Conditions: Renal Impairment Multiple Myeloma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: no

Brief summary:
This was a multicenter study of the pharmacokinetics (PK) of melphalan during treatment with melflufen and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) and impaired renal function.

Detailed description:
This was a multicenter study assessing the safety, tolerability, and efficacy of melflufen given on Day 1 of a 28-day cycle, together with weekly dexamethasone, in patients with relapsed multiple myeloma or RRMM and impaired renal function, as well as the relationship between renal function and PK parameters for the active metabolite melphalan.

Arms:
arm 1: Patients with moderate renal impairment (eGFR ≥30 to \<45 mL/min/1.73m²) and a starting dose of melflufen of 40 mg arm 2: Patients with moderate renal impairment (eGFR ≥30 to \<45 mL/min/1.73m²) and a starting dose of melflufen of 30 mg arm 3: Patients with severe renal impairment (eGFR ≥15 to \<30 mL/min/1.73m²) and a starting dose of melflufen of 20 mg

Interventions: intervention 1: Melflufen intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Melflufen was distributed in the European Union (EU) as a powder for concentrate for solution for infusion; in the US, it was distributed as a powder for injection. Melflufen was administered as a 30-minute intravenous infusion on Day 1 of every 28-day cycle via a central catheter. intervention 2: Tablets. Administered orally on Days 1, 8, 15, and 22 of each 28-day cycle. Dose of 40 mg for patients aged \<75 years. Dose of 20 mg for patients aged ≥75 years.

Protocol document:
Prot_000.pdf: 
Protocol OP-107  
Version 6.0, April 30, 2021 
 
Protocol Title: A Study of the Pharmacokinetics of Melphalan During Treatment 
with Melflufen and Dexamethasone in Patients with Relapsed Refractory Multiple 
Myeloma and Impaired Renal Function 
 
 
National Clinical Trial number: NCT03639610 


 
 
Confidential 
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Oncopeptides AB 
 
Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Clinical Development Protocol 
OP-107 
BRIDGE TRIAL 
A Study of the Pharmacokinetics of Melphalan During Treatment with 
Melflufen and Dexamethasone in Patients with Relapsed Refractory 
Multiple Myeloma and Impaired Renal Function 
Investigational Product 
 
Study Sponsor 
 
Melflufen  
 
Oncopeptides AB 
Västra Trädgårdsgatan 15 
SE-111 53 Stockholm, Sweden 
 
Protocol Number 
OP-107 
EudraCT number 
2018-000478-31 
Investigational New Drug Number 
 
Clinical Research Organization (CRO) 
116362 
PSI CRO AG,  
Baarerstrasse 113a, 6300  
Zug, Switzerland 
Development phase 
Phase 2 
Document status 
 
 
 
Version 1.0: March 2, 2018 
Amendment 1: Version 2.0: November 19, 2018 
Amendment 2: Version 3.0: September 26, 2019 
Amendment 3: Version 4.0: March 26, 2020 
Amendment 4: Version 5.0: January 22, 2021 
Amendment 5: Version 6.0: April 30, 2021 
 
CONFIDENTIAL 
This document contains confidential information belonging to Oncopeptides AB. Except as 
may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree 
to hold such information in confidence and not to disclose it to others (except where required 
by applicable law) nor use it for unauthorized purposes. In the event of actual or suspected 
breach of this obligation, Oncopeptides AB should be promptly notified. 


 
 
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Oncopeptides AB 
 
Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
 
 
Signature Page 
 
Protocol Number: OP-107 
 
Protocol Title: 
A Study of the Pharmacokinetics of Melphalan During Treatment with 
Melflufen and Dexamethasone in Patients with Relapsed Refractory 
Multiple Myeloma and Impaired Renal Function. 
 
 
Date of Original Protocol:   Version 1.0: March 2, 2018 
 
       Amendment 1:  Version 2.0: November 19, 2018 
 
       Amendment 2:  Version 3.0: September 26, 2019 
 
       Amendment 3:  Version 4.0: March 26, 2020 
 
       Amendment 4: Version 5.0: January 22, 2021 
 
 
Amendment 5: Version 6.0: April 30, 2021 
 
 
 
 
 
 
 
 
Approved By: 
 
 
________________________________ 
________________________________ 
 
 
Date 
Clinical Study Physician 
Oncopeptides AB 
Luntmakargatan 46 
111 37 Stockholm, Sweden 
  
 
 
________________________________ 
________________________________ 
 
 
 
Date 
Global Lead Investigator 
University Hospital Brno, Czech Republic 
 
 
________________________________ 
________________________________ 
 
 
 
