glomerular filtration may be used (Appendix G). Cases with
borderline values of creatinine clearance based on the
Cockcroft-Gault formula may be discussed with the medical
monitor.
• Pregnancy testing
• Electrocardiogram
• Chest X-ray
Adverse experiences, including clinical laboratory and vital sign 
abnormalities, will be graded using the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events version 
4.03.   
Analysis Sets & 
Statistical methods 
Efficacy Analysis Set: 
The primary efficacy evaluable population will be comprised of all 
patients who received at least 2 doses of melflufen, had a baseline 
disease assessment and at least 1 post-baseline disease assessment. 
All Treated Analysis Set: 


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Compound Name 
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Protocol Name 
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All patients that receive any melflufen or dexamethasone treatment 
will be considered evaluable for safety analysis.  
Statistical Methods: 
The overall response rate (ORR) will be estimated as the proportion 
of patients who achieve a confirmed sCR, CR, VGPR, or PR as their 
best response as assessed by the investigator. At the end of the trial 
an exact two-sided 95% confidence interval for ORR will be 
determined. 
The distribution of PFS will be summarized using the Kaplan Meier 
(K-M) method (Kaplan et al. 1958).  The median PFS will be 
estimated from the 50th percentile of the corresponding K-M 
estimates.   
Other time to events endpoints will be analyzed using the same 
method as for PFS. 
Clinical benefit rate (CBR), will be presented with its associated 95% 
exact two-sided confidence interval.  
The absolute values as well as change in EQ-5D-3L scores and QLQ-
C30 scores will be described at each measured time point using 
descriptive statistics.  
The maximum grade (according to CTCAE v4.03) for each type of 
adverse event will be recorded for each patient, and frequency tables 
will be presented and reviewed to determine patterns.  Additionally, 
the relationship of the adverse event(s) to the study treatment will be 
taken into consideration. 
ICH and Ethics 
This clinical study was designed and shall be implemented and 
reported in accordance with the ICH Harmonized Tripartite 
Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code 
of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki. The study protocol will be 
reviewed and approved by Independent ethics committees (IEC) or 
Institutional Review Boards (IRBs) and patients will sign Informed 


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Compound Name 
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Protocol Name 
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Consent Forms before enrolling to the trial. 


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List of Abbreviations 
ADCC 
Antibody-dependent cellular-mediated cytotoxicity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem-cell transplantation 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDC 
Complement-dependent cytotoxicity 
CHMP 
Committee for Medicinal Products for Human Use 
CBR 
Clinical benefit rate 
CKD-EPI 
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
CMV 
Cytomegalovirus 
CRF(e) 
Case report form (electronic) 
CRO 
Contract research organization 
CR 
Complete response 
CT 
Computerized tomography 
CTCAE 
Common terminology criteria for adverse events 
CXR 
Chest-X-Ray 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSMC 
Data safety monitoring committee 
eCCr 
Estimated creatinine clearance rate 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
EDC 
Electronic data capture 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End of therapy 
EQ-5D-3L 
EuroQol-5 Dimensions 3 Level 
FCBP 
Female of child bearing potential 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
FLC 
Free light chain 
GCP 
Good clinical practice 
GVHD 
Graft-versus-host-disease 
HDAC 
Histone deacetylase 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 


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ICF 
Informed consent form 
ICH 
International conference of harmonization 
IEC 
Independent ethics committee 
IFE 
Immunofixation 
IgG 
Immunoglobulin 
IMiD 
Immunomodulator drug 
IMWG 
International myeloma working group 
IND 
Investigational new drug 
IRAC 
Independent review and adjudication committee 
IRB 
Institutional review board 
ISS 
International staging system 
iv 
Intravenous 
LDH 
Lactate dehydrogenase 
K-M
Kaplan Meier 
mAb 
Monoclonal antibodies 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial infarction 
MM 
Multiple myeloma 
MR 
Minor response 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National comprehensive cancer network 
NCI 
National cancer institute 
ORR 
Overall response rate 
OS 
Overall survival 
PARP 
Poly ADP ribose polymerase 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PI 
Proteasome Inhibitor 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetics 
p.o.
Per os/by mouth/orally 
POEMS 
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein 
(M-protein) and skin changes 
PR 
Partial response 
PRO 
Patient Reported Outcome 
q.d.
Quaque die/ one a day 
QLQ-C30 
Quality of Life Questionnaire Core 30 
RBC 
Red blood count 
RRMM 
Relapsed and refractory multiple myeloma 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SFLC 
Serum free light chain 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
VGPR 
Very good partial response 


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1 
BACKGROUND 
1.1 
OVERVIEW OF MULTIPLE MYELOMA 
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 nearly 26,8500 patients with myeloma are 
diagnosed in the United States in 2015 (SEER 2014).  
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, hyperviscosity of the blood and renal function compromise 
(including renal failure). The disease course for MM varies with the disease stage at diagnosis, 
cytogenetic profile, as well as age and patient comorbidities. The median survival is approximately 
5 to 7 years with some significant variation in survival depending on host factors, tumor burden, 
biology and response to treatment (Kumar et al. 2008).  However, the disease remains ultimately 
fatal.   
There are currently 6 classes of approved drugs available for the treatment of MM, including 
steroids (prednisone and dexamethasone), immunomodulatory drugs (IMiDs) (thalidomide, 
lenalidomide and pomalidomide), proteasome inhibitors (PIs) (bortezomib, carfilzomib and 
ixazomib), histone deacetylase (HDAC) inhibitors (panobinostat), conventional chemotherapy 
(melphalan, cyclophosphamide, doxirubicin), including high dose melphalan with autologous 
stem-cell transplantation (ASCT) and the most recent addition of monoclonal antibodies (mAb) 
(elotuzumab and daratumumab). The selection of treatment in relapsed refractory multiple 
myeloma (RRMM) is challenging.  The NCCN guidelines (NCCN 2015) and a recent overview 
published in the Mayo Clinic Proceedings (Rajkumar et al. 2016) detail an array of single agent, 
doublet and triplet combination regimens that can be considered. In many cases, the same agents 
used as induction therapy may be reinstituted for relapsed disease if the disease recurred more than 
6 to 12 months after the last therapy ended.  However, if the time to relapse is of shorter duration, 
the patient is refractory to initial therapy, or the disease is associated with severe symptoms like 
renal failure or hypercalcemia, a regimen with different mechanism of action (class switch) is often 
selected. 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, 
myeloma patients will receive an average of 4 to 8 different regimens during their lifespan.   
 
Anti-CD38 mAbs 
Daratumumab: 
Daratumumab, a human anti-CD38 monoclonal antibody, received accelerated approval by the 
FDA on November 16, 2015 for myeloma patients who have received at least three prior lines of 
therapy, including both an IMiD and a PI, and for patients who are “double refractory”, meaning 
their disease no longer responds to treatment with at least one IMiD and at least one PI. The 
efficacy was demonstrated in two open-label studies.  In the Phase 2 MMY2002 (SIRIUS) study, 
1.1.1 


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of the 106 participants receiving daratumumab, 29 percent of patients achieved a complete or 
partial reduction in their tumor burden, which lasted for an average of 7.4 months, and PFS was 
3.7 months.  In the Phase 1/2 GEN501 study, of the 42 participants receiving daratumumab, 36 
percent had a complete or partial reduction in their tumor burden. 
Isatuximab 
Isatuximab (SAR650984) is a humanized anti-CD38 mAb that binds selectively to a unique 
epitope on the human surface antigen CD38.  Isatuximab kills tumor cells via multiple biological 
mechanisms, antibody-dependent cellular-mediated cytotoxicity (ADCC), complement-dependent 
cytotoxicity (CDC), direct induction of apoptosis (pro-apoptosis) without crosslinking, and 
inhibition of CD38 enzymatic activity. CD38 is highly expressed on myeloma cells but is 
expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues of 
non-hematopoietic origin, making it a relevant target for the treatment of multiple myeloma. 
Several clinical combination studies with isatuximab are ongoing, including phase 3 studies in 
RRMM patients such as one comparing carfilzomib/ dexamethasone with and without isatuximab 
(ICARIA-MM), and another in which isatuximab is combined with pomalidomide/ 
dexamethasone (IKEMA).    
 
Pomalidomide 
Pomalidomide (in combination with dexamethasone) is approved for the treatment of patients with 
MM who have received at least two prior therapies, including lenalidomide and bortezomib and 
have demonstrated disease progression on or within 60 days of completion of the last therapy.  The 
FDA accelerated approval of pomalidomide was based on the results in the Phase 2 trial (MM 
002), where 113 patients in the pomalidomide + dexamethasone trial arm had an ORR of 29.2% 
(FDA Pomalyst precribing information 2016). An updated analysis demonstrated a median 
progression free survival (PFS) of 4.2 months (primary endpoint) and an overall response rate 
(ORR) of 33% and a clinical benefit response (CBR) of 45% (Richardson et al. 2014).  In the 
subsequent pomalidomide Phase 3 clinical trial (MM-003) patients were randomized to either 
pomalidomide plus dexamethasone or high-dose dexamethasone and evaluated with PFS as 
primary endpoint.  Based on a median follow-up of 4.2 months (data cutoff of 7 September 2012), 
the 302 patients randomized to pomalidomide plus dexamethasone showed a median PFS of 3.6 
months.  A later data cutoff on 1 March 2013 with median follow-up of 10 months, showed an 
ORR of 23.5% (Independent Review and Adjudication Committee (IRAC) assessed data), and 
these data supported the regular FDA approval of pomalidomide in 2015.  This Phase 3 study was 
also published as investigator assessed data with the same 1 March 2013 cutoff (San Miguel et al. 
2013).  The authors showed a median PFS of 4.0 months and ORR of 31%.  The CHMP approval 
of pomalidomide in European Union (EU) in 2013 was based on the IRAC assessed data from the 
7 September 2102 data cut-off in trial MM-003 (with a median of 4.2 months follow-up) with 
support from trial MM-002 (Imnovid EPAR 2013). 
Recent improvements in therapies have significantly increased both the expected life span and the 
quality of life for these patients.  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 relapsed-refractory MM patients typically respond to any 
1.1.2 


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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.   
1.2 
OVERVIEW OF MELFLUFEN 
 
Melflufen Description 
The chemical name for Melflufen is 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-
phenylalanine ethyl ester hydrochloride and the chemical structure is provided in Figure 1.  The 
molecular weight is 498.4 as free base and 534.9 as the HCl salt. 
Figure 1-1:  Structure of Melflufen 
 
Melflufen Scientific Rationale 
Melflufen is a peptidase-potentiated therapy designed for targeted delivery of alkylating moieties 
to tumor cells. In contrast to other alkylating agents that are hydrophilic, the lipophilicity of 
melflufen leads to rapid and extensive distribution into tissues and cells. Inside cells, melflufen 
may directly bind DNA or is readily metabolized by intracellular peptidases into the well-known 
antitumor compound melphalan or by esterases into des-ethylmelflufen, which also has alkylating 
properties.  Due to the high activity of peptidases and esterases in human tumor cells, the formation 
of melflufen’s metabolites is rapid in these cells with continued inflow of more melflufen (Gullbo 
et al. 2003c, Wickstrom et al. 2010).  Since des-ethylmelflufen and melphalan are relatively 
hydrophilic, there is a possibility for intracellular trapping of these alkylators.  This can be 
explained by a more efficient transport of melflufen into these cells, an efficient conversion into 
other alkylating molecules (i.e. melphalan and des-ethylmelflufen) inside the cells and a less rapid 
disappearance of these molecules from the cells. 
The properties of melflufen are supported by clinical pharmacokinetic data.  Melflufen has a 
relatively low rate of hydrolysis in plasma according to in vitro studies. After intravenous infusion, 
1.2.1 
~ ....,__,...,COOEt 
0 
1.2.2 


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melflufen shows a very rapid disappearance from plasma with no signs of redistribution back to 
the plasma, indicating that a complete metabolism occurs predominantly outside the plasma 
compartment.  Following administration of melflufen, melphalan is found in plasma with a peak 
concentration at 5 to 10 minutes after the end of melflufen infusion [pharmacokinetics (PK) data 
from clinical trial O-12-M1]. The total melphalan plasma exposure assessed as AUC after 
melflufen administration is similar to historical data on exposure after melphalan administration 
(Mougenot et al. 2004, Nath et al. 2010).  However, the intracellular concentration in tumor cells 
could be considerably higher as discussed above. The metabolite des-ethylmelflufen reaches only 
very low concentrations in plasma with peak concentrations coinciding with end of melflufen 
infusion followed by a short elimination half-life.  
The addition of melflufen to panels of primary cultures of human tumor cells, including MM, 
results in 50- to 100-fold higher efficacy to that of melphalan (Wickstrom et al. 2008), which is 
explained by the 50-fold higher intracellular exposure as Area Under the Curve (AUC) of 
alkylating agents compared to that observed after an equimolar dose of melphalan (Chauhan et al. 
2013a).   Mechanistically-oriented studies have shown that melflufen-induced apoptosis is 
associated with (i) activation of caspases and poly ADP ribose polymerase (PARP) cleavage; (ii) 
reactive oxygen species generation; (iii) mitochondrial dysfunction and release of cytochrome c; 
and (iv) induction of DNA damage (Chauhan et al. 2013a).  Moreover, melflufen inhibits MM cell 
migration, tumor-associated angiogenesis and DNA repair.  Importantly, in vitro studies in MM 
cell lines resistant to dexamethasone, bortezomib and melphalan have shown cytotoxic activities 
of melflufen at concentrations similar to those observed in the parenteral, non-resistant cell lines. 
Potent cytotoxic activity has also been demonstrated in primary MM cells from patients including 
those relapsing after multiple prior therapies with bortezomib, lenalidomide, and dexamethasone. 
These results suggest a different resistance mechanism for melflufen than for other agents used in 
MM. In efficacy studies conducted in mice and rats carrying different human tumors, including
MM, superior antitumor activity of melflufen over equimolar dosage of melphalan was observed
at seemingly comparable toxicity (Gullbo et al. 2004, Wickstrom et al. 2007, Chauhan et al.
2013a).
A preliminary assessment of data from clinical trial O-12-M1 was performed on patients who were 
evaluable for efficacy by 11 Feb 2016.  Of the 30 efficacy evaluable patients with late stage 
relapsed and relapsed-refractory MM treated with 40 mg melflufen in combination with 
dexamethasone, 19 patients (63%) have reported a best response of minimal response (MR) or 
better and 12 patients (40%) have reported partial response (PR) or better.  These 30 patients had 
a median of 4 prior lines of therapy, including IMiDs, PIs and alkylators. 
The safety profile of melflufen suggested by preclinical studies is supported by clinical data from 
45 patients with solid tumors and from a total of 57 patients with RRMM in the Phase 1/2a clinical 
trial O-12-M1 [40 patients dosed at the maximum tolerated dose (MTD) of 40 mg of melflufen 
and 17 patients dosed at other doses in Phase 1 of the trial].  Taken together, clinical and preclinical 
data support that melflufen provides peptidase-potentiated delivery of alkylating moieties to tumor 
cells (such as MM cells) and thereby exerts a higher anti-tumor activity compared with equimolar 
administration of melphalan but with a seemingly similar safety profile. The efficacy seems to be 


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consistent across MM populations including patients who are double-refractory to IMiDs and PIs 
and refractory to alkylators. 
Please see the Investigator’s Brochure for additional information. 
 