 
Date 
 
Clinical Operations Director 
 
 


 
 
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Oncopeptides AB 
 
Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Protocol Acceptance Page 
 
 
Protocol Number:  OP-107 
 
Protocol Title:   
A Study of the Pharmacokinetics of Melphalan During Treatment with 
Melflufen and Dexamethasone in Patients with Relapsed Refractory 
Multiple Myeloma and Impaired Renal Function 
 
 
Protocol Date:  Version: 1.0: March 2, 2018 
Amendment 1: Version 2.0: November 19, 2018 
Amendment 2: Version 3.0: September 26, 2019 
Amendment 3: Version 4.0: March 26, 2020 
Amendment 4: Version 5.0: January 22, 2021 
Amendment 5: Version 6.0: April 30, 2021 
 
 
    
 
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 
 
 
Study Centre Name: 
 
Study Center Address: 
 
Study Center Phone number:  
 
This clinical study was designed and shall be implemented and reported in accordance with 
the International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice (GCP), with applicable local regulations (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 (Appendix F). 
 
The study protocol and any amendments are to be reviewed by an Independent Ethics 
Committee (IEC) 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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Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
TABLE OF CONTENTS 
 
List of Figures ............................................................................................................. 7 
List of Tables .............................................................................................................. 7 
Protocol Synopsis ....................................................................................................... 8 
List of Abbreviations ................................................................................................ 19 
1 
Background ............................................................................................................... 22 
1.1 
Overview of Multiple Myeloma ................................................................... 22 
1.2 
Renal Impairment in Multiple Myeloma ...................................................... 22 
1.3 
Overview of Melflufen ................................................................................. 23 
1.3.1 
Melflufen Description .................................................................. 23 
1.3.2 
Melflufen Scientific Rational ....................................................... 24 
1.4 
Clinical Experience ....................................................................................... 25 
1.4.1 
Clinical Experience in RRMM ..................................................... 25 
1.4.2 
Safety Summary ........................................................................... 26 
1.5 
Clinical Efficacy ........................................................................................... 26 
1.5.1 
Clinical Pharmacokinetics ............................................................ 27 
1.5.2 
Melflufen and Renal Function...................................................... 28 
2 
Rationale ................................................................................................................... 28 
2.1 
Study Rationale ............................................................................................. 28 
2.2 
Rationale for Patient Selection and PK Sampling Schedule......................... 29 
2.3 
Rationale for Dose Selection ........................................................................ 30 
2.4 
Rationale for Amendment 1 .......................................................................... 30 
2.5 
Rationale for Amendment 2 .......................................................................... 31 
2.6 
RAtionalE for amendment 3 ......................................................................... 31 
2.7 
Rational for amendment 4............................................................................. 31 
2.8 
RATIONAL FOR AMENDMENT 5 ........................................................... 31 
3 
Study Objectives ....................................................................................................... 32 
3.1 
Primary Objectives ....................................................................................... 32 
3.1.1 
Primary Objectives ....................................................................... 32 
3.2 
Secondary Objectives ................................................................................... 32 
3.3 
Exploratory Objective ................................................................................... 32 
4 
Study Design............................................................................................................. 32 
4.1 
Description of Study Design ......................................................................... 32 
5 
Patient Population ..................................................................................................... 33 
5.1 
Patient Screening .......................................................................................... 33 
5.1.1 
Screening Failures ........................................................................ 33 
5.2 
Patient Eligibility .......................................................................................... 33 
5.2.1 
Inclusion Criteria .......................................................................... 33 


 
 
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Protocol: Version 6.0: April 30, 2021 
5.2.2 
Exclusion Criteria ......................................................................... 35 
5.3 
Patient Enrollment ........................................................................................ 36 
5.3.1 
Enrollment Procedure ................................................................... 36 
5.3.2 
Patient Numbering........................................................................ 36 
5.3.3 
Replacement Policy ...................................................................... 37 
6 
Study Treatment ....................................................................................................... 37 
6.1 
Initiation of Therapy (Cycle 1 Day 1) .......................................................... 37 
6.2 
Study Drug Administration ........................................................................... 37 
6.2.1 
Melflufen Administration ............................................................. 37 
6.2.2 
Dexamethasone Administration ................................................... 38 
6.3 
Initiation of a New Cycle of Therapy ........................................................... 38 
6.4 
Dose Modifications ....................................................................................... 39 
6.4.1 
Dose Reduction Steps................................................................... 39 
6.4.2 
Dose Modification Guidelines Based on Toxicity ....................... 40 
6.4.3 
Dose Modifications for Dexamethasone ...................................... 42 
6.5 
Treatment Duration ....................................................................................... 43 
7 
Concomitant Therapy ............................................................................................... 43 
7.1 
Required Concomitant Therapy .................................................................... 43 
7.2 
Recommended Concomitant Therapy .......................................................... 44 
7.3 
Prohibited Concomitant Therapy .................................................................. 45 
8 
Visit Schedule and Assessments............................................................................... 45 
8.1 
Study Flow and Visit Schedule ..................................................................... 45 
8.2 
Study Assessments ........................................................................................ 50 
8.2.1 
Screening Disease Assessments ................................................... 50 
8.2.2 
Efficacy Assessments ................................................................... 50 
8.2.3 
Safety and Tolerability Assessments............................................ 52 
8.2.4 
Pharmacokinetic Assessments...................................................... 52 
8.2.5 
End of Treatment .......................................................................... 53 
8.2.6 
Follow Up Assessments ............................................................... 53 
8.2.7 
Criteria for Premature Patient Withdrawal................................... 54 
9 
Study Drug Supply and Handling ............................................................................. 54 
9.1 
Melflufen ...................................................................................................... 54 
9.1.1 
Melflufen Packaging and Labeling .............................................. 54 
9.1.2 
Melflufen Storage ......................................................................... 55 
9.1.3 
Melflufen Supply.......................................................................... 55 
9.1.4 
Melflufen Special Handling ......................................................... 55 
9.1.5 
Melflufen Drug Preparation ......................................................... 55 
9.2 
Dexamethasone ............................................................................................. 56 
9.2.1 
Dexamethasone Packaging and Labeling ..................................... 56 


 
 
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9.2.2 
Dexamethasone Storage ............................................................... 56 
9.2.3 
Dexamethasone Supply ................................................................ 56 
9.3 
Study Drug Compliance and Accountability ................................................ 56 
9.3.1 
Study Drug Compliance ............................................................... 56 
9.3.2 
Study Drug Accountability........................................................... 56 
10 Safety Monitoring and Reporting ............................................................................. 56 
10.1 
Adverse Events ............................................................................................. 56 
10.1.1 
Definitions .................................................................................... 56 
10.1.2 
Grading of Severity ...................................................................... 57 
10.1.3 
Causality ....................................................................................... 57 
10.1.4 
Adverse Event Reporting ............................................................. 58 
10.1.5 
Laboratory Test Abnormalities .................................................... 58 
10.2 
Serious Adverse Events ................................................................................ 59 
10.2.1 
Definitions .................................................................................... 59 
10.2.2 
Serious Adverse Event Reporting ................................................ 60 
10.3 
Pregnancy...................................................................................................... 61 
10.4 
Data Safety Monitoring Committee .............................................................. 62 
11 Data Collection and Management ............................................................................ 62 
11.1 
Data Confidentiality ...................................................................................... 62 
11.2 
Site Monitoring ............................................................................................. 62 
11.3 
Data Collection ............................................................................................. 63 
11.4 
Database Management and Quality Control ................................................. 63 
12 Statistical Methods and Data Analysis ..................................................................... 63 
12.1 
Study Endpoints ............................................................................................ 63 
12.1.1 
Primary Endpoints ........................................................................ 63 
12.1.2 
Secondary Endpoints .................................................................... 63 
12.2 
Exploratory Endpoint .................................................................................... 64 
12.3 
Sample Size................................................................................................... 64 
12.4 
General Considerations for the Statistical Analyses ..................................... 64 
12.4.1 
Analysis Populations .................................................................... 64 
12.5 
Analysis of Primary Endpoints ..................................................................... 65 
12.5.1 
Pharmacokinetic Analysis ............................................................ 65 
12.5.2 
Analysis of Safety Endpoints ....................................................... 66 
12.6 
Analysis of Secondary Endpoints ................................................................. 67 
12.7 
Analysis of Exploratory Objectives .............................................................. 68 
12.8 
Handling of Drop-outs and Missing Data ..................................................... 68 
12.9 
interim analysis ............................................................................................. 69 
13 Ethical Considerations and Administrative Procedures ........................................... 69 
13.1 
Regulatory and Ethical Compliance ............................................................. 69 


 
 