Clinical Experience 
Please refer to the IB for further details. 
The preclinical properties are supported by clinical data from 45 patients with solid tumors (data 
not presented, refer to the IB for details) and 57 patients (as of 11 February, 2016) with advanced 
relapsed and RRMM including patients that are refractory to IMiDs, PIs and alkylators. 
1.2.3.1 
Clinical Experience in RRMM 
Please refer to the IB for further details. 
Melflufen is currently being evaluated in combination with low dose dexamethasone, and as single 
agent, in a Phase 1/2a clinical trial O-12-M1 in RRMM.  Adult patients with documented RRMM 
with at least 2 prior lines of therapy, including an IMiD and a PI, and who demonstrated disease 
progression on or within 60 days of last therapy, Eastern Cooperative Oncology Group (ECOG) 
performance status ≤ 2, life expectancy of ≥ 6 months and preserved organ function were eligible 
to enter the study. Phase 1 followed the standard 3 + 3 modified Fibonacci design with 3 to 6 
patients per dose cohort, depending on dose limiting toxicities (DLTs) observed, at each dose level 
that was tested.  
The Phase 1 part of the clinical trial was completed in September 2014 (Paba-Prada et al. 2014). 
Based on data from 23 patients in four dose groups (15 mg, 25 mg, 40 mg and 55 mg), a MTD was 
established as 40 mg of melflufen given every 3 weeks in combination with 40 mg dexamethasone 
weekly.  Following identification of the MTD, the Phase 2 part of the trial was initiated and all 
subsequently treated patients received a starting dose of 40 mg of melflufen.   
The O-12-M1 study is complete as per 09 November 2017. Please refer to the IB for further details. 
Clinical Safety 
As of 11 February 2016, 40 patients had received 183 doses of melflufen 40 mg. The median 
number of cycles is 3.5 (range 1 – 14). 
The most common treatment emergent adverse events (TEAE) to date in trial O-12-M1 were 
hematological events, such as thrombocytopenia, neutropenia and anemia.  This is not unexpected 
since hematological events are both common as a consequence of MM and of treatment with 
alkylators. These events were assessed to be dose-related, reversible, monitorable and mechanism-
driven. 
Treatment related Grade 3 and 4 AEs were reported in 34 patients out of 40 patients (85%). Those 
related to melflufen and occurring in ≥5% of the patients are presented in Table 1-1.  
1.2.3 


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Table 1 -6XPPDU\RI0HOIOXIHQ7UHDWPHQW5HODWHG*UDGHPatients Dosed with 40 mg Melflufen in Clinical Trial O-12-
M1 
System Organ Class 
(Preferred Term)  
Patients with Grade 3 or 4 
AEs  
Q 
Patients with Grade 4 
$(VQ
 
Any treatment -related event  
34 (85) 
20 (50) 
Blood and lymphatic system 
disorders  
Thrombocytopenia 
Neutropenia 
Anemia 
Febrile neutropenia  
33 (83) 
25 (63) 
23 (58) 
17 (43) 
2 (5) 
20 (50) 
16 (40) 
12 (30) 
0 (0) 
0 (0) 
General 
disorders 
and 
administration site conditions
 
Fatigue 
Pyrexia 
Asthenia 
7 (18) 
2 (5) 
2 (5) 
2 (5) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
Investigations 
Neutrophil count decreased 
White blood cell count decreased 
5 (13) 
4 (10) 
2 (5) 
0 (0) 
0 (0) 
0 (0) 
Infections and infestations  
Pneumonia 
2 (5) 
2 (5) 
0 (0) 
0 (0) 
Continuous review of safety data in the Phase 2 part of the study lead the data safety monitoring 
committee (DSMC) to include an additional week to the cycle length (i.e. to 28 days) to allow 
further recovery of platelet and neutrophil count and potentially allow the patients to stay on 
treatment longer and achieve more benefit. 
After a fatal pneumonia case occurred during the summer of 2015, a thorough evaluation of all 
cases of pneumonia and sepsis in the study was conducted.  
A total of 7 cases of pneumonia (2 associated with sepsis) and 2 other cases of sepsis in various 
dose cohorts were reported as SAEs SDWLHQWV>@LQWKHPJFRKRUW
 Four cases resulted 
in death, both cases of sepsis and 2 cases of pneumonia (1 associated with sepsis and one diagnosed 
as pneumocystis carinii). Three of the fatal events were in the 40 mg cohort. 
As of 23 October 2015, 53 20 patients) of the 40 mg melflufen (+dexamethasone) treated 
SDWLHQWVKDGUHSRUWHGJUDGHQHXWURSHQLDSQHX
3SDWLHQWXSSHUUHV
ory 


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infection and 0VHSVLVUHJDUGOHVVRIUHODWLRQVKLSWRVWXG\Comparative data from the 
pomalidomide+dexamethasone arm in the pomalidomide Phase 3 study (FDA US label) showed 
QHXWURSHQLDSQHXPRQLDXSSHUUHVSLUDWRU\LQIH
grade 3/4 events.  The Grade 3/4 AE rate with respect to neutropenia, pneumonia, upper respiratory 
infections and neutropenic sepsis were similar between the two studies. 
All 9 infections cases were reviewed in detail by DSMC on November 9th 2015.  The overall rate 
of infections was similar to that expected.  With respect to the 4 fatal infectious events, the DSMC 
concluded: even though there are likely alternative explanations for each individual case, such as 
rapid tumor progression, it cannot be excluded that treatment with melflufen may have contributed 
to the outcome of the events. 
The DSMC therefore recommended: 
x Future pneumonia cases should be followed closely
x Study guidelines for antimicrobial prophylaxis treatment in patients with intermediate
and high infection risk should be issued (NCCN guidelines) or institutional guidelines.
x The study could continue as planned
The O-12-M1 study is complete as of 09 November 2017. Please refer to the IB for further details. 
Evaluation of QTcF I ntervals from Holter R ecordings  
Continuous 12-lead Holter recordings from before start of infusion to 120 minutes after start of 
the 30-minute infusion have been obtained on Day 1 of treatment cycles in a subset of patients for 
general screening purposes.  Data for in total 37 treatment cycles in 19 patients were available by 
2 Nov 2015 for a preliminary analysis of the change in QTcF from baseline over the melflufen 
dose range 15 mg to 55 mg.  No changes in QTcF during or after infusion of melflufen up to 25 
mg have been observed. After 40 mg and 55 mg small mean increases by up to approximately 7 
PVHFKDYHEHHQREVHUYHG7KHFRQILGHQFHLQWHUYDOmsec for the 40 mg dose which is well below the limit of 20 msec which is commonly assessed as 
acceptable for anticancer drugs.  
No patient in the study has developed absolute QTcF values that are associated with a meaningful 
increased risk of arrhythmias 
Safety Summary  
Please refer to the IB for further details. There is no change to the overall safety evaluation of 
melflufen.   
The clinical trials results, to date, indicate that the safety profile for melflufen is similar to that for 
other alkylators, where thrombocytopenia, anemia and neutropenia are the most common AEs, 
followed by leukopenia and pyrexia.  The DSMC investigated the 9 infectious SAEs in November 
2015. The DSMC recommended that the international NCCN or institutional guidelines for 
infectious prophylaxis in MM should be followed. The incidences of Grade 3 and 4 neutropenia 
and thrombocytopenia after 40 mg doses of melflufen are comparable to the incidences observed 
in studies with low dose melphalan regimens in combination with high dose steroids (Richardson 


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et al. 2010).  There have been no reports of syncope, seizures, ventricular arrhythmias, ventricular 
tachycardia, ventricular fibrillation, flutter, torsade de pointes, or sudden deaths in the clinical 
trials.  The safety profile for melflufen is thus similar to that of other alkylators. Final data from 
O-12-M1 study are available since 09 November 2017.
Clinical Efficacy
Please refer to the IB for further details.
As of 11 February 2016, 30 patients were evaluable for efficacy (patients receiving at least two 
doses of 40 mg melflufen with appropriate follow-up).  Of these 30 patients, 3 achieved very good 
partial response (VGPR), 9 partial response (PR) and 7 minimal response (MR).   Ten patients 
maintained stable disease (SD) and one progressive disease (PD).  Median time from initial 
diagnosis to first dose of melflufen was 5.0 years (1-15).   Median number of prior therapies was 
4 (2-9).  All patients but two had been exposed to (IMiD compounds), PIs and alkylators.  
Refractory status was available for 29 patients (missing data for 1 patient) at the time of the data 
cut-off. Of these 29 patients, 24 patients (83%) patients were IMiD-refractory, 19 (66%) were PI-
refractory and 15 (52%) were alkylator refractory.  Seventeen out of the 29 patients (59%) were 
double-refractory (IMiDs+PIs) and 9 (31%) were double- and alkylator-refractory.  Twenty-three 
patients (78%) were refractory to last line of treatment. 
The median PFS in the trial has been evaluated both for the protocol efficacy evaluable patients 
(PP), [i.e. treated with ≥2 doses of melflufen (n=30)] and all patients [those evaluable after ≥1 dose 
of melflufen (N=40)] with baseline and appropriate follow-up assessments.  The median PFS for 
the efficacy evaluable population was at the time of data cut-off 8.0 months (95% confidence 
interval 4.1 to 14 months) based on 21 events in 30 patients with available data.  Nine patients 
were still alive, had not progressed and were therefore censored at the latest time of tumor 
assessment. For all treated patients, the median PFS was 4.5 months (95% confidence interval 
3.7 to 11 months) based on 30 events in 40 patients with available data. Ten patients were still 
alive, had not progressed and were therefore censored at the latest time of tumor assessment.  These 
preliminary data suggest that the responses could be of considerable duration and that also the MR 
and SD patients may have a benefit of considerable duration until progression. 
Final data from O-12-M1 study are available as of 09 November 2017, showing a median PFS of 
5.7 months, and a median OS of 20.7 months in the 45 patients treated with 40 mg melflufen in 
combination with dexamethasone. Please refer to the IB for further details.  
1.2.3.2 
Clinical Pharmacokinetics 
In humans, melflufen is metabolized to des-ethyl-melflufen, melphalan and the non-alkylating 
para-fluoro-phenylalanin ethyl ester.  PK data for melflufen and melphalan are available from the 
completed clinical trial O-05-001 in patients with solid tumors and from six MM patients in the 
clinical trial O-12-M1.  The elimination phase for melflufen could not be followed in clinical trial 
O-05-001 since the plasma concentrations were generally below the limit of quantitation during
this phase.  Subsequent improvements of the bioanalytical method and sampling schedule have
allowed estimation of the melflufen elimination phase in clinical trial O-12-M1.  Further, the


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metabolite des-ethyl-melflufen is quantified in clinical trial O-12-M1, while it was not measured 
in clinical trial O-05-001.  
In clinical trial O-05-001 (patients with solid tumors), melflufen plasma concentrations could be 
followed only up to end of infusion or very shortly thereafter. Melphalan concentrations were 
generally higher than those of melflufen both during and after the infusion.  Melflufen and 
melphalan exposures increased slightly less than proportional to dose and the intra-patient 
variability in exposure between treatment cycles was low after administration of the same dose 
amount. Gender and body weight had no significant influence on the PK parameters of melflufen 
or melphalan.  
In the clinical trial O-12-M1 in MM patients, PK data from eight patients covering the dose range 
15 mg to 55 mg were available as of 10 February, 2015. Preliminary analysis showed that the 
melflufen plasma concentration reached a peak before end of infusion and is thereafter eliminated 
with a half-life of 3 to 5 minutes. Melphalan PK parameters were similar to those observed in 
clinical trial O-05-001. Des-ethyl-melflufen reached only very low concentrations in plasma and 
is eliminated with a half-life of approximately 15 minutes.  
The combined results from the two clinical trials demonstrate that the PK of melflufen is 
characterized by low plasma concentrations and a very rapid disappearance from plasma after end 
of the iv infusion. The reasons for the decrease in melflufen concentrations during the ongoing 
infusion, frequently observed in both studies, are not known. The PK of melphalan after 
administration of melflufen is characterized by a rapid formation, where plasma concentrations 
exceed those of melflufen within 15 minutes after start of melflufen infusion, but where peak 
plasma concentrations are lower and AUC similar compared with equimolar infusions of 
melphalan at a similar rate (Mougenot et al. 2004, Nath et al. 2010).  Peak plasma concentrations 
of melphalan appear with a delay by up to 10 minutes after the end of melflufen infusion. The 
elimination phase of melphalan is similar after melflufen and melphalan infusions, according to 
published data for melphalan administration. (Mougenot et al. 2004, Nath et al. 2010). 
Overall, the observations suggest a mechanism where melflufen is rapidly and widely distributed 
to tissues or blood components outside of the plasma compartment in which melphalan is 
predominantly formed.  Melphalan is thereafter distributed back to the plasma. 
2 
STUDY RATIONALE 
2.1 
RATIONALE FOR THE SELECTED PATIENT POPULATION 
The proposed initial target patient population for melflufen is a heavily pre-treated and highly 
refractory population, consisting of MM patients who have received at least two prior lines of 
therapy including a PI and an IMiD compound, and are refractory to pomalidomide and/or 
daratumumab.  In this population, there is a clear lack of treatment alternatives and a high unmet 
medical need. Early preliminary efficacy data suggest considerable clinical benefit in terms of 
PFS, tumor response as well as response duration in patients regardless of refractory status to 


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available treatments (IMiDs, PIs, alkylators and/or MAb) as described above and in the 
Investigator’s Brochure (IB). The side effect profile in heavily pretreated patients with MM has 
been reported to be similar to that expected after treatment with alkylators.  Melflufen may 
therefore offer a meaningful benefit with acceptable toxicity profile for patients with heavily pre-
treated disease and refractory to pomalidomide and/or daratumumab.  
The purpose for Amendment 6 is to expand the drug class of anti-CD38 mAbs from daratumumab 
to include also isatuximab, currently in Phase 3 clinical trials, and other anti-CD38 mAbs in 
development.  Given the broad patient exposure to these alternate monoclonal antibodies in clinical 
trials, the late stage development of isatuximab and the rapidly evolving landscape of approved 
drugs for the treatment of MM, it is adequate to evaluate the activity of melflufen following failure 
of the drug class rather than just the specific drug (daratumumab).  In addition, a targeted sub-
group of patients who are triple-class refractory (i.e. refractory to an IMiD, a PI and an anti-CD38 
mAb) has been identified as a subgroup of particular interest. All efficacy and safety analyses will 
be performed both in the total population and the subgroup in the clinical study report.  
2.2 
RATIONALE FOR DOSE SELECTION 
Patients will be treated with melflufen 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 
15 and 22 of each 28-day cycle.  The starting dexamethasone dose will be reduced to 20 mg/day 
in all patients equal to or older than 75 years in line with previous studies (San Miguel et al. 2013). 
The dose and schedule of melflufen is based on data from the Phase 1/2 trial with melflufen in 
combination with dexamethasone in RRMM patients. The Phase 1 portion of the trial established 
the MTD to be 40 mg melflufen iv every 21 days with 40 mg oral dexamethasone weekly.  In the 
Phase 2 part of the trial, the DSMC decided to increase the cycle length to 28 days to improve 
tolerability by allowing additional time for hematologic recovery, and enable patients to stay on 
therapy longer. It was found that this increase resulted in a higher proportion of cycle lengths 
according to the protocol default. Thus the 28-day schedule will be implemented in this trial. 
Melflufen may be given until disease progression or unacceptable toxicity, and dose and schedule 
should be adjusted based on tolerability.  
2.3 
RATIONALE FOR STUDY EXPANSION 
The patients in OP-106 Horizon study are heavily pre-treated with a median of 5.5 prior treatment 
lines. Of the 62 patients treated in the study by 10 May 2018, 90% were pomalidomide-refractory 
and 65% were daratumumab-refractory. Six of the 62 treated patients were not evaluable at the 
time of the cut-off: 5 patients had recently started treatment, and 1 patient experienced a fatal SAE 
during first cycle. The preliminary efficacy data are promising with an ORR for the whole 
population (N=56) of 32.1%.  In the 56 patients, 12 patients had achieved PR, 5 patients had 
achieved VGPR and 1 patient had achieved CR, with 22 patients still actively on treatment at the 
time of the cut off. In addition, 4 patients achieved an MR as their best response.  
Preliminary data show higher response rates in some subgroups – e.g. ORR of 40.0% among 
patients refractory to pomalidomide without being refractory to daratumumab (N=20), and ORR 
of 66.7% in patients refractory to daratumumab without being refractory to pomalidomide (N=6). 