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13.2 
Responsibilities of the Investigator and IEC ................................................ 69 
13.3 
Informed Consent Procedures ....................................................................... 69 
13.4 
Discontinuation of the Study ........................................................................ 70 
13.5 
Publication of Study Protocol and Results ................................................... 70 
13.6 
Study Documentation, Record Keeping and Retention of Documents ........ 70 
13.7 
Confidentiality of Study Documents and Patient Records ........................... 71 
13.8 
Audits and Inspections .................................................................................. 71 
13.9 
Financial Disclosures .................................................................................... 71 
14 Protocol Adherence .................................................................................................. 71 
14.1 
Amendments to the Protocol......................................................................... 72 
15 References ................................................................................................................ 73 
16 Appendices ............................................................................................................... 77 
Appendix A.  Eastern Cooperative Oncology Group (ECOG) Performance Scale ........ 77 
Appendix B.  National Cancer Institute CTCAE Version 4.03 ....................................... 77 
Appendix C.  IMWG Uniform Response Criteria ........................................................... 78 
Appendix D.  Line of Therapy Definition ....................................................................... 80 
Appendix E.  Definition of Relapsed Disease ................................................................. 81 
Appendix F.  Declaration of Helsinki .............................................................................. 81 
Appendix G.  Estimated Glomerular Filtration Rate (eGFR) by  CKD-EPI equation .... 81 
Appendix H.  Assessment of QTC Interval ..................................................................... 82 
Appendix I.    ISS and R-ISS Score ................................................................................. 82 
List of Figures 
Figure 1-1:   Structure of Melflufen ........................................................................................ 23 
List of Tables 
Table 1-1    Summary of Melflufen Treatment-Related Grade 3 or 4 AE in ≥ 2 Patients
 ...................................................................................................... 25 
Table 6-1    Dose Reduction Steps for Melflufen ............................................................ 39 
Table 6-2    Dose Reduction Steps for Dexamethasone .................................................. 40 
Table 6-3    Dose Modification Guidelines for Hematologic Toxicity............................ 40 
Table 6-4    Dose Modifications for Toxicity Related to Dexamethasone ...................... 42 
Table 8-1    Schedule of Events ....................................................................................... 46 
Table 10-1  Adverse Event Severity ................................................................................ 57 
Table 12-1 Conventions for Censoring for PFS .............................................................. 68 
 
 
 


 
 
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Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Protocol Synopsis 
 
Compound Name 
Melflufen 
Protocol Name 
OP-107 
Chemical Name 
4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine 
ethyl ester hydrochloride   
International 
nonproprietary name 
(INN) 
Melphalan flufenamide 
Study Protocol Title 
A Study of the Pharmacokinetics of Melphalan During Treatment with 
Melflufen and Dexamethasone in Patients with Relapsed Refractory 
Multiple Myeloma and Impaired Renal Function. 
Study Sponsor 
Oncopeptides AB 
 
Global Lead 
Investigator 
 
Site(s)  
Approximately 16 sites in Europe 
 
Study Period  
FPI September 2018 
 
Background and 
Rationale 
Melphalan flufenamide (hereinafter referred to as 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 desethyl-melflufen, 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, Wickström 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. 
Melflufen has been evaluated in combination with low dose 
dexamethasone in a Phase 1/2a clinical trial (O-12-M1) in 
relapsed/refractory multiple myeloma (RRMM).  The trial established the 
recommended dose at 40 mg of melflufen every 28 days combined with 
40 mg dexamethasone weekly.  
As of November 9, 2017, clinical trial O-12-M1 in RRMM was evaluable 
for efficacy.  There were 34 efficacy evaluable patients treated with at 
least 2 doses of 40 mg melflufen in combination with weekly 
dexamethasone, 22 patients (65%) have reported a best response of 
minimal response (MR) or better and 14 patients (41%) have reported 
partial response (PR) or better.  These 34 patients had a median of 4 prior 


 
 