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The safety profile continues to be acceptable, with primary adverse events being 
thrombocytopenia, neutropenia and anemia, and few grade 3/4 non-hematological adverse 
reactions (EHA 2018 poster, IB edition 8.0). 
On 21 December 2017, following the protocol defined futility analysis, the DSMC assessed the 
benefit/risk balance for both of the predefined groups of the study (pomalidomide-refractory and 
daratumumab-refractory, respectively) and rejected futility. Due to the overall positive benefit/risk 
balance, the DSMC recommended the study to be continued. 
Based on the preliminary safety and efficacy data available to date, the sponsor believes the 
benefit-risk ratio to be positive for the OP-106 study patient population.   The population treated 
in this study is heavily pre-treated patients (median prior lines 5,5) with almost no remaining 
treatment alternatives. It is therefore considered justified to enroll additional patients to obtain 
further efficacy and safety data in this population. In addition, the sponsor would like to initiate 
the collection of preliminary functional status and well-being information. No such data has been 
collected in melflufen clinical trials to date. 
3 
OBJECTIVES AND ENDPOINTS 
3.1 
PRIMARY OBJECTIVE 
x To assess ORR, LHSURSRUWLRQRISDWLHQWVZLWK
partial response (PR) [stringent CR (sCR),
complete response (CR), very good partial response (VGPR), and PR] as best response in
efficacy evaluable patients as assessed by the investigator according to International Myeloma
Working Group (IMWG) Uniform Response Criteria (URC) (Rajkumar et al. 2011)
(Appendix C).
 
Key Secondary Objectives 
x To assess PFS according to IMWG (Rajkumar et al. 2011),
x To assess duration of response (DOR) in efficacy HYDOXDEOHSDWLHQWVZLWK
VGPR, PR) as best response according to IMWG-URC (Rajkumar et al. 2011), (Appendix
C).
x To assess Overall Survival (OS).
 
Other Secondary Objectives 
x To assess CBR (i.e. proportion of patients with MR), as best response in efficacy evaluable
patients),
x To assess Time to Response (TTR)
x To assess time to Progression (TTP)
x To assess the safety and tolerability
x To assess functional status and well-being
3.1.1 
3.1.2 


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3.2 
PRIMARY ENDPOINT  
x Best response of PR or better, as assessed by the investigator according to IMWG-URC. ORR
will be estimated as the proportion of patients who achieve a confirmed sCR, CR, VGPR, or
PR as their best response as assessed by the investigator.
 
Secondary Endpoints  
x PFS
x DOR
x OS
x Best response of MR or better. CBR will be estimated as the proportion of patients who achieve
a best response of MR or better.
x TTR
x TTP
x Duration of SD
x Frequency and grade of AEs
x Change from baseline in QLQ-C30 assessment
x Change from baseline in EQ-5D-3L assessment
* All tumor response and progression-depended objectives are as assessed by the investigators
assessment of response according to the IMWG-URC (Rajkumar et al. 2011), (Appendix C).
4 
STUDY DESIGN  
4.1 
DESCRIPTION O F STUDY DESIGN 
This is a single arm, open-label, Phase 2 multicenter study which will enroll patients with RRMM 
following at least 2 lines of prior therapy (Appendix D), including an IMiD and a PI, and who are 
refractory to pomalidomide and/or an anti-CD38 antibody defined as patients who relapse while 
on therapy or within 60 days of last dose.  
Patients will be treated with melflufen 40 mg infusion on Day 1 and dexamethasone 40 mg orally 
on Days 1, 8, 15 and 22 of each 28-day cycle.  Patients  75 years of age will have a reduction of 
the starting dose of dexamethasone from 40 mg to 20 mg on the same schedule. In the event of 
cycle delays, in the absence of dexamethasone toxicity, it is recommended that dexamethasone 
continue weekly. 
Patients may receive treatment until there is documented disease progression, unacceptable 
toxicity or the patient/treating physician determine it is not in the patients best interest to continue. 
Dose modifications and delays in therapy may be implemented based on patient tolerability as 
detailed in the protocol (Section 7.7).  
3.2.1 


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A Schedule of Events for the study is outlined in Section 8.1. 
5 
PATIENT POPULATION  
5.1 
PATIENT SCREENING  
Written informed consent must be obtained before any protocol-specific screening tests or 
procedures are performed.  After informed consent is obtained, the screening assessments will be 
performed as detailed in Section 8 of the protocol. Table 8-1, Schedule of Event, lists all of the 
screening assessments including frequency and time lines of when assessments are to be 
performed.  
Assessments performed as part of the patients routine clinical evaluation and not specifically for 
this study need not be repeated after signed informed consent has been obtained provided the 
assessments fulfill the study requirements and are performed within the specified timeframe prior 
to enrollment.  Laboratory results noted in the inclusion criteria must remain within the limits 
specified prior to first dose of study drug on Cycle 1 Day 1. 
 
Screening Failures  
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered screen failures.   
5.2 
PATIENT ELIGIBILITY  
The Investigator must ensure that patients meet all the following inclusion and exclusion criteria. 
Population diversity:  This study will be available to all eligible patients, regardless of race, gender, 
or ethnic origin.  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to expect such 
differences to exist. The planned analysis will explore differences in treatment effect based on 
racial and gender groupings, but the sample size is not increased in order to provide additional 
power for such subset analyses. Investigators are encouraged to recruit a diverse population. 
5.3 
INCLUSION CRITERIA 
Eligible patients will be considered for inclusion in this study if they meet all of the following 
criteria: 
1.
Male or female, age 18 years or older.
2 
A prior diagnosis of multiple myeloma with documented disease progression in need of 
treatment at time of screening.  
3.
Measurable disease defined as any of the following:
x Serum monoclonal protein  0.5 g/dL J/ by serum protein electrophoresis (SPEP)
x  200 mg/24 hours of monoclonal protein in the urine on 24-hour urine protein
electrophoresis (UPEP)
5.1.1 


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x Serum immunoglobulin free light chain 10 mg/dL 00 mg/L) AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio
4.
A minimum of 2 prior lines of therapy, including an IMiD and a PI, and is refractory to
pomalidomide and/or an anti-CD38 mAb. (Refractory status includes patients who relapse
while on therapy or within 60 days of last dose of pomalidomide and/or an anti-CD38 mAb
in any line, regardless of response).
5.
Life expectancy of  months.
6.
(&2*SHUIRUPDQFHVWDWXV3DWLHQWVZLWK
worse performance status based solely on
bone pain secondary to multiple myeloma may be eligible following consultation and
approval of the medical monitor).
7.
Female of child bearing potential (FCBP)* and non-vasectomized male agree to practice
appropriate methods of birth control (See Section 7.6.1).
8.
Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information.
9.
12-lead ECG with QTcF iQWHUYDO RI   PVHF
 calculated by Fridericia Formula
(Appendix H).
10.
The following laboratory results must be met during screening (within 21 days) and also
prior to study drug administration on Cycle 1 Day 1:
x Absolute neutropKLOFRXQW$1&FHOOVPP
3 (1.0 x 109/L) (Growth factors
cannot be used within 10 days prior to initiation of therapy)
x 3ODWHOHWFRXQWFHOOVPP
3 (75 x 109/L) (without transfusions required during
the 10 days prior to initiation of therapy)
x +HPRJORELQJGO5%&WUDQVIXVLRQVDUHSHUPLW
x 7RWDO%LOLUXELQ[XSSHUOLPLWRIQRUPDO8/1
; or higher value in patients
diagnosed with Gilberts syndrome after review and approval by the medical monitor
x Aspartate transaminase (AST) and alanine transaminase (ALT) [8/1
x Renal function: Estimated creatinine clearance by Cockcroft-Gault IRUPXOD  
mL/min.  )RUZRPHQ 
cm in height and with normal BMI (18.5  24.9 kg/m2) the
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method for
calculation of glomerular filtration may be used. (Appendix G). Cases with borderline
values of creatinine clearance based on the Cockcroft-Gault formula may be discussed
with the medical monitor.
11.
Must have, or accept to have, an acceptable central catheter for infusion of melflufen (Port
a cath, PICC line, or central venous catheter).


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*(FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive months. 
5.4 
EXCLUSION CRITERIA 
Patients will be ineligible for this study if they meet any one  of the following criteria: 
1. Evidence of mucosal or internal bleeding and/or is platelet transfusion refractory (i.e.
platelet count fails to increase by > 10,000 cells/mm3 after a transfusion of an appropriate
dose of platelets).
2. 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
(MI), significaQWFRQGXFWLRQV\VWHPDEQRUPDOLWLHVXQFRQ
thromboembolic event in the last 6 months)
3. Active infection, treated with parenteral anti-infectives within 14 days, or oral anti-
infectives within 7 days, prior to initiation of treatment (exceptions may be considered after
review and approval by the medical monitor).
4. Primary refractory (never respondHG05WRDQ\prior therapy
)
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, and very-low and low risk prostate cancer patients in active
surveillance as defined in NCCN version 3, 2016.
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. Known HIV or active hepatitis B or C viral infection
9. Concurrent symptomatic amyloidosis or plasma cell leukemia
10. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes]
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple
myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.  IMiDs,
PIs and/or corticosteroids within 2 weeks prior to 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 investigational therapies and monoclonal antibodies or live vaccines within
4 weeks prior to initiation of therapy (other washout times may be considered following
consultation with the medical monitor).
12. Residual side effects to previous therapy > grade 1 prior to initiation of therapy (Alopecia


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any grade and/or neuropathy grade 2 without pain are permitted) 
13. Prior autologous or allogeneic stem cell transplant within 12 weeks of initiation of therapy
14. Prior allogeneic stem cell transplant with active graft-versus-host- disease (GVHD)
15. 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).
16. Known intolerance to steroid therapy
6 
PATIENT ENROL LMENT 
6.1 
ENROLLMENT PROCEDURE
 
Site initiation visits must be complete at each site before patients can be screened at that site. 
Informed consent must be signed before any study-specific tests may be performed.  
Patients must meet all the entry criteria detailed in Section 5.3 and Section 5.4 in order to be 
enrolled. The medical monitor must verify entry criteria are met and provide approval for 
enrollment.  Documentation of the enrollment process is filed in the Investigator Site File.  
Patients that do not meet all the eligibility criteria will be considered screen failures and will not 
be enrolled into the trial.  
6.2 
PATIENT NUMBERING  
A unique patient number will be assigned by the site, at the time of screening that will be used to 
identify the patient throughout the clinical study and must be used on all study documentation 
related to that patient.  
6.3 
REPLACEMENT P OLICY 
Patients will not be replaced unless they fail to start treatment or if they are considered non-
evaluable for response.  The response data will be assessed in efficacy evaluable patients (all 
patients who receive at least 2 doses of melflufen, had a baseline disease assessment, and had at 
least 1 post-baseline disease assessment).  
7 
TREATMENT 
7.1 
STUDY TREATMENT  
Patients must begin treatment 5 calendar days of enrollment. Pretreatment tests/procedures must 
remain within the screening timelines specified in Table 8-1: Schedule of Events. 
Treatment will be given in an outpatient treatment setting.  Patients will receive the following 
treatment:  


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x Melflufen 40 mg will be administered as a 30-minutes intravenous (iv) infusion on Day 1 of
every 28-day cycle via an acceptable central catheter *.
x Dexamethasone will be administered orally on Days 1, 8, 15 and 22 of each 28-day cycle at
the following dose based on age:
o
Dexamethasone 40 mg for patient < 75 years of age
OR 
o
Dexamethasone 20 mg orally for patient  75 years of age.
Oral dexamethasone may be substituted with iv dexamethasone at the investigators discretion 
(USA only). 
*All patients must have a central catheter  prior to the initiation of the first dose of melflufen. (Port
A Cath, PICC line or central venous catheter).
Dose modifications and delays may be implemented based on patient tolerance as detailed in 
Section 7.7.  In the event of cycle delay, in the absence of dexamethasone toxicity, it is 
recommended that dexamethasone continue weekly. 
7.2 
INITIATION OF THERAP Y 
Prior to initiation of therapy, patients must continue to meet eligibility criteria including ECOG 
SHUIRUPDQFHVWDWXVRIDQGthe Cycle 1 Day 1 laboratory 
results must meet the entry criteria as 
follows: 
x $EVROXWHQHXWURSKLOFRXQW$1&FHOOVPP
3 (1.0 x 109/L) (Growth factors cannot be
used within 10 days of initiation of therapy).
x 3ODWHOHWFRXQWFHOOVPP
3 (75 x 109/L) (without transfusion during the previous 10
days to initiation of therapy).
x +HPRJORELQJGO5%&WUDQVIXVLRQVDUHSHUPLWWHG
.
x Total Bilirubin [XSSHUOLPLWRIQRUPDO
(ULN) except patients diagnosed with Gilberts
syndrome that have been reviewed and approved by the medical monitor.
x $67DQG$/7[8/1
x Renal function: Estimated creatinine clearance by Cockcroft-*DXOWIRUPXODP/PL
n. For
women below 155 cm in height and with normal BMI (18.5  24.9 kg/m2) the CKD-EPI
method for calculation of glomerular filtration may be used (Appendix G). Cases with
borderline values of creatinine clearance based on the Cockcroft-Gault formula may be
discussed with the medical monitor.


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Protocol No.  OP -106 
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7.3 
MELFLUFEN  
 
Melflufen Packaging and Labeling
 
The drug product, melflufen powder for solution for infusion, is filled in 50 mL glass vials with 
grey rubber stoppers and flip-off seals.  Please refer to the Pharmacy Manual for further details on 
packaging and labeling. 
 
Melflufen Storage  
Melflufen must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access.  Upon receipt, the temperature log should be checked and notice given to 
supplier of the condition of the shipment.  Melflufen shall be stored at +2 - 8°C (refrigerated).   
 
Preparation of Melflufen Solution for I
nfusion  
0HOIOXIHQSRZGHUIRUVROXWLRQIRULQIXVLRQLVSUHSDUHand then further diluted in a 250 ml infusion bag of either JOXFRVHVROXWLRQ
(ambient or cold) 
RUVDOLQ
e (cold). The iv tubing must be primed with the same solution either before or after 
the dilution of melflufen in the 250 ml bag. Careful attention and documentation of the 
preparation procedures and time frames are required since melflufen rapidly degrades in solution.  
Time to infusion requirements: 
x POEDJRIJOXFRVH
o
$PELHQWWKHPOEDJRI JOXFRVHVKRXOG EHD
adding melflufen. The maximum allowed time from start of reconstitution until the
start of iv infusion is 30 minutes.
o
Pre-FRROHG WKH  PO EDJ RI  JOXFRVH VKRXOG EH
-cooled prior to adding
melflufen. The maximum allowed time from start of reconstitution until the start of
iv infusion is 45 minutes.
x POEDJRIVDOLQH
o
Pre-FRROHGWKHPOEDJRIVKRXOGEHSUH
-cooled prior to adding melflufen.
The maximum allowed time from start of reconstitution until the start of iv infusion
is 3.5 hours.  Use of ambient saline is not permitted.
Refer to the Pharmacy Manual for detailed instruction for reconstitution and dilution of 
melflufen in preparation for infusion. A well-coordinated plan between the pharmacy and 
treatment room is recommended. See Pharmacy Manual for details. 
 