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Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Compound Name 
Melflufen 
Protocol Name 
OP-107 
lines of therapy, including immunomodulatory drugs (IMiD)s, 
proteasome inhibitors (PI)s and alkylators.   The median progression free 
survival (PFS) was 5.7 months at the time of data-cut based on 41 events 
in 45 patients with ≥ 1 cycle.  Median number of cycles completed was 
5.0 (Range 1 – 14) (Palumbo et al. 2016).  Taken together, clinical and 
preclinical data support that melflufen provides peptidase potentiated 
alkylating metabolites to tumor cells such as MM and thereby exerts a 
higher anti-tumor activity compared with equimolar administration of 
melphalan but with a similar safety profile.  
Renal impairment is a diagnostic feature of the end-organ damage of 
Multiple myeloma (MM) (Dimopoulos et al. 2016). Approximately 50% 
of MM patients will have some degree of renal impairment at diagnosis 
and/or during the course of disease (Knudsen et al. 2000).   Reduction of 
tumor cell mass with therapy and with the use of supportive care, 
improvement or reversal of renal dysfunction is possible (Dimopoulos et 
al. 2008). However, renal impairment may affect the toxicity profile, as 
well as the disease response to treatment and it is therefore essential to 
establish the impact of melflufen in the context of renal impairment.  
During treatment with melflufen, the great majority of alkylating activity 
is expected to occur from melflufen instantly reaching cells and tissues 
outside of the plasma compartment (including any tumor cells present) 
and from the metabolite melphalan that is formed intracellularly from 
melflufen. Once formed, melphalan is distributed back to plasma from the 
cells, but melphalan in plasma is likely to have only a minor contribution 
to intra-cellular alkylating activity as the initial local concentrations when 
formed from melflufen in cells are much higher than those coming from 
redistributed melphalan in the circulation. Melphalan is eliminated from 
plasma primarily by spontaneous plasma hydrolysis to monohydroxy-
melphalan and dihydroxy-melphalan, a process which is independent of 
renal function and hepatic metabolism. In addition, there is a minor 
contribution of direct renal elimination. Our expectation is that renal 
impairment will have no effect on melflufen pharmacokinetics (PK) and 
effects, and a minor effect on melphalan PK and effects. 
The OP-12-M1 trial as well as the ongoing Phase 3 OP-103 trial 
(melflufen and dexamethasone compared to pomalidomide and 
dexamethasone in RRMM) and OP-106 trial (melflufen and 
dexamethasone for RRMM patients’ refractory to pomalidomide and/or 
daratumumab) required patients to have a baseline creatinine clearance 
(CrCl) of ≥ 45 mL/min based on Cockcroft Gault formula (Cockcroft 
1976) combined with a serum creatinine of ≤ 2.0 mg/dL. In this OP-107 
trial, we include RRMM patients with an estimated glomerular filtration 
rate (eGFR)of ≥ 30 mL/min/1.73m2 to < 45 mL/min/1.73m2 (cohort 1) 
corresponding to a moderate decrease in GFR. The trial will evaluate the 
relationship between renal function and the PK parameters for the 
metabolite melphalan during treatment with melflufen, and the safety and 
efficacy of the treatment in this patient population.   
Amendment 1 will include a potential cohort 2 of at least 6 patients with 
severe renal impairment. This cohort is added after recommendation by 


 
 
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Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Compound Name 
Melflufen 
Protocol Name 
OP-107 
the FDA, since it would be beneficial to allow clinical use of melflufen 
also in patients with severe renal impairment and since there are no 
unacceptable safety concerns with use of melphalan in patients with renal 
impairment, even after high dose treatment with melphalan 200 mg/m2 
(Sweiss 2016).  Cohort 2 will only be initiated following DSMC review 
of the pharmacokinetic and safety profile of at least 6 patients in cohort 1. 
If the DSMC advises to proceed with Cohort 2, at least 6 patients with 
eGFR of ≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2  will be enrolled 
and analyzed for safety and pharmacokinetics data. 
Since scientific data show that the Cockcroft-Gault formula is unreliable 
for patients with low CrCl (Michels 2010), guidelines advise not to use 
this formula for patients with CrCl of 30 mL/min or lower (Levey 2009, 
Tattersall 2011, KDIGO 2013). The Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula which estimates GFR, 
has better reliability especially at low CrCl value (Levey 2009, Michels 
2010, KDIGO 2013, Levey 2017) and will therefore be used in the 
present study for all patients following approval of Amendment 1. 
The FDA also recommended to evaluate patients in later lines of therapy, 
limited to those who received 2-4 prior lines, as the treatment paradigm 
for multiple myeloma (MM) has shifted and there are approved therapies 
in the first 2 lines with known clinical benefit. Therefore, we will include 
only those patients with 2 – 4 prior lines of therapy. 
Amendment 2: Following PK evaluations from 9 patients enrolled in this 
study, 6 patients with eGFR ≥ 30 - < 45 mL/min/1.73m2, and 3 patients 
with eGFR > 45 mL/min/1.73m2 it was observed that Melphalan AUC 
increases with decreasing eGFR and this was linked to an increased 
myelotoxicity with lower nadir in platelets and neutrophils. DSMC 
recommended on 10 September 2019, further evaluation of melflufen 30 
mg for patients with eGFR ≥ 30 - < 45 mL/min/1.73m2 with a minimum 
of 6 additional patients in cohort 1 (Cohort 1b).  
Amendment 3: The current protocol requires all patients to have weekly 
CBC assessments. From cycle 3 onwards they can be done at a local 
laboratory close to the patient, and not necessarily at the clinic. Patients 
with good tolerability will no longer require all weekly CBC assessments. 
Specifically, if patient’s 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. 
For patients not visiting the site weekly they should still be contacted 
weekly by phone to follow up on AE/SAEs and dexamethasone 
compliance. 
Amendment 4, an amendment to update the CSP with the by DSMC 
confirmed starting dose for Cohort 2 of 20 mg, including dose reductions 
steps for this cohort, Table 6.1 updated.  
Cohort 2 will consist of two groups (a and b).  


 
 
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Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Compound Name 
Melflufen 
Protocol Name 
OP-107 
- 
Cohort 2a, evaluating patients with eGFR of ≥ 15 mL/min/1.73m2 
to < 30 mL/min/1.73m2 with a starting dose of 20 mg melflufen.  
- 
Cohort 2b, evaluating patients with eGFR of ≥ 15 
mL/min/1.73m2 to < 30 mL/min/1.73m2 with a starting dose of 30 
mg melflufen.  
Cohort 2b will only open if recommended by DSMC after evaluating data 
from Cohort 1a, 1b and 2a. 
This amendment also includes adding an interim analysis for an interim 
clinical study report (iCSR), to conclude the results from Cohort 1, 
patients with eGFR ≥ 30 - < 45 mL/min/1.73m2.  
As more cohorts are added the number of PK evaluable patients have 
increased from 25 to approximately 35. 
Amendment 5: Due to difficulties in recruiting eligible patients for 
Cohort 2a and b an updated feasibility assessment was performed 
alongside discussions with the investigators to identify potential 
eligibility hurdles in the current design of the protocol. The most frequent 
reasons for pre-screened patients not being eligible for screening was that 
they had received more than 4 prior lines of therapy (inclusion criteria no 
3) or had deteriorating kidney function (inclusion criteria no 10). The 
protocol is therefore updated to allow at least 2 prior lines of therapy with 
no upper limit and a wider eGFR window for patients to proceed from 
Screening 1 to Screening 2. 
SAE reporting details have been updated to reflect the change of safety 
CRO from PSI PVG Unit to TFS. SAE reporting email address updated to 
.  
Study Design 
This multicenter study will enroll patients with RRMM who have 
received at least 2 lines of prior therapy.  
There are four Cohorts in the study 1a, 1b and 2a and 2b. 
• 
Cohort 1a (eGFR of ≥ 30 mL/min/1.73m2 to < 45 
mL/min/1.73m2): 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. 
Following approval of Amendment 2, Cohort 1a will close for enrollment 
and Cohort 1b will open for a minimum of 6 additional patients. 
• 
Cohort 1b (eGFR of ≥ 30 mL/min/1.73m2 to < 45 
mL/min/1.73m2): Patients will be treated with melflufen 30 mg 
on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of 
each 28-day cycle. 
After evaluating data from Cohort 1a and 1b the recommendation from 
DSMC was to open Cohort 2a for enrollment of a minimum of 6 
additional patients.  
• 
Cohort 2a (eGFR of ≥ 15 mL/min/1.73m2 to < 30 
mL/min/1.73m2): Patients will be treated with melflufen 20 mg 


 
 
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Protocol No. OP-107 
 
Protocol: Version 6.0: April 30, 2021 
Compound Name 
Melflufen 
Protocol Name 
OP-107 
(recommended dose by DSMC) on Day 1 and dexamethasone 40 
mg on Days 1, 8, 15 and 22 of each 28-day cycle. 
Cohort 2b will only open if recommended by DSMC after evaluating data 
from Cohort 1a, 1b and 2a. 
• 
Cohort 2b (eGFR of ≥ 15 mL/min/1.73m2 to < 30 
mL/min/1.73m2): Patients will be treated with melflufen 30 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 reduced dose of dexamethasone of 
20 mg on Days 1, 8, 15 and 22. 
Patients may receive treatment until there is documented disease 
progression, unacceptable toxicity or the patient/treating physician 
determines 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.  In the event of a cycle 
delay, unrelated to dexamethasone toxicity, it is recommended to continue 
dexamethasone weekly.  
A Schedule of Events for the study is outlined in Section 8, Table 8-1 of 
the protocol. 
Objectives   
Primary Objectives  
• To evaluate the relationship between renal function and the PK 
parameters for melphalan during treatment with melflufen  
• To assess the safety and tolerability of melflufen in patients with 
moderate (cohort 1a and 1b) and severe (cohort 2a and 2b) renal 
impairment 
Secondary Objectives 
• To assess the best tumor response as well as overall response rate 
(ORR) 
• To assess the PFS 
• To assess duration of response (DOR) in patients with ≥ PR 
(stringent complete response (sCR), complete response (CR), very 
good partial response (VGPR), PR) as best response  
• To assess clinical benefit rate (CBR) and duration of clinical benefit 
(i.e., proportion of patients with ≥ MR) as best response  
• To assess time to response (TTR) in patients with a PR or better and 
time to CB for patients with MR or better. 
• Overall survival (OS) 
 