Melflufen Administration   
Prophylactic treatment with anti-emetic drug(s) prior to melflufen solution administration is 
recommended. Subsequent anti-emetic drugs against delayed emesis will be administered at the 
discretion of the investigator. Concomitant medication shall be documented in the concomitant 
medication page in the eCRF. 
7.3.1 
7.3.2 
7.3.3 
7.3.4 


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Protocol No.  OP -106 
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The study treatment will be administered via an acceptable central catheter, which will be inserted 
according to standard local practice. All patients must have an acceptable central catheter for 
infusion prior to the initiation of the first dose of melflufen.  (Port A Cath, PICC line or central 
venous catheter).  
Refer to Pharmacy Manual for complete instructions on melflufen preparation for infusion.  
Before infusion:  
x Document vital signs prior to start of infusion.
x Prepare the central catheter by flushing with approximately 20 ml of the same type of
VROXWLRQJOXFRVHRUVDOLQHWKDWLVXVHGIRU
ml bag.
Infusion:  
x The melflufen should be administered as a 30-minute intravenous infusion.
x Record start and stop time of infusion
After infusion: 
x Document vital signs at the end of the infusion.
x )LUVWIOXVKWKHFHQWUDOFDWKHWHUZLWKDSSUR[LPDW
glucose or VDOLQHWKDWLVXVHGIRUGLOXWLRQRIWKHfollow with additional flushing as per institutional guidelines if necessary.
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.  
7.4 
DEXAMETHASONE  
 
Dexamethasone Packaging and Labeling 
Oral dexamethasone will be supplied by Oncopeptides AB to sites located in Europe. Oral 
dexamethasone may be substituted with iv dexamethasone at the investigators discretion (USA 
only).  Only oral dexamethasone will be supplied to sites outside of USA.  USA sites will use 
commercially available dexamethasone supplies.  
 
Dexamethasone Storage 
Dexamethasone is to be stored at controlled room temperature.  Consult the package insert or 
Summary of Product Characteristics (SmPC) for dexamethasone for additional storage and usage 
instructions.  
 
Dexamethasone Administration  
Dexamethasone should be administered orally.  Sites are responsible to record administration and 
patient compliance regarding dexamethasone dosing in the source documents and eCRF.  Consult 
the package insert or SmPC for the respective product for additional instructions for 
7.4.1 
7.4.2 
7.4.3 


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dexamethasone administration. Dexamethasone is best taken prior to melflufen on days when both 
drugs are given on the same day (Day 1 of each cycle).  
7.5 
STUDY DRUG COMPLIANCE AND ACCOUNTABILITY
 
 
Study Drug Compliance  
Compliance should 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 weekly dexamethasone will be verified by patient 
inquiry and documented in the source documents and eCRF.  
 
Study Drug Accountability  
The investigator or designee must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log.  Drug accountability will be noted by the 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 dexamethasone, 
melflufen and drug labels should be discarded according to a CRO approved site drug destruction 
policy.  A copy of the drug destruction policy and completed drug accountability log should be 
provided to the monitor.  
7.6 
CONCOMITANT THERAPY  
All blood products and baseline medications that the patient is taking within 21 days prior to the 
initiation of therapy must be recorded.  All additional medications (other than study drug) or 
changes in baseline medications and significant non-drug therapies (including blood products, 
physical therapy and herbal/natural medications) administered during the study must be listed on 
the Concomitant Medications section of the eCRF.   
 
Required Concomitant Therapy
 
x Contraceptive measures
Male patients, and female patients of child-bearing potential, shall be required to use effective
contraceptive methods (or abstinence) prior to initiation of melflufen, while on therapy and
for 28 days after the last dose for women and 3 months after the last dose for men. The best
method should be determined in consultation with the Investigator.
Females:
Birth control methods that can are considered as highly effective include: tubal ligation, intra
uterine device, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or
implants), or partners vasectomy.
Reliable contraception is indicated even where there has been a history of infertility, unless
due to hysterectomy or bilateral oophorectomy.
Males:
7.5.1 
7.5.2 
7.6.1 


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Males must use a latex or synthetic condom during any sexual contact with females of child-
bearing potential even if they have had a successful vasectomy. Males should not donate 
sperm during the study and for 3 months after treatment has been stopped.  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. 
 
Recommended Concomitant T herapy  
x Pneumocystis prophylaxis
o
All patients are recommended to receive pneumocystis prophylaxis concomitant with
treatment according to the NCCN or institutional guidelines.
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf or NCCN.org
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
x Prophylactic treatment with anti-emetic(s) prior to melflufen administration is recommended.
Subsequent anti-emetic drugs against delayed emesis should be administered at the discretion
of the investigator.
x Patients should receive full supportive care, including transfusions of blood and blood products
(including platelets), antibiotics, anti-diarrheals, analgesics, etc. and prophylactic treatment
for tumor lysis syndrome when appropriate.
o
Melflufen is a potent myelosuppressive agent, it is essential that careful attention be paid
to the monitoring of blood counts. General supportive measures, together with
appropriate blood and platelet transfusions and hematological growth factors should be
instituted if necessary. It is recommended, at the investigator discretion, that platelet
transfusion should be avoided less than 5 days of the next dose of melflufen 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
7.2 for use of growth factors and platelet transfusions prior to the first dose of melflufen).
x Bisphosphonate therapy iv or p.o. should be administered if indicated in accordance with
institutional guidelines.
x The prophylactic use of growth factors and platelet transfusions are not permitted to render the
patient eligible for trial participation except as described within the entry criteria.
x Recommended Antimicrobial prophylaxis
o
For patients with history of CMV infection that required treatment, prophylactic
treatment 
per 
NCCN 
or 
institutional 
guidelines 
is 
recommended.
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf  or NCCN.org
o
Patients with neutropenia are strongly recommended to receive antimicrobial
7.6.2 


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Protocol No. OP-106 
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prophylaxis throughout the treatment period per NCCN or institutional guidelines. 
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf  or NCCN.org 
o
Antiviral and antifungal prophylaxis should be considered.
Contraindicated Concomitant Therapy
• Concurrent therapy with any approved or investigative anticancer therapeutic drug with
activity against multiple myeloma is not allowed.
• Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) >
prednisone 10 mg/day (or its equivalent) are not permitted.
• Other investigative agents must not be used during the study.
• The use of live vaccines is prohibited during the study and for 30 days after last dose of study
drug
• Radiation therapy to a limited area for bone pain to a pre-existing lesion may be considered in
consultation with and approval of the medical monitor.
• Limitations on the use of growth factors and platelet transfusions are detailed in Section 7.6.2.
7.7 
DOSE MODIFICATIONS 
Dose adjustments are permitted for drug related toxicity according to guidelines described in this 
section. Toxicity should be assessed using the CTCAE version 4.03 (Appendix B).  All dose 
modifications should be based on the worst preceding toxicity. 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.   
Administration of the study treatment should be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the investigator, 
warrants discontinuation.  All interruptions or changes to study treatment administration must be 
recorded in the eCRF.  In case of dose reduction of any study therapy, the dose should not be re-
escalated to the higher dose once the AE resolves. 
Dose Reduction Steps for Melflufen 
Table 7-2 outlines the dose reduction steps for melflufen based on the starting dose for Cycle 1 or 
subsequent cycles.   
Table 7-2    Dose Reduction Steps for Melflufen 
Starting Dose 
Dose reduction 
Step - 1 
Dose reduction 
Step - 2 
40 mg 
30 mg 
20 mg 


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Protocol No. OP-106 
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Dose Modification Guidelines for Melflufen 
Dose modifications of melflufen for drug related toxicity are permitted. Multiple dose reductions 
are permitted down to 20 mg.  If a patient is unable to tolerate the 20 mg dose of melflufen due to 
drug related toxicity, the patient should discontinue study treatment. 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. 
Prior to each cycle of melflufen the criteria for initiation of therapy must be met.  (See Section 
7.7.5).  
7.7.2.1 
Hematologic Toxicity 
Melflufen is a potent myelosuppressive agent, it is essential that careful attention be paid to the 
monitoring of blood counts. General supportive measures, together with appropriate blood and 
platelet transfusions and hematological growth factors should be instituted if necessary. It is 
recommended, at the investigator discretion, that platelet transfusion should be avoided within 5 
days of the next dose of melflufen in order to assess endogenous platelet recovery and avoid the 
possibility of excessive myelosuppression. 
The following guidelines for dose modification due to drug related hematologic toxicity should be 
followed (see also Table 7-3). Criteria for a new cycle is detailed in (Section 7.7.5). 
Please note: The guidelines in Table 7-3 are based on the laboratory values obtained at each cycle 
on Day 29 (scheduled day 1) or subsequent weekly evaluations as noted below (not the blood 
counts during the cycle on days 8, 15 or 22).  Patients that experience a grade 4 thrombocytopenia 
or neutropenia on Day 29 in more than one consecutive cycle on the same dose level will require 
a one level dose reduction when the criteria for initiation of a new cycle are met.      
Table 7-3    Dose Modifications of Melflufen for Hematologic Toxicity: 
Hematologic criteria for initiation of a new cycle 
•
ANC ≥ 1,000 cell/mm3 (1.0 x109/L)
•
Platelet count ≥ 50,000 cell/mm3 (50.0 x 109/L)
Day 
Criteria met for new cycle 
Criteria not met for new cycle 
Day 29 
 
Continue at same dose level 
Investigator discretion: 
•
Optional to hold one week
(to Day 36)
Hold dose.  
Evaluate in one week (to Day 36) 
7.7.2 


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Day 36 
Continue at same dose level* 
Investigator discretion: 
•
Optional one level dose
reduction
•
Optional to hold one week
(to Day 43)
Hold dose.  
Evaluate in one week (to Day 43) 
Day 43 
Continue at same dose level* 
Investigator discretion: 
(consultation with medical monitor 
is encouraged) 
•
Optional one level dose
reduction
•
Optional to hold one week
(to Day 50)
Hold dose.  
Evaluate in one week (to Day 50) 
NOTE: The cycle length may not 
exceed 43 days if criteria are met on 
Day 29 or 36 
Day 50 
Continue with required one level 
dose reduction  
Hold dose.  
Evaluate in one week (to Day 57) 
Day 57 
Continue with required one level 
dose reduction 
Discontinue from therapy** 
*Second failure to recover from treatment related Grade 4 neutropenia or thrombocytopenia
on Day 29 in a subsequent cycle within the same dose level will result in a one-step dose
reduction once recovered. Optional dose delays to allow for further recovery are permitted
as detailed in this table above.
** If the criteria for initiation of a new cycle of therapy are not met by Day 57 due to drug 
related toxicity, then the patient must be discontinued from therapy, 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.  
Alternate dose modification (prolongations/reductions) 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 drug related cycle 
prolongations (for example: influenza). 
Patients who discontinue treatment for a study related adverse event including abnormal laboratory 
value must be followed as described in Section 8.2.5 and 8.2.6.   


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7.7.2.2 
Non-hematologic Toxicity 
The resolution of all non-hematologic drug related toxicity must be to ≤ Grade 1 or baseline (except 
alopecia any grade and fatigue ≤ Grade 2) on Day 1 of each cycle.  
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), the dose should be held and the patient should be re-evaluated
weekly.
• If cycle prolongation, due to non-hematologic toxicity, 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 time lines in Table 7-3 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-
diarrheals 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. 
 
Dose Reduction Steps for Dexamethasone 
Table 7-4 outlines the dose reduction steps for dexamethasone.  Dose reductions of dexamethasone 
other than those listed in Table 7-4 or discontinuation may be considered in consultation with the 
medical monitor.  
Table 7-4    Dose Reduction Steps for Dexamethasone 
Starting Dose 
Dose reduction 
step - 1 
Dose reduction 
step - 2 
40 mg 
20 mg 
12 mg 
20 mg 
12 mg 
8 mg 
7.7.3 


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Dose Modification Guidelines for Dexamethasone 
Multiple dose reductions of dexamethasone are permitted.  If a patient is unable to tolerate 
dexamethasone due to dexamethasone related toxicity, dexamethasone may be discontinued in 
consultation with the medical monitor.  However, the patient may continue on treatment with 
melflufen at the investigator’s discretion. In the event of a cycle delay, in the absence of 
dexamethasone toxicity, it is recommended to continue dexamethasone weekly. 
7.7.4 


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Table 7-5    Dose Modifications for Toxicity Related to Dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2  
(requiring medical 
management) 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist, 
despite above measures, decrease 
dexamethasone dose by 1 dose 
level. 
Gastrointestinal 
≥ Grade 3  
(requiring hospitalization or 
surgery) 
Hold dexamethasone until 
symptoms adequately controlled. 
Restart and decrease one dose level 
of current dose along with 
concurrent therapy with H2 
blockers, sucralfate, or omeprazole. 
If symptoms persist despite above 
measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do 
not resume 
Cardiovascular 
Edema 
≥ Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose 
level; if edema persists despite 
above measures, decrease dose 
another dose level. Discontinue 
dexamethasone and do not resume 
if symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood alteration 
≥ Grade 3 (interfering with 
function +/- interfering with 
activities of daily living) 
Hold dexamethasone until 
symptoms resolve. Restart with one 
dose level reduction. If symptoms 
persist despite above measures, 
discontinue dexamethasone and do 
not resume. 
Musculoskeletal 
Muscle weakness 
≥ Grade 3 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone dose by 
one dose level. If weakness persists 
despite above measures, decrease 
dose by one additional dose level. 
Discontinue dexamethasone and do 
not resume if symptoms persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by one 


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Protocol No. OP-106 
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Body System 
Symptom 
Recommended Action 
dose level until levels are 
satisfactory. 
 
Initiation of a New Cycle of Treatment 
Patients should be assessed at the beginning of each cycle according to the tests and evaluations 
outlined on Day 1 of each cycle in Table 8-1 Schedule of Events.  To begin a new cycle of treatment 
the following criteria must be met: 
• 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 less than 5 days of subsequent melflufen dose (see Section 7.6.2)
• All non-hematologic study drug related toxicities must be ≤ Grade 1 or returned to baseline
(except alopecia any grade and fatigue ≤ grade 2).
If these criteria are not met on the scheduled Day 1, the new cycle should be held and patients 
should be re-evaluated weekly following the guidelines in Section 7.7.2.1, 7.7.2.2 and Table 7-3. 
A new cycle can only be initiated when the criteria are met.  
The maximum amount of time for which melflufen may be held due to drug related toxicity is 28 
days from a scheduled Day 1 (Day 57).  If study drug is held for more than 28 days due to drug 
related toxicity, the patient will be removed from the study treatment and enter progression free 
survival follow-up (PFS-FU).  If, however the patient was clearly benefitting from therapy, the 
patient may be able to continue treatment at the Investigator discretion and in consultation with 
the medical monitor, after resolution of the AE.  
 
Treatment Duration 
Patients will receive treatment until there is documented disease progression according to the 
IMWG guidelines (to be confirmed on two consecutive assessments), unacceptable toxicity or the 
patient/treating physician determines it is not in the patient’s best interest to continue.  Confirmed 
PD (on 2 consecutive assessments) should be verified by the medical monitor prior to treatment 
discontinuation.  
8 
VISIT SCHEDULE AND ASSESSMENTS 
8.1 
SCHEDULE OF EVENTS 
Table 8-1 lists all of the assessments required in the study and marked with an “X”, indicating 
when they are to be performed. Evaluations marked with (X) are only required if clinically 
indicated.  All data obtained from these assessments must be supported in the patient’s source 
documentation.  
7.7.5 
7.7.6 


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Table 8–1   Schedule of Events 
Evaluation 
Screening 
Days -21 to 
-1
All Cycless, u 
End of 
Treatment 
p
PFS-
FUq,s 
OS-
FUr,s 
Day 1 
Day 8 
Day 15 
Day 22 
Informed consent a
X 
Inclusion/exclusion criteria 
X 
Medical and disease history b
X 
Physical examination and 
symptom assessment c
X 
X 
(X) 
(X) 
(X) 
X 
Vital signs d
X 
X 
X 
ECOG performance status 
X 
X 
X 
Pregnancy test e
(X) 
(X) 
(X) 
Electrocardiogram f 
X 
X 
Chest X-ray 
X 
Hematology g
X 
X 
X v 
X 
X v 
X 
Coagulation h 
X 
Blood chemistries i 
X 
X 
X 
(X)q
Bone marrow aspiration j
X 
(X) 
(X) 
(X)q
M- protein assessments
(SPEP/UPEP, IFE, SFLC) k
X 
X 
X 
Xq 
Serum β2-microglobulin 
X 
Assessment of extramedullary 
plasmacytoma l 
X 
(X) 
(X) 
(X)q
Assessment of lytic bone lesions m 
X 
(X) 
(X) 
(X)q
PRO assessmentt 
(X)t
X 
X 
(X) 
Dexamethasone administration n 
X 
X 
X 
X 
Melflufen administration n
X 
Concomitant medications o 
X 
X 


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Adverse event monitoring 
X 
Follow-up PFS 
Xq 
Follow-up-OS 
Xr 
(X) Only if clinically indicated
a) All patients must sign an IRB/IEC-approved informed consent document prior to enrollment and prior to any study related
procedures.
b) Medical History including demographics, prior and current medical illness and conditions, prior surgical procedures. Disease
history includes date of initial diagnosis, ISS and R-ISS stage at diagnosis and cytogenetics (if previously evaluated).  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 (Appendix E).
c) A complete physical examination (PE), including height (screening only) and weight, neurologic assessment and assessment for
extramedullary myeloma (if present on PE) 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 a cycle. A site visit is required for Cycle 1 and 2 for
weekly symptom assessment. Plasmacytomas that can be followed by PE are to be evaluated on Day 1 of each cycle.  Baseline
symptoms and residual toxicity from previous therapy is to be assessed within 21 days prior to initiation of therapy.
d) Vital signs including blood pressure, pulse, respiration rate, temperature.  To be assessed at screening and pre and post melflufen
infusion.
e) All FCBP must have a negative pregnancy test (urine or serum) documented prior to start of therapy with melflufen, repeat
pregnancy test on Day 1 of each cycle and at End of Treatment visit. A FCBP is a sexually mature female who: 1) has not undergone
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has
had menses at any time in the preceding 24 consecutive months).
f)
A 12-lead ECG assessment will be performed on all patients at baseline and End of Treatment visit and as clinically indicated.  Q-
Tc interval to be assessed by Fridericia formula (Appendix H).


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g) Hematology: Complete blood count (CBC) with differential, and platelet count. Patients are required to have all laboratory
evaluations completed at the study center during Cycles 1 and 2.  Following Cycle 2, CBC evaluations may be done at the study
center laboratory or other local laboratory as long as the results are reviewed by the study center within 24 hours and toxicity
assessment is completed.   Exceptions may be made only in consultation with the medical monitor or as a measure to protect patients
with good tolerability from additional risks as a result of COVID-19 spread, see footnote v) below. All CBC values collected in
addition to protocol specified time points must be recorded in the eCRF (See Section 9.1.2).
h) Coagulation: prothrombin time (PT), international normalized ratio (INR).
i)
Blood chemistry:  sodium, chloride, potassium, magnesium, phosphate, uric acid, carbon dioxide, blood urea nitrogen (BUN),
glucose (fasting at baseline), AST, ALT, alkaline phosphatase, total protein, total bilirubin, albumin, serum creatinine, calcium and
lactate dehydrogenase (LDH), and estimated creatinine clearance by Cockroft-Gault Equations (or by CKD-EPI method for
calculation of glomerular filtration for women below 155 cm in height and with normal BMI (18.5 – 24.9 kg/m2) (Appendix G).
Patients are required to have all evaluations completed at the treatment center during Cycles 1 and 2.   Following Cycle 2, Chemistry
evaluations may be done at the study center laboratory or other local laboratory as long as the results are reviewed by the study
center within 24 hours and toxicity assessment is completed.   Exceptions may be made only in consultation with the medical
monitor.
j)
BMA to be collected at screening for % plasma cells, morphology, cytogenetics by FISH. Minimum FISH probes include 17p,
4;14, 14;16.   Repeat for % plasma cells at the time of suspected CR (negative IFE).  If a bone marrow aspirate and/or biopsy has
been collected within 6 weeks prior to initiation of therapy, it does not need to be repeated.
k) SPEP, UPEP, serum and urine protein IFE (IFE if SPEP or UPEP are not detectable at screening, and subsequently if not detected
in both SPEP and UPEP, as well as to confirm CR), with quantitative immunoglobulins per routine laboratory practice (quantitative
Ig required to be repeated for patients with IgA or IgD myeloma) and serum free light chain (SFLC) assay (only required if SPEP
and UPEP are not measurable [UPEP is < 200 mg/24 hrs and SPEP is < 0.5 g/dL] and to confirm a sCR). To be conducted at
screening, Cycle 1 Day 1 and Day 1 of each additional cycle even if treatment is delayed.  All assessment of SPEP, UPEP, IFE and
FLC must be completed in the same laboratory for a given patient (see also footnote q).  In the event of cycle delay beyond day 43,
M protein disease assessment are required to be repeated on the day the new cycle starts i.e., Day 1 of the new cycle.  If treatment
is discontinued beyond day 43, the assessments should be repeated on the day of that determination (or as soon as possible 30 days
after the last dose of study drug) as part of the EoT visit.  Refer to Laboratory Guidance Document for details. All response
assessments require 2 consecutive evaluations according to the IMWG criteria.  Confirmed PD should be verified by the medical
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l)
Known or suspected extramedullary plasmacytomas are to be assessed and measured at screening (within 28 days), as clinically
indicated, and to confirm a response obtained by M protein assessment or a suspected progression according to IMWG-UCR. The
same method of evaluation should be used throughout the study (e.g. CT/MRI/PET), and bi-dimensional measurements must be
obtainable. All imaging assessments should be documented in the eCRF.
m) Assessment of lytic bone lesions can be done either by skeletal survey, or low dose CT scan. Assessment includes:  lateral
radiograph of the skull, and anterioposterior views of femur and humeri, aterioposterior and lateral views of the spine, and
anterioposterior views of the pelvis and ribs or low dose CT scan. Required ≤ 6 weeks prior to study entry. Additional imaging
assessments may be performed at the investigator’s discretion and should be documented in the 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.
n) See Section 7 in the protocol for complete details on study drug administration, dose modifications and start of a new cycle of
therapy.
o) Concomitant medications: All blood products and medications within 21 days prior to first dose of study drug until the End of
Treatment Visit
p) End of Treatment visit should be scheduled 30 days (accepted time window ±3 days) after last dose of melflufen 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 unresolved
toxicity), with evaluation of safety variables including recording of new and ongoing adverse events, review of concomitant
medications and any other new disease related therapy.  If a new treatment for multiple myeloma 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 stabilization or
initiation of subsequent therapy.  Serious Adverse Events should be followed until resolution or stabilization with no expected
resolution.
q) Follow-up for Disease Progression: Patients who discontinue therapy for reasons other than disease progression should continue to
have monthly disease assessments done until documented progression (confirmed on 2 consecutive assessments) or initiation of
subsequent therapy. (Confirmed PD should be verified by medical monitor prior to discontinuation of therapy). If the patient enters
PFS-FU, the first PFS M protein disease assessment should be scheduled 30 days +/- 7 days after the EoT visit. Patients unwilling
or unable to return to the site for PFS evaluations may have the laboratory assessments done locally following approval by the
medical monitor. If PD has not been confirmed prior to the initiation of subsequent therapy, the reason for the subsequent therapy


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should be documented.  Documentation of the date and regimen of the first subsequent therapy is required. M-protein assessments 
required monthly, imaging of lytic lesions and/or plasmacytomas and serum calcium (corrected calcium) required only if suspected 
as evidence of PD.  
r)
Follow-up for overall survival:  Following confirmed disease progression or initiation of subsequent therapy, follow-up for overall
survival status, second primary malignancies and (documentation of the date and regimen of first) subsequent therapy, if not done
during PFS-FU, will take place every three months +/- 7 days for 24 months. The first OS follow-up should be scheduled 3 months
after the last PFS-FU or EOT visit. In the event that Oncopeptides AB would like to determine the OS status of patients following
24 months, future inquiries about their health status may be conducted.
s) Follow-up may be completed by phone contact. Serious Adverse Events should be followed until resolution or stabilization with
no expected resolution. Death information from public sources, e.g. death registry, obituary listing, etc. can also be used when it is
available and verifiable.
t)
PRO: the QLQ-C30 and EQ-5D-3L questionnaires should be administered to the patient before any other study procedures are
performed and before the administration of study drug. To be completed at C1D1, C2D1, C4D1, C6D1, C8D1, EOT, PFS-FU and
at OS-FU (only if patient conducts the follow up visit onsite). 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.
u) +/- 3-day window permitted for all visits (except Cycle 1 Day 1 [no leeway].
v) 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 Day 8 and Day
22. Patients should  still be contacted weekly by phone to follow up on AE/SAEs and dexamethasone compliance.


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8.2 
STUDY ASSESSMENTS 
All assessments should be done according to the timelines outlined in Table 8-1; Schedule of 
Events. 
 
Screening Disease Assessments 
• M-protein determination using the following procedures:
o
SPEP and serum protein IFE with quantitative Ig;
•
Quantitative immunoglobulin evaluation may be based on regional availability of
the test
•
Immunofixation of serum is required at screening if M protein by SPEP is not
detectable
o
UPEP and urine protein IFE (all using the same 24-hour urine collection)
•
Immunofixation of urine is required at screening if M protein by SPEP is not
detectable
o
SFLC and SFLC ratio
•
FLC assessment is not required at screening in the presence of measurable SPEP
and/or UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 mg/24 hours)
•
If the M protein is non-measurable in SPEP and UPEP at screening or Cycle 1,
Day 1, the FLC is required
• BMA to quantify percent myeloma cell involvement
• Extramedullary plasmacytoma evaluation of known or suspected lesions (by PE and/or
imaging procedures)
• Skeletal survey: lateral radiograph of the skull, and anterioposterior views of femur and
humeri, anterioposterior and lateral views of the spine, and anterioposterior views of the pelvis
and ribs or low dose CT scan may be used (with the same technique to be used at screening
and each evaluation).
• Beta2 microglobulin
• LDH
• Cytogenetics by FISH
• ISS staging score and revised R-ISS (Appendix I)
 
Efficacy Assessments 
Efficacy Assessments 
• M-protein determination using the following procedures:
o
SPEP and serum protein IFE with quantitative Ig (quantitative Ig required only for patients
8.2.1 
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for patients with IgA and IgD myeloma); 
•
Immunofixation of serum is required at any time when M protein by both SPEP
and UPEP becomes non-detectable and to confirm a CR.
o
UPEP and urine protein IFE (all using the same 24-hour urine collection);
•
Immunofixation of urine is required at any time when M protein by both UPEP
and SPEP becomes not detectable and to confirm a CR.
o
SFLC and SFLC ratio.
•
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.
It is up to the site to work with the laboratory that performs the response analyses to ensure 
that the laboratory completes the immunofixation and FLC evaluations when required, to 
enable response assessments according to IMWG criteria. 
• Extramedullary plasmacytoma evaluation with the same technique to be used with each
evaluation. Bi-dimensional measurements must be obtainable by the selected imaging
technique.
• Bone marrow aspirate to quantify percent myeloma cell involvement
• Assessment of lytic bone lesions: skeletal X-rays or CT scan (with the same technique at
screening and each evaluation).
• Serum calcium (corrected calcium)
M protein disease status (assessed by M-protein quantitation and IFE and free light chain from 
serum and 24-hour urine collection), should be assessed at screening and Cycle 1 Day 1, and on 
planned Day 1 (i.e. Day 29 of the previous cycle) of each cycle even if treatment is delayed. In the 
event treatment for a new cycle is delayed beyond Day 43 of the previous cycle, M protein disease 
status is required to be repeated on the day the new cycle starts, i.e. Day 1 of the new cycle (e.g. 
Day 50 or 57 of the previous cycle).  If treatment is discontinued beyond Day 43, the assessment 
should be repeated on the day of that determination (or as soon as possible 30 days after the last 
dose of study drug) as part of end of treatment (EoT) visit.  If the patient enters PFS-FU, the first 
PFS M protein disease status assessment should be scheduled 4 weeks after the EoT visit.  If the 
patient is discontinued mid-cycle, prior to Day 28, the EoT visit should be scheduled 30 days (+/- 
3 days) after the last dose of study drug.  
Starting with Cycle 2, M protein response to treatment should be assessed every cycle. Disease 
status, including skeletal x-rays of bones or low dose CT scan and imaging assessment (i.e. CT/ 
positron emission tomography [PET]/ magnetic resonance imaging [MRI] scan) of known or 
suspected extramedullary plasmacytomas, will be performed at screening and if indicated 
according to the IMWG response criteria. Bone marrow aspirate will be performed at screening 


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and to confirm suspected CR in patients who have achieved a negative IFE.  Additional skeletal 
x-rays and/or imaging assessments may be performed at the investigator’s discretion at screening
to further evaluate plasmacytomas. All imaging assessments should be documented in the eCRF.
Repeat assessments if the patient has symptoms suggestive of progression of lesion(s) documented
at screening or new lesions. If extramedullary plasmacytomas are present at screening and
measurable on physical examination, they will be assessed at every cycle.  Extramedullary
plasmacytomas documented and measurable only by imaging assessments will be assessed by the
same relevant modality to confirm response or progression according to the IMWG response
criteria.
• Functional status and well-being
Two different PROs will be used to evaluate functional status and well-being in the study; the
EORTC QLQ-C30 and the EQ-5D-3L.
-
EORTC QLQ-C30, which includes 30 items resulting in 5 functional scales, 1 Global
Health Status scale, 3 symptom scales, and 6 single items. The recall period is 1 week (the
past week). The EORTC QLQ-C30 has been widely used among cancer patients. Scores
are transformed to a 0 to 100 scale. Administration time is approximately 11 minutes. QLQ-
C30 domain scores will be summarized at each time point and change from baseline will
be derived. The relationship between clinical response and change in domain scores will
be explored.
-
EQ-5D-3L, a generic measure of health status. For the purpose of this study the EQ-5D-
3L will be used to generate utility scores for use in cost-effectiveness analyses. The EQ-
5D-3L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual
activities, pain/discomfort and anxiety/depression plus a visual analog scale (EQ VAS)
rating “health today” with anchors ranging from 0 (worst imaginable health state) to 100
(best imaginable health state). The scores for the 5 separate questions are categorical and
are cannot be analyzed as cardinal numbers. However, the scores for the 5 dimensions are
used to compute a single utility score ranging from zero (0.0) to 1 (1.0) representing the
general health status of the individual. The 5 domains of EQ-5D-3L and the EQ VAS will
be summarized at each time point and change from baseline will be derived. Functional
status and well-being.
-
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.  If the patient wishes to have the
questions read aloud and then answer orally and the study personnel write the answer on
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Safety and Tolerability Assessments 
Safety Assessments: 
• Serial physical examinations with vital signs and assessment of performance status and
neurological status.
•
Routine safety laboratory tests (CBC with differential and platelets; serum chemistry,
coagulation tests) with calculation of creatinine clearance according to the Cockcroft-Gault
equation.  For women below 155 cm in height and with normal BMI (18.5 – 24.9 kg/m2) the
CKD-EPI method for calculation of glomerular filtration may be used (Appendix G).  Cases
with borderline values of creatinine clearance based on the Cockcroft-Gault formula may be
discussed with the medical monitor.
• Chest X-ray (postero-anterior/lateral).
• Grade 3 and 4 thrombocytopenia and neutropenia (See Section 9.1.5).
• Pregnancy testing.
• ECG.
• Assessment and grading of adverse events.
Adverse experiences, including clinical laboratory and vital sign abnormalities, will be graded 
using the CTCAE version 4.03 (Appendix B).  Patients are evaluable for toxicity if they receive 
one dose of study treatment.   
 