All tumor response and progression-depended objectives are assessed by 
investigators according to the International Myeloma Working Group 
Uniform Response Criteria (IMWG-URC) (Rajkumar et al. 2011, 
Appendix C) unless otherwise specified. 
Exploratory Objective 
• 
To assess changes in renal function 


 
 
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Protocol No. OP-107 
 
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Compound Name 
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Protocol Name 
OP-107 
Endpoints 
Primary Endpoints 
• PK parameters of melphalan  
• Frequency and grade of Adverse Events (AE)  
Secondary Endpoints 
• ORR  
• CBR  
• PFS 
• DOR and duration of clinical benefit 
• TTR 
• Best response during the study (sCR, CR, VGPR, PR, MR, stable 
disease [SD] or progressive disease [PD])  
• Overall survival (OS) 
Exploratory Endpoint 
• The changes in eGFR over time. 
 
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 at the time of signing the 
informed consent 
2. A prior diagnosis of MM with documented disease progression 
requiring further treatment at time of screening 
3. Received at least 2 prior lines of therapy. (Appendix D) 
4. Measurable disease defined as any of the following: 
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein 
electrophoresis (SPEP).   
•  ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-
hour urine electrophoresis (UPEP) 
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal 
serum kappa to lambda free light chain ratio  
5. Life expectancy of ≥ 6 months  
6. Eastern Cooperative Oncology Group (ECOG) performance 
status ≤ 2. (Patients with lower performance status based solely on 
bone pain secondary to MM may be eligible following consultation 
and approval of the medical monitor) (Appendix A) 
7. Patient is a female of childbearing potential (FCBP)* with a 
negative serum or urine pregnancy test prior to initiation of therapy 
and agrees to practice appropriate methods of birth control, or the 
patient is male and agrees to practice appropriate methods of birth 
control (Section 7.1) 
8. Ability to understand the purpose and risks of the study and provide 
signed and dated informed consent. 
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by 
Fridericia Formula (QTcF) interval of ≤ 470 msec (Appendix H). 
10. Renal function: Estimated GFR by CKD-EPI formula (Appendix 
G) on 2 consecutive screening evaluations. Patients meeting criteria 
for Screening 1, must also meet criteria for Screening 2 following 


 
 
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Compound Name 
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Protocol Name 
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optimal hydration (as determined by the investigator). Screening 2 
must be on or as close as possible to treatment start date (preferably 
< 24-48 hours) but cannot exceed 72 hours. 
 
Cohort 1 (a and b): 
Screening 1:  eGFR between ≥25mL/min/1.73 m2 to <45 
mL/min/1.73m2   
Screening 2:  eGFR between ≥30 mL/min/1.73m2 to <45 
mL/min/1.73m2.   
 
Cohort 2 (a and b):  
Screening 1: eGFR between ≥ 10 mL/min/1.73m2 to < 35 
mL/min/1.73m2.   
Screening 2: eGFR between ≥15 mL/min/1.73m2 to < 30 
mL/min/1.73m2.  
  
Enrollment into Cohort 2b will only be initiated following approval 
from the DSMC.  
Patients with fluctuating values of eGFR may be eligible following 
consideration of additional assessments in consultation with the 
medical monitor.  
 
11. The following laboratory results must be met during screening and 
immediately before 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 [14 
days for pegfilgrastim] prior to initiation of study therapy) 
• Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without 
transfusions during the 10 days prior to initiation of study 
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 in 
patients diagnosed with Gilberts syndrome that have been 
reviewed and approved by the medical monitor.  
• Aspartate transaminase/serum glutamic oxaloacetic transaminase 
(AST/SGOT) and alanine transaminase/serum glutamic pyruvic 
transaminase (ALT/SGPT) ≤ 3.0 x ULN. 
12. Must have, or be willing to have, an acceptable central catheter. 
(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: 


 
 