Electrocardiogram Assessments 
At screening and End of Treatment (EoT) visit, a 12-lead ECG assessment will be performed on 
all patients and as clinically indicated.  QTc interval to be assessed by Fridericia formula 
(Appendix H). 
 
End of Treatment 
The EoT visit should be scheduled 30 days (accepted time window ±3 days) after last dose of 
melflufen or as soon as possible if the decision to remove patient from therapy occurs later than 
30 days after last dose (e.g. in the case of prolonged toxicity).  At the EoT visit, evaluation of 
safety variables including recording of new and ongoing AEs, review of concomitant medications 
and any other new disease related therapy should be performed.  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 a new treatment for multiple myeloma 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 stabilization, or 
initiation of subsequent therapy.  Serious Adverse Events should be followed until resolution or 
stabilization with no expected resolution. The date and regimen of the first subsequent therapy 
should be recorded in the eCRF. 
8.2.3 
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Follow Up Assessments 
PFS-FU and OS-FU assessments should be completed on all patients unless due to death, lost to 
follow-up or the patient specifically has withdrawn consent for follow-up.  Treatment 
discontinuation alone does not preclude the need to complete follow-up assessments. 
8.2.6.1 
Progression Free Survival Follow-up 
Patients who discontinue therapy for reasons other than disease progression should continue to 
have monthly disease assessments done for PFS-FU until progression or initiation of subsequent 
therapy.  If PD has not been confirmed prior to initiation of subsequent therapy, the reason for the 
subsequent therapy should be documented.  The date and regimen of the first subsequent therapy 
should be recorded in the eCRF if occurs during PFS-FU.  
8.2.6.2 
Overall Survival Follow-up 
Following confirmed disease progression, patients will be followed for OS-FU.  Follow-up for 
overall survival status, second primary malignancies and first subsequent therapy will take place 
every three months +/- 7 days for 24 months. In the event that Oncopeptides AB would like to 
determine the OS status of patients following 24 months, future inquiries about their health status 
may be conducted. This information may be recorded outside of the eCRF established for this 
study. OS-FU may be completed by phone contact.  Death information from public sources, e.g. 
death registry, obituary listing, etc. can also be used when it is available and verifiable. The date 
and regimen of the first subsequent therapy should be recorded in the eCRF if it occurs during OS-
FU. 
8.2.6.3 
Assessment of Functional Status and Well-being during Follow up 
Patients should complete PROs for the assessment of functional status and well-being at each 
follow up visit (PFS-FU and OS-FU) that the patient performs onsite. The completion of PROs is 
to be done first in the day, prior to any other procedures.   
8.2.6.4 
Lost to Follow-Up 
Patients lost to follow up should be recorded as such on the eCRF.  For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
 
Criteria for Premature Patient Withdrawal 
Patients may be withdrawn from treatment if any of the following occur: 
1. Documented confirmed disease progression (2 consecutive evaluations) verified by the
medical monitor.
2. Patients may choose to discontinue from the study treatment at any time and continue in
follow-up.
3. AEs that, in the judgment of the investigator, may cause severe or permanent harm or which
require study drug discontinuation (See section 7.7).
8.2.6 
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4. Clinical judgment of the investigator:  A patient may be withdrawn from the study
treatment, if in the opinion of the investigator, it is not in the patient's best interest to
continue.
5. Requiring other anti-neoplastic therapies.
6. Major violation of the study protocol (i.e., unable to adhere to study schedule).
7. Confirmed pregnancy.
8. Lost to follow-up
Patients may be withdrawn from the study if any of the following occur: 
1. Withdrawal of consent for study participation.
2. Death.
3. Lost to follow-up.
4. Discontinuation of the study by Oncopeptides AB.
5. Completed OS follow up as per protocol
The reason(s) for withdrawal of treatment or study participation and the date at which the decision 
is made should be documented. Safety monitoring and follow-up assessments should continue as 
appropriate according to the study schedule, unless the patient has withdrawn consent for study 
participation. 
9 
SAFETY MONITORING AND REPORTING 
9.1 
ADVERSE EVENTS 
 
Definitions 
An AE is any untoward medical occurrence in a study patient administered an investigational 
product and that does not necessarily have a causal relationship with this treatment.  
An AE therefore can be any unfavorable and unintended sign (including laboratory finding), 
symptom or disease temporally associated with participation in an investigational study, whether 
or not considered drug-related.  In addition to new events, any increase in the severity or frequency 
of a pre-existing condition that occurs after the patient begins study therapy is considered an AE. 
This includes any adverse reactions, injury, toxicity, or sensitivity reaction.  
An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent 
with the current IB of melflufen or prescribing information for dexamethasone.  Also, reports 
which add significant information on specificity or severity of a known, already documented AE 
constitute unexpected AEs.  For example, an event more specific or more severe than described in 
the Melflufen IB would be considered “unexpected”.   
 
Grading of Severity 
Whenever possible, the CTCAE version 4.03 should be used to describe the event and for assessing 
the severity of AEs (see Appendix B).  Any events representing a change in the CTCAE Grade 
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needs to be reported on the AE eCRF.  This includes any abnormal laboratory values that the 
investigator considers clinically significant (Section 9.1.5). 
For AEs not adequately addressed in the CTCAE, the severity table below may be used: 
Table 9-1    Adverse Event Severity 
Severity 
Description 
Grade 1 – Mild 
Transient or mild discomfort; no limitation in 
activity; no medical intervention/therapy 
required. 
Grade 2 – Moderate 
Mild to moderate limitation in activity—some 
assistance may be needed; no or minimal 
medical intervention/therapy required. 
Grade 3 - Severe 
Marked limitation in activity, some assistance 
usually required; medical intervention/therapy 
required; hospitalizations possible. 
Grade 4 - Life-
threatening 
Extreme limitation in activity, significant 
assistance required; life-threatening (immediate 
risk of death); significant medical 
intervention/therapy required, hospitalization or 
hospice care probable. 
Grade 5 – Fatal 
Death related to AE 
 
Causality 
The assessment of causality will be based on the information available and may be changed upon 
receipt of additional information. 
Causality should be assessed using the following categories: 
• Unrelated: Clinical event with an incompatible time relationship to investigational agent
administration, and that could be explained by underlying disease or other drugs or chemicals
or is incontrovertibly not related to the investigational agent
• Possibly related: Clinical event with a reasonable time relationship to investigational agent
administration, and that is unlikely to be attributed to concurrent disease or other drugs or
chemicals
• Probably related: Clinical event with plausible time relationship to investigational agent
administration, and that cannot be explained by concurrent disease or other drugs or chemicals
The investigator must appraise all abnormal laboratory results for their clinical significance.  If 
any abnormal laboratory result is considered clinically significant, the investigator must provide 
details about the action taken with respect to the test drug and about the patient's outcome 
(Section 9.1.5.1). 
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Adverse Event Reporting 
All adverse events that are spontaneously reported by the patient or detected during or between 
visits by non-directive questioning, through physical examination, laboratory test, or other 
assessments should be reported in the eCRF.  As far as possible, each adverse event should be 
evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5).
2. Its duration (Start and end dates).
3. Its relationship to the study treatment (causality).
4. Action taken with study drug (e.g. none, dose reduced, dose held, permanently
discontinued, other).
5. Whether medication or therapy was given (concomitant medication or procedure).
6. Outcome (e.g. not resolved, resolved, resolved with sequalae, fatal, unknown).
7. Whether it is a serious adverse event (SAE) as defined in Section 9.2.
All adverse events should be treated appropriately.  If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the eCRF. 
Any adverse event (i.e. a new event or an exacerbation of a pre-existing condition) that occurs 
after the first dose of study medication up to 30 days after the last study drug administration must 
be recorded as an adverse event on the appropriate page(s) of the CRF. Should a patient discontinue 
from treatment or complete the study and commence subsequent anticancer therapy within 30 days 
of the last study drug administration, adverse events attributable to this subsequent therapy should 
not be recorded.   
 
Laboratory Test Abnormalities 
9.1.5.1 
Definitions and Reporting 
Laboratory abnormalities are usually not recorded as adverse events; however, signs and/or 
symptoms that are associated with laboratory findings requiring treatment discontinuation, dose 
modification, or medical intervention (e.g. anemia requiring transfusions or hyperglycemia 
requiring treatment) or other abnormal assessments (e.g. ECG, radiographs, vital signs) must be 
recorded as adverse events (or serious adverse events) if they meet the definition of a serious 
adverse event as described in Section 9.2.  In addition, laboratory abnormalities assessed as 
clinically significant should also be recorded as adverse events.  The Investigator will record the 
grade of the clinically significant laboratory abnormality and will evaluate its relationship to the 
study drug and clinical condition. Adverse events as a result of laboratory abnormalities 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). 
Clinically significant laboratory abnormalities are those that: 
• Induce clinical signs and symptoms
• Require concomitant therapy
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• Require change in study treatment
• Investigator considers clinically significant for any reason
Additional laboratory reporting guidelines. 
Extra attention should be given to reporting all Grade 3 and 4 thrombocytopenia and neutropenia 
events. They must be: 
• Collected and reported during the study period and the EoT visit.
• Ongoing grade 3 and 4 thrombocytopenia and neutropenia 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 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.
Supportive care such as platelet transfusions and G-CSF given for adverse events or prophylactic 
reasons must be reported in the eCRF and if applicable also in the SAE report. 
9.2 
SERIOUS ADVERSE EVENTS 
 
Definitions 
A Serious Adverse Event (SAE) is defined as any AE, occurring at any dose that meets any one or 
more of the following criteria: 
• Is fatal or immediately life-threatening
• Results in persistent or significant disability/incapacity
• Constitutes a congenital anomaly/birth defect
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may require
medical or surgical intervention to prevent one of the outcomes listed above
• Requires inpatient hospitalization or prolongation of existing hospitalization.
• (AEs requiring hospitalization of less than 24 hours, will not be reported as SAEs unless
another seriousness criteria is fulfilled)
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or if the patient may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
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home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
Note that hospitalizations for the following reasons should not be reported as serious adverse 
events: 
• Routine treatment or monitoring of the studied indication, not associated with any deterioration
in condition
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication
under study and has not worsened since signing the informed consent
• Social reasons and respite care in the absence of any deterioration in the patient’s general
condition
• Treatment on an emergency outpatient basis that does not result in hospital admission and
involves an event not fulfilling any of the definitions of a SAE given above is not a serious
adverse event
• Disease progression: In instances of SAE’s due to “disease progression” the event or condition
that met the criteria for the SAE should be indicated as the event term or condition rather than
disease progression to the extent possible (e.g. “respiratory failure” or “renal failure” due to
progressive MM).
 
Serious Adverse Event Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has signed informed consent and until 30 days after the last administration of any study drug must 
be reported to the Oncopeptides AB designated CRO, within 24 hours of the onset or after the 
investigator became aware of the SAE.  
An SAE reporting form must be filled out and sent via fax or email to: 
• SAE Fax line (United States): 1-877-853-3275
• SAE Fax line (Europe): +34 91 307 60 47
• Email: drugsafety@pivotal.es
The initial SAE report form should have the following data elements, at a minimum, to constitute 
a valid report: a patient identifier (patient number), an identifiable investigational agent (study 
drug), an identifiable reporting source (investigator’s name or site number) as well as an 
identifiable serious adverse event.  The investigator’s initial causality assessment must also be 
included if available. 
Each re-occurrence, change in grade, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs.  The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated and whether 
the patient continued or withdrew from study participation. A SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
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Any SAE that occurs after the above defined regular SAE reporting period, should also be reported 
if the investigator suspects a causal relationship to the study treatment.  All deaths occurring during 
the regular SAE reporting period must be reported, regardless of cause (See Section 9.2.2.1).   
SAEs should be followed until resolution, or stabilization with no anticipation of resolution 
regardless of 30-days reporting time line unless deemed by the investigator as not expecting to 
resolve at the last study visit or patient is lost to follow-up and this is documented in the study file. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
Health Competent Authorities and concerned Ethics Committees (ECs)/Institutional Review 
Boards (IRBs) in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.  For the purpose of SUSARs reporting, only possibly or probably related 
SAEs (i.e. there is a reasonable possibility of causality) will be considered serious adverse drug 
reactions.  See Section 9.1.3 for further information. 
9.2.2.1 
Reporting of Death 
• Death is an outcome of a serious adverse event and not a serious adverse event 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.
9.3 
PREGNANCY 
To ensure patient safety, any pregnancy occurring while the patient is on study treatment must be 
reported by the investigator to the designated CRO, within 24 hours of learning of its occurrence. 
The pregnancy should be followed-up to determine its outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications and possible relationship to 
the study treatment. 
A pregnancy reporting form must be filled out and sent via fax or email to: 
• SAE Fax line (United States): 1-877-853-3275
• SAE Fax line (Europe): +34 91 307 60 47
• Email: drugsafety@pivotal.es
Any SAE experienced during pregnancy (such as congenital anomaly/birth defect/spontaneous 
abortions) must be reported via fax or email as noted above. 
Male patients, who impregnate their female partners during study participation, should be 
requested to provide the outcome and details of the pregnancy, with details completed as above. 


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9.4 
DATA SAFETY MONITORING COMMITTEE  
An independent data and safety monitoring committee (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 participants. The DSMC will consist of key investigator(s) and Sponsor 
representative(s) and headed by an independent chairperson.  All activities and processes 
surrounding the DSMC will be outlined in the DSMC Charter. 
10 
DATA COLLECTION AND MANAGEMENT 
10.1 
DATA CONFIDENTIALITY 
Information about study patients should be kept confidential and managed under the applicable 
laws and regulations.  Those regulations require a signed patient consent form informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study
• Who will have access to that information and why
• Who will use or disclose that information
• The rights of a research patient to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the Sponsor and its agents, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
Access to the data collection system will be controlled by user identification codes and passwords, 
and made available only to authorized personnel who have completed prerequisite training. 
10.2 
SITE MONITORING 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Oncopeptides AB 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and their 
staff.  During the study, the monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the eCRFs, the adherence to the protocol to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, dispensed, 
and accounted for according to specifications.  Key study personnel must be available to assist the 
field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or assessments. 
All information recorded on eCRFs must be traceable to source documents in the patient's file. 
The investigator must also keep the original signed informed consent form (a copy of the signed 
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries.  Oncopeptides AB (or CRO) monitoring standards require full 
source data verification for the presence of signed and dated informed consent, adherence to the 
inclusion/exclusion criteria and documentation of AE/SAEs.  Additional checks of the consistency 
of the source data with the eCRFs are performed according to the study-specific monitoring plan. 
10.3 
DATA COLLECTION 
An electronic Case Report Form (eCRF) is required and should be completed for each patient. The 
patient’s identity should always remain confidential.  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. 
The designated investigator staff will enter the data required by the protocol into the eCRF.  The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the electronic data capture 
(EDC) system until they have been trained.  Automatic validation programs will check for data 
discrepancies in the eCRFs and allow modification or verification of the entered data by the 
investigator staff. 
The study Investigators are responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
10.4 
DATABASE MANAGEMENT AND QUALITY CONTROL 
Oncopeptides AB personnel (or designated CRO) will review the data entered by investigational 
staff for completeness and accuracy.  Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system.  Designated investigator site staff are required to respond 
promptly to queries and to make any necessary corrections to the data. 
11 
STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
STUDY ENDPOINTS 
 
Primary Endpoint 
The primary endpoint is a best response of PR or better, as assessed by the investigator according 
to IMWG-URC, from which overall response rate (ORR) is calculated. ORR is defined as the 
proportion of patients with a best confirmed response of sCR, CR, VGPR, or PR according to the 
IMWG-URC (Rajkumar et al. 2011), (Appendix C), as assessed by the Investigator and reported 
in the eCRF using the study center laboratory evaluation.   
 
Secondary Endpoints 
PFS: is defined as time (months) from date of first dose to the earlier of confirmed disease 
progression or death due to any cause.  The conventions for censoring of PFS are described in 
Table 11-1.  
11.1.1 
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Progression status will be assessed by the investigator using the IMWG-URC, (Rajkumar et al. 
2011).  
Best response of MR or better, from which clinical benefit rate will be calculated. CBR, i.e. 
proportion of patients with ≥ MR): is the rate of efficacy evaluable patients that achieve a 
confirmed minimal response or better.  
TTR: is defined as the time from the date of first dose to the date of the first documented confirmed 
response in a patient that has responded with ≥ PR. 
TTP: is defined as the time from the first date of first dose to the date of the first documented 
confirmed PD.   
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. 
Duration of stable disease: is defined as the date of first dose to the first documented PD in patients 
who fail to achieve response (≥ MR)  
OS: is defined as time (months) from date of first dose to death due to any cause.  Patients still 
alive at end of study, or lost to follow up, will be censored at last day known alive. 
The maximum grade (according to Common Terminology Criteria for Adverse Events (CTCAE 
v4.03) for each type of adverse event will be recorded for each patient, and frequency tables will 
be presented and reviewed to determine patterns.  Additionally, the relationship of the adverse 
event(s) to the study treatment will be taken into consideration. 
Functional status and well-being: The PROs QLQ-C30 and EQ-5D-3L will be used to evaluate 
functional status and well-being. The derivation of summary scores as well as subscales will be 
performed at each measured time point following the guidelines related to the Questionnaire. 
Observed results will be presented at each measured time point as well as change from baseline.   
11.2 
SAMPLE SIZE CALCULATION 
A total number of approximately 150 patients are planned to be enrolled in the study, to achieve 
130 patients evaluable for efficacy, and 50 patients evaluable for EQ-5D-3L. 
Initially, one group of approximately 39 efficacy evaluable patients that are refractory to 
pomalidomide and one group of approximately 39 efficacy evaluable patients that are refractory 
to daratumumab were planned to be enrolled (see interim analysis Section 11.3.4).    
Based on the positive benefit-risk ratio in this patient population to date, as well as the objective 
to obtain functional status and well-being data in this patient population, this was changed to allow 
an increased sample size.  
Instead of calculating the sample size on the power to show superiority on ORR versus a fixed 
value, the sample size is now based on the precision of the estimates. As for the ORR, given a 
sample size of 130 evaluable patients and an observed ORR of 30%, the exact 95 % confidence 
interval would range from 22.3 % to 38.7 %. 


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Further enrollment to each group may continue to establish a sufficient dataset if deemed 
appropriate at the discretion of the Sponsor regardless of the number of patients recruited at that 
time. 
11.3 
SUB-GROUP OF SPECIFIC INTEREST 
Patients that are refractory to all three currently approved classes of drugs (IMiDs, PIs and anti-
CD38 mAbs) have emerged as a sub-group of particular interest. 
All efficacy and safety analyses performed for the total population will be repeated in a similar 
way for this sub-population. In a retrospectively analysis as of 06 February 2019, this triple-class 
refractory sub-group represented 70% of the total population (67 of 95 patients). All triple-class 
refractory patients that are enrolled in the study on or after the date of the retrospective analysis 
will be followed prospectively. The ORR for patients of this sub-group accrued retrospectively 
before 06 February 2019 will be reported as well as patients prospectively enrolled after this 
date. If there is no substantial difference in ORR, the results will be presented for the total sub-
group.  Assuming a similar (or slightly higher) proportion of patients within the remaining 
approximately 55 patients, about 40 patients of the sub-group of specific interest can be followed 
prospectively. 
11.4 
STATISTICAL METHODS 
 
General Considerations for the Statistical Analysis 
The statistical analyses as outlined in this section will be further described in the statistical analysis 
plan (SAP), which will be finalized prior to locking the database.  Statistical analyses will be 
reported using summary tables, inferential analyses, figures, and data listings.   
For continuous variables, the number of patients with non-missing data (n), mean, standard 
deviation (SD), median, minimum, and maximum will be summarized.  For discrete data, the 
frequency and percent distribution will be summarized.  Graphical methods will be used, as 
appropriate, to illustrate study endpoints.  Individual patient data recorded on the electronic case 
report forms (eCRFs) and any derived data will be presented by in data listings. 
 
Analysis populations 
11.4.2.1 Efficacy Analysis Set  
The primary efficacy population will be comprised of all patients who received at least 2 doses of 
melflufen, had a baseline disease assessment and at least 1 post-baseline disease assessment 
(efficacy evaluable patients).  
To be evaluable for functional and well-being analysis, patients must be evaluable for efficacy and 
have a completed baseline (C1D1) and at least one post baseline (C2D1 and/or later) assessment. 
11.4.1 
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11.4.2.2 Safety (All Treated) Analysis Set 
The safety (all treated) analysis set will be comprised of all patients that receive any study 
treatment (melflufen or dexamethasone).  
 
Analysis of Efficacy Endpoints 
11.4.3.1 Primary Endpoint 
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. At the end of the 
trial an exact two-sided 95% confidence interval for ORR will be determined.  The ORR will 
primarily be based on the efficacy evaluable analysis set. 
11.4.3.2 Analyses of Secondary Endpoints 
PFS is measured from the date of first study drug to the date of documented disease progression 
or death.  PFS will be right-censored for patients who met one of the following conditions:  
• No post baseline disease assessments,
• Non-protocol systemic anticancer treatment started before documentation of disease
progression or death,
• Death or disease progression after more than 1 missed disease assessment visit, or
• Death or PD between planned disease assessments
• Death before first disease assessment
• Alive without documentation of disease progression before a data analysis cutoff date.
These conventions are based on the May 2007 FDA Guidance for Industry, (FDA 2007). For such 
patients, the primary analysis of PFS will be right-censored according to the conventions described 
in Table 11-1. 
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Table 11-1  Conventions for Censoring for PFS 
Situation 
Date of Progression or 
Censoring 
Outcome 
No post baseline disease 
assessments, except in the case of 
death 
Date of first dose 
Censored 
New anticancer therapy started 
before documentation of PD or 
death 
Date of last disease assessment 
prior to start of new anticancer 
therapy  
Censored 
Death or PD immediately after 
more than 1 consecutively missed 
disease assessment visit 
Date of last disease assessment 
visit without documentation of PD 
that is before the first missed visit  
Censored 
Alive and without PD 
documentation  
Date of last disease assessment 
Censored 
Death or PD between planned 
disease assessments 
Date of death or first disease 
assessment showing PD, 
whichever occurs first  
Progressed 
Death before first disease 
assessment 
Date of death 
Progressed 
The distribution of PFS will be summarized using the Kaplan Meier method.  The median PFS 
will be estimated from the 50th percentile of the corresponding Kaplan Meier estimates.  The 95% 
CI for median PFS will be constructed using the method of Brookmeyer (Brookmeyer et al. 1982).  
Duration of follow-up for PFS will be estimated by the reverse Kaplan-Meier method of Schemper 
(Schemper et al. 1996).   PFS will be based on both the All Treated and the Efficacy analysis set.  
Other time to events endpoints will be described in the same way as PFS. 
CBR, will be estimated with its associated 95% confidence interval assuming binomial 
proportions.  
Functional status and well-being: 
QLQ-C30: The observed value, as well as change from C1D1 (baseline), in the QLQ-C30 
summary score as well as all subscales will be summarized.  
EQ-5D-3L will be summarized both for the descriptive system as well as for the EQ VAS scores 
at each measured time point. Furthermore, the results from the EQ-5D-3L will be used in the 
evaluation of cost effectiveness of melflufen.  
11.4.3.3 Independent review of primary and secondary endpoints 
Oncopeptides will implement an independent review of the response and progression assessments 
performed by the investigator. The investigator will be notified of any discrepancies in the form 
of a data query.   


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Interim Analysis 
An interim analysis for futility (according to the Simon two-stage design) for each group 
(pomalidomide-refractory and daratumumab-refractory patients) was planned and conducted after 
19 patients had been enrolled and were evaluable for the primary endpoint (ORR) (Simon 1989).  
Following the futility analysis, on 21 December 2017, the study DSMC assessed the benefit/risk 
balance, and found this balance to be positive in both of the groups as well as for the total study 
population. Due to the overall positive benefit/risk balance, the DSMC recommended that the 
study recruitment would proceed without changes or limitations. 
 
Analysis of Safety Data 
All safety results will be presented for the All Treated analysis set. No formal statistical analysis 
will be performed for the safety endpoints. 
Study treatment administration, including duration of exposure, total dose, and dose modifications 
will be summarized.   
Each reported AE term will be mapped to a preferred term (PT) and a system organ class (SOC) 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  The 
summaries of adverse events (AEs) will be based on TEAEs.  TEAEs are defined as AEs that start 
on or after the first day of study treatment is administered and within 30 days of the last 
administration of study treatment or before start of subsequent anticancer treatment (whichever 
occurs first) or that worsen on or after the first day of study treatment.   
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 All Treated 
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 and change from baseline for all hematology, serum chemistry, and coagulation 
parameters will be summarized at each scheduled visit.  Selected laboratory test results will be 
assigned toxicity grades using CTCAE 4.03.  Shift tables assessing the  
toxicity grade at baseline versus worst toxicity recorded on study will be presented.  A listing of 
all grade 3 or higher laboratory values will be provided. 
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. 
11.4.4 
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11.5 
HANDLING OF DROP-OUTS AND MISSING DATA 
The SAP describes how dropouts and missing data impact the calculation of the time to event 
variables.  Missing data will not be estimated or carried forward for any of the other summaries or 
analyses.  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 date will be imputed.  Detail of the methods of imputation 
will be provided in the SAP. 
Handling of partial missing data for the PRO measurements will be done in accordance with the 
instructions for the QLQ-C30 questionnaire and EQ-5D-3L and described in the SAP.   
12 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
12.1 
REGULATORY AND ETHICAL COMPLIANCE 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations Title 
21), and with the ethical principles laid down in the Declaration of Helsinki. 
12.2 
RESPONSIBILITIES OF THE INVESTIGATOR AND IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC) before 
study start. A signed and dated statement that the protocol and informed consent have been 
approved by the IRB/IEC must be given to Oncopeptides AB (or designated CRO) before study 
initiation.  Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all of 
the instructions and procedures found in this protocol and to give access to all relevant data and 
records to Oncopeptides AB (or designated CRO) monitors, auditors, Clinical Quality Assurance 
representatives, designated agents of Oncopeptides AB, IRBs/IECs and regulatory authorities as 
required. 
12.3 
INFORMED CONSENT PROCEDURES 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent  
Informed consent must be obtained before conducting any study-specific procedures.  The process 
of obtaining informed consent should be documented in the patient source documents. The date 
when a patient’s informed consent form (ICF) was actually obtained will be captured in the eCRFs. 
Oncopeptides AB (or designated CRO) will provide to investigators, in a separate document, a 
proposed ICF that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements.  Any changes to this ICF suggested by the investigator 
must be agreed to by Oncopeptides AB or designee before submission to the IRB/IEC, and a copy 


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of the approved version must be provided to the Oncopeptides AB (or designated CRO) monitor 
after IRB/IEC approval. 
12.4 
DISCONTINUATION OF THE STUDY 
Oncopeptides AB reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement at a single study center or the study as a whole.  A study group may be 
discontinued at interim futility analysis as described in Section 11.3.4. Specific conditions for 
terminating the study at any time for reasonable medical or administrative reasons in any single 
center could include but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality.
• Inaccurate or incomplete data collection.
• Falsification of records.
• Failure to adhere to the study protocol.
12.5 
PUBLICATION OF STUDY PROTOCOL AND RESULTS 
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.  Any publication will be a joint 
publication between Oncopeptides AB and the investigators and authorship will be determined by 
mutual agreement. 
12.6 
STUDY DOCUMENTATION, RECORD KEEPING AND RETENTION OF 
DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for 
the protection of confidentiality of patients.  As part of participating in an Oncopeptides AB 
sponsored study, each site will permit authorized representatives of the sponsor(s) and regulatory 
agencies to examine (and when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, and patient files and records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site Investigator.  The study eCRF is the primary data collection instrument for the study. The 


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investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the eCRFs and all other required reports.  Data reported on the eCRF, that are derived 
from source documents, should be consistent with the source documents or the discrepancies 
should be explained. All data requested on the eCRF must be recorded. Any missing data must be 
explained. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator must retain the study records for a minimum of 2 years after the last marketing 
application for the indication is approved in an ICH region or for 2 years after the IND is 
withdrawn.  For IND studies conducted outside the US, the investigator must retain study records 
for the time period described above or according to local laws or requirements, whichever is 
longer. 
12.7 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Oncopeptides AB, their agents or Health Authorities.  Signed 
informed consent forms and patient enrollment log must be kept strictly confidential to enable 
patient identification at the site. Refer to Section 10.1 for additional details regarding patient 
confidentiality.  
12.8 
AUDITS AND INSPECTIONS 
Source data/documents must be available to inspections by Oncopeptides AB or designee or Health 
Authorities. 
12.9 
FINANCIAL DISCLOSURES 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site prior to study start. 
12.10 
PROTOCOL ADHERENCE 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Notwithstanding 
the need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol.  In such cases, Oncopeptides AB or designated CRO 
should be notified of this action and the IRB/IEC at the study site should be informed according 
to local regulations.   
12.11 
AMENDMENTS TO THE PROTOCOL 
Any change or addition to the protocol can only be made in a written protocol amendment by 
Oncopeptides AB.  The amendment must be approved by the Health Authorities where required, 


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and the IRB/IEC before it may be implemented.  Only amendments that are required for patient 
safety may be implemented prior to IRB/IEC approval.  


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13 
REFERENCES 
American Society of Hematology Annual Meeting San Diego 2018, oral presentation of abstract 
#600 
Brookmeyer, R. and J. Crowley (1982). "A Confidence Interval for the Median Survival Time." 
Cavo, M., S. V. Rajkumar, A. Palumbo, et al. (2011). "International Myeloma Working Group 
consensus approach to the treatment of multiple myeloma patients who are candidates for 
autologous stem cell transplantation." Blood 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. 
FDA (2007). "Guidance for Industry Clinical Trail Endpoints the Approval of Cancer Drugs and 
Biologics." US Food and Drug Administration. 
FDA Pomalyst Prescribing Information (2013). 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204026s012s014lbl.pdf 
Gullbo, J., E. Lindhagen, S. Bashir-Hassan, et al. (2004). "Antitumor efficacy and acute toxicity 
of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo." Invest New 
Drugs 22(4): 411-420. 
Gullbo, J., M. Wickstrom, M. Tullberg, et al. (2003c). "Activity of hydrolytic enzymes in tumour 
cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1." J Drug 
Target 11(6): 355-363. 
Investigator Brochure, Melflufen Oncopeptides AB (2018), Edition 8 
Kaplan, E. L. and P. Meier (1958). "Nonparametric estimation from incomplete observations." 
Journal of the American Statistical Association 53: 457-485. 
Koyama, T. and H. Chen (2008). "Proper inference from Simon's two-stage designs." Stat Med 
27(16): 3145-3154. 
Kumar, S. K., S. V. Rajkumar, A. Dispenzieri, et al. (2008). "Improved survival in multiple 
myeloma and the impact of novel therapies." Blood 111(5): 2516-2520. 
Levey AS, Coresh J, Greene T, et al; Chronic Kidney Disease Epidemiology Collaboration. Using 
standardized serum creatinine values in the modification of diet in renal disease study equation for 
estimating glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54. 
Mateos, M., Oriol, A., Larocca, A. et al (2018). The Horizon: a preliminary report on efficacy and 
safety of melflufen in late stage relapsed-refractory myeloma (RRMM) patients refractory to 


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pomalidomide and/or daratumumab. 23rd Congress of the European Hematology Association 
(EHA), poster number PF581.  
Mougenot, P., F. Pinguet, M. Fabbro, et al. (2004). "Population pharmacokinetics of melphalan, 
infused over a 24-hour period, in patients with advanced malignancies." Cancer Chemother 
Pharmacol 53(6): 503-512. 
Nath, C. E., P. J. Shaw, J. Trotman, et al. (2010). "Population pharmacokinetics of melphalan in 
patients with multiple myeloma undergoing high dose therapy." Br J Clin Pharmacol 69(5): 484-
497. 
NCCN (2016). "National Comprehensive Cancer Network: Clinical Practice Guidelines Multiple 
Myeloma Version 1.2017. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp 
NCCN (2016). "National Comprehensive Cancer Network: Clinical Practice Guidelines Prostate 
Cancer Version 3.2016. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf  
Oken, M. M., R. H. Creech, D. C. Tormey, et al. (1982). "Toxicity and response criteria of the 
Eastern Cooperative Oncology Group." Am J Clin Oncol 5(6): 649-655. 
Paba-Prada, C., A. Palumbo, U. H. Mellqvist, et al. (2014). "Determination of the MTD and 
Preliminary Results in an Ongoing Open-Label Phase I/IIa Study of the Safety and Efficacy of 
Melflufen and Dexamethasone in Combination for Patients with Relapsed and Relapsed-
Refractory Multiple Myeloma (RRMM)." Blood 124:2123. 
Palumbo A, Avet-Loiseau H, Oliva S, et al.  Revised International Staging System for Multiple 
Myeloma: A Report from International Myeloma Working Group. Journal of Clinical Oncology. 
2015 33:26, 2863-2869  
Pomalidomide Celgene EPAR (2013). 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/hu
man/002682/WC500147721.pdf.  
Rajkumar, S. V., J. L. Harousseau, B. Durie, et al. (2011). "Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus 
Panel 1." Blood 117(18): 4691-4695. 
Rajkumar S.V.  Richardson P, San Miguel, J.  (2015).  “Guidelines for determination of the number 
of prior lines of therapy in multiple myeloma.” Blood 126:921-922. 
Rajkumar, S. V. and S. Kumar (2016). "Multiple Myeloma: Diagnosis and Treatment." Mayo 
Clinic Proceedings 91(1): 101-119. 


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Richardson, P. G., J. Laubach, C. Mitsiades, et al. (2010). "Tailoring treatment for multiple 
myeloma patients with relapsed and refractory disease." Oncology (Williston Park) 24(3 Suppl 2): 
22-29.
Richardson, P. G., D. S. Siegel, R. Vij, et al. (2014). "Pomalidomide alone or in combination with 
low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 
study." Blood 123(12): 1826-1832. 
San Miguel, J., K. Weisel, P. Moreau, et al. (2013). "Pomalidomide plus low-dose dexamethasone 
versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma 
(MM-003): a randomised, open-label, phase 3 trial." Lancet Oncol 14(11): 1055-1066. 
Schemper, M. and T. L. Smith (1996). "A note on quantifying follow-up in studies of failure time." 
Control Clin Trials 17(4): 343-346. 
SEER (2015). "Surveillance, Epidemiology, and End Results Program Cancer statistics Stat Fact 
Sheets: Myeloma." National Cancer Institute; 
http://www.seer.cancer.gov/statfacts/html/mulmy.html. 
Simon, R. (1989). "Optimal two-stage designs for phase II clinical trials." Control Clin Trials 
10(1): 1-10. 
Wickstrom, M., C. Haglund, H. Lindman, et al. (2008). "The novel alkylating prodrug J1: 
diagnosis directed activity profile ex vivo and combination analyses in vitro." Invest New Drugs 
26(3): 195-204. 
Wickstrom, M., J. I. Johnsen, F. Ponthan, et al. (2007). "The novel melphalan prodrug J1 inhibits 
neuroblastoma growth in vitro and in vivo." Mol Cancer Ther 6(9): 2409-2417. 
Wickstrom, M., K. Viktorsson, L. Lundholm, et al. (2010). "The alkylating prodrug J1 can be 
activated by aminopeptidase N, leading to a possible target directed release of melphalan." 
Biochem Pharmacol 79(9): 1281-1290. 
Wisloff, F., Eika, S., Hippe E., et al. (1996). “Measurement of health-related quality of life in 
multiple myeloma. Nordic Myeloma Study Group.” Br J Haematol. 1996;92:604–613 
Wisloff F, Hjorth M. (1996). “Health-related quality of life assessed before and during 
chemotherapy predicts for survival in multiple myeloma” Br J Haematol. 1997;97:29–37 


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14 
APPENDICES 
Appendix A.  ECOG Performance Scale 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically 
strenuous but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 
 (Oken et al. 1982) 


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Appendix B.  NCI CTCAE Version 4.03  
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute 
(NCI) v4.03 
Publish Date: (v4.03: June 14, 2010)  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 


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Appendix C.  IMWG Response Criteria 
Response 
IMWG criteria (Rajkumar et al. 2011) 
Stringent 
Complete 
Response 
(sCR) 
CR as defined below plus: 
•
normal FLC ratio and
•
absence of clonal cells in bone marrow by immunohistochemistry
or 2 – 4 color flow cytometry
Complete 
Response 
(CR) 
•
Negative immunofixation on the serum and urine and
•
disappearance of any soft tissue plasmacytomas and
•
< 5% plasma cells in bone marrow.
•
In patients with only FLC disease, a normal FLC ratio of 0.26–1.65
is required.
Very Good 
Partial 
Response 
(VGPR) 
•
Serum and urine M-protein detectable by immunofixation but not
on electrophoresis or
•
> 90% reduction in serum M-protein plus urine M-protein level
< 100 mg/24 h.
•
In patients with only FLC disease, >90% decrease in the difference
between involved and uninvolved FLC levels is required.
Partial 
Response 
(PR) 
•
50% reduction of serum M-protein and reduction in 24 hours
urinary M-protein by > 90% or to < 200 mg/24 h
•
If the serum and urine M-protein are unmeasurable,3 a > 50%
decrease in the difference between involved and uninvolved FLC
levels is required in place of the M-protein criteria
•
If serum and urine M-protein are not measurable, and serum free
light assay is also not measureable, > 50% reduction in plasma
cells is required in place of M-protein, provided baseline bone
marrow plasma cell percentage was > 30%
•
In addition to the above listed criteria, if present at baseline, a
> 50% reduction in the size of soft tissue plasmacytomas is also
required
Minimal 
Response  
•
≥ 25% but < 49% reduction of serum M protein and reduction in
24 hour urine M protein by 50 – 89%, which still exceeds 200
mg/24hrs.
•
In addition to above; if present at baseline, 25-49% reduction in the
size of soft tissue plasmacytomas is also required
•
No increase in size or number of lytic bone lesions (development
of compression fractures does not exclude response)


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Stable 
Disease 
(SD) 
•
Not meeting criteria for CR, VGPR, PR or progressive disease
Progressive 
disease 
(PD) 
Increase of > 25% from lowest response value in any one of the following: 
•
Serum M-component (the absolute increase must be > 0.5 g/dL)4
and/or
•
Urine M-component (the absolute increase must be > 200 mg/24 h)
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 (CR, sCR, VGPR, PR, MR and PD) require two consecutive assessments 
made at any time before the institution of any new therapy; complete response and PR and SD 
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 be 
confirmed.  For progressive disease, serum M-component increases of ≥ 1 g/dl are sufficient to 
define relapse if starting M-component is ≥ 5 g/dl. 
IMWG clarification for coding PD:  Clarified that Bone marrow criteria for PD are to be used only 
in patients without measurable disease by M protein and by FLC levels.  Clarified that 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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Appendix D.  Line of Therapy Definition 
According to the IMWG Consensus panel 1 on uniform reporting criteria in clinical trials
(Rajkumar et al. 2011). 
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 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 
Response Criteria. 
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 (eg, 3-6 cycles 
of initial therapy with bortezomib-dexamethasone [VD] followed by stem cell transplantation 
[SCT], consolidation, and lenalidomide maintenance is considered 1 line). 
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 be captured.


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Appendix E.  Definition of Relapsed Refractory Disease 
This study will use the 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). 
Appendix F.  Declaration of Helsinki 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-
research-involving-human-subjects/ 


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Appendix G. Renal Function Calculations 
Cockcroft-Gault formula  
   For males: 
Creatinine Clearance = (140-age[years] × weight [kg]) OR (140–age[years] × weight [kg]) 
72 × (serum creatinine[mg/dL]) 0.81 × (serum creatinine[µmol/L]) 
For females: 
Creatinine Clearance = 0.85 (140-age[years] × weight [kg]) OR 0.85 (140-age[years] × weight 
[kg]) 
72 × (serum creatinine[mg/dL]) 
0.81 × (serum creatinine[µmol/L]) 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41. 
Chronic Kidney Disease Epidemiology Collaboration equation 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for women below 
155cm in height and with normal BMI (18.5 – 24.9 kg/m2) 
The CKD-EPI equation, expressed as a single equation, is: 
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 2006) 
Appendix H.  QTc Fridericia Formula  
Assessment of QTC Interval using Fridericia Formula 
QT 
QTp = ifi[ii, 


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Appendix I.    ISS and R-ISS Score  
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 B 2-microglobulin ≥ 5.5 mg/L 
Chromosomal abnormalities by interphase by 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 
LDH 
Normal 
Serum LDH < upper limit of normal 
High 
Serum LDH > upper limit of normal 
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 
(Palumbo et al. 2015)   


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Appendix J.    QLQ-C30  
EORTC QLQ-C30 (venion 3) 
\ e a.re int~tecl in some tbin!l$ about you and your heallh. Please answer all of the questions yourself by 
circling the number lhat best applies to you. There are no "right" or "Wrong• answers. The infonnation thal you 
pro 'de will remain slrictly con.lidentiat 
Please fill in your initials: 
Your bi11falate (Da_y, Month, Year)'. 
Today' dale( 
, ~nth, Year): 
31 
I. 
4. 
Do you need to stay in 
5. 
Do you n.eed help with~ dre.s ing, r') 
}'Ourself or u ing the toilel7 
( 
, 
During the past week: 
6. 
7. 
Were you limited in pursuing your hobbies or o 
leisure time acti11ities? 
&. 
Were you hort ofbreadt'! 
9. 
Have }'OU bad pain? 
I 0. Did you need to rest'? 
11 . Ha\.-e }'OU had troubte sleeping? 
12. Have you felt weak"/ 
13. Ha\'e}'OU lackedappetiie? 
14. Have }'OU feJt nauseated'/ 
15. Ha\.-e you \/Omited'/ 
16. Ha\-e }'OU been constipated'/ 
.J 
Please 
on to the next page 
ot at 
II 
ot at 
All 
A 
Uttle 
2 
2 
2 
2 
2 
A 
Uttle 
2 
2 
2 
2 
2 
Quite 
a Bit 
3 
3 
3 
3 
3 
Quite 
a Bit 
3 
3 
3 
3 
3 
3 
e;ry 
Much 
4 
4 
4 
4 
4 
esry 
Much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 


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During the past week: 
17. Have you had dianhea? 
18. Were you tired? 
19. Did pain interfere with your daily activities? 
20. 
2 L r id yo 
eel tense? 
.,-
:: D•dy;zQ 
24. Did you feel depressed? A~) 
25. Have you had difficulty r~ngs? 
26. Hasyourphysical co~medical treatment ) 
interfered with your f 
? ? 
27. Has your physical condition or medic treatment 
interfered with your social activities? 
28. Has yourphyS1cal condition ormedi~
ment 
/ 
; 
) 
Not at 
A 
All 
Little 
Quite 
a Bit 
Viry 
Much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
causedyoufinanc1ald1fficulhes? 
/ 
/ .  
For the following questions please ~£ 
between 1 and 7 that 
best applies to you 
/
n"7 
29. 
4 
5 ~t? 
30. 
How would you rate your overall quality of life during the past week? 
./ / 
2 
3 
4 
5 
6 
7 
Very poor 
Very poor 
Excellent 
© Cop,ngl,11995 EORTC Qialityoflife Grrup. An ,igl,ts ,.,..,.,..,,. Version3 0 


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Appendix K. EQ-5D-3L 
Health Questionnaire 
English version for the UK 
(Validated for Ireland) 
UK (p,,jish) © 1900.E.uroQo/ 
EQ-fD"' is a trade Marlf ofthe EuroQol Group 


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By placing a tick in one box in each group below, please indicate which statements best 
describe your own health state today. 
Mobility 
I have no problems in walking about 
I have some problems in walking about 
I am confined to bed 
Self-Care 
I have no problems with self-care 
I have some problems washing or dressing myself 
I am unable to wash or dress myself 
Usual Activities (e g war/<., study, housework family or leisure activitieey 
I have no prob le ms with performing my usual activ iii es 
I have some problems with performing my u sua I actw itie s 
I am unable to perform my usual activities 
Pain/ Discomfort 
I have no pain or discomfort 
I have moderate pain or discomfort 
I have extreme pain or discomfort 
Anxiety/Depress ion 
I am not anxious or depressed 
I am moderately anxious or depressed 
I am extremely anxious or depressed 
2 
UK (&,glisll) © 1990EuroQ:,/ Group EQ-fD"' is a trade "1arl<ofthe EuroQ:,/ Group 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 


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To help people say how good or bad a h ea Ith state is, 
we have drawn a scale (rather like a thermometer) on 
which the best state you can imagine is marked 100 and 
the worst state you can imagine is marked 0. 
We would like you to indicate on this scale how good or 
bad your own he a Ith is today, in your opinion Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your he a Ith 
state is today. 
Your own health 
state today 
3 
UK ($1<;/ish) © 1900 E.uro Qol Group E.Q-W"' is a trade ., arl<0ftlle E.uro Qol Group 
Best imaginable 
health state 
100 
0 
Worst imaginable 
health state