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1. Primary refractory disease (i.e. never responded with ≥ MR to any 
prior therapy)  
2. Evidence of mucosal or internal bleeding and/or platelet transfusion 
refractory (platelet count fails to increase by > 10,000 cells/mm3 
[10.0 x 109/L] after a transfusion of an appropriate dose of platelets)  
3. Any medical conditions that, in the Investigator’s opinion, would 
impose excessive risk to the patient or would adversely affect 
his/her participating in this study.  Examples of such conditions are: 
a significant history of cardiovascular disease (e.g., myocardial 
infarction, significant conduction system abnormalities, 
uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the 
last 6 months),  
4. Known active infection requiring parenteral or oral anti-infective 
treatment within 14 days of initiation of 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 or very low and low risk prostate cancer in active 
surveillance.  
6. Pregnant or breast-feeding females 
7. Serious psychiatric illness, active alcoholism, or drug addiction that 
may hinder or confuse compliance or follow-up evaluation 
8. Known human immunodeficiency virus 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 and skin 
changes) 
11. Previous cytotoxic therapies, including cytotoxic investigational 
agents, for MM within 3 weeks (6 weeks for nitrosoureas) prior to 
initiation of therapy. The use of live vaccines within 30 days before 
initiation of therapy. IMiDs, PIs and corticosteroids within 14 days 
prior to initiation of study therapy. Other investigational therapies 
and monoclonal antibodies within 4 weeks of initiation of study 
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 study therapy. Plasmapheresis is not permitted within 
14 days of initiation of therapy. 
12. Residual side effects to previous therapy > Grade 1 prior to 
enrollment (Alopecia any grade and/or neuropathy Grade 2 without 
pain are permitted)  
13. Prior peripheral stem cell transplant within 12 weeks of initiation of 
study therapy 
14. Prior allogeneic stem cell transplantation with active graft-versus-
host-disease. 
15. Prior major surgical procedure or radiation therapy within 4 weeks 
of the initiation of study therapy (this does not include limited 
course of radiation used for management of bone pain to be 
completed within 7 days of initiation of study therapy). 


 
 
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16. Known intolerance to steroid therapy 
17. Prior renal transplant 
18. Currently in need of renal dialysis 
Study Treatment(s) 
Treatment will be given in an outpatient treatment setting in cycles.  Each 
cycle is 28 days.  
Melflufen 10-40 mg will be administered as a 30-minutes intravenous 
infusion on Day 1 of every 28-day cycle via acceptable central catheter. 
Dexamethasone 40 mg administered orally on Days 1, 8, 15 and 22 of 
each 28-day cycle for patient < 75 years of age.  
OR 
Dexamethasone 20 mg administered orally on Days 1, 8, 15 and 22 of 
each 28-day cycle for patient ≥ 75 years of age. 
In the event of cycle delays, it is recommended that dexamethasone 
continue weekly.  
Dose modifications and delays may be implemented based on patient 
tolerance as detailed in the protocol.  
Duration of 
treatment 
Patients will receive treatment until there is documented disease 
progression according to IMWG criteria (Rajkumar et al.2011, Appendix 
C) (to be confirmed on two consecutive assessments of the applicable 
disease parameters), unacceptable toxicity or the patient/treating 
physician determines it is not in the patient’s best interest to continue.  
Duration of  
follow-up 
Patients who discontinue treatment for reasons other than disease 
progression will continue to be followed for disease response monthly 
until progression (PD to be confirmed on two consecutive assessments) or 
initiation of subsequent therapy.  Patients with Grade 3 or 4 neutropenia 
or thrombocytopenia at the end of treatment (EoT) visit will continue to 
be followed until resolution (≤ Grade 2) or initiation of subsequent 
therapy.  OS will be followed in all patients until the last patient 
completes progression free survival follow-up (PFS-FU), after which 
time, an OS assessment at a future date may be done if requested by the 
sponsor.  
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 the protocol 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 2018) or institutional 
guidelines. 
Number of Patients 
Approximately 35 PK evaluable patients given at least one dose of 
melflufen with acceptable PK sampling, at least 6 PK evaluable patients 
per Cohort.  
Assessments 
Screening Disease Assessments 
• M-protein determination using the following procedures: 
- SPEP and serum protein immunofixation (IFE) with quantitative 
immunoglobulins (Ig); and  


 
 
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Protocol Name 
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- Urine protein electrophoresis (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 (by physical examination 
or imaging technique) 
• Skeletal survey and/or low dose computerized tomography (CT) scan 
• Beta2 microglobulin 
• Cytogenetics/ Fluorescence In Situ Hybridization (FISH) 
• Lactate dehydrogenase (LDH)  
• International staging system (ISS) Staging Score and Revised ISS 
(R-ISS) (Appendix I) 
Pharmacokinetic sampling 
Three plasma samples for determination of melphalan concentrations will 
be drawn in connection to the first two melflufen treatment cycles (Cycle 
1 and 2); 5-10 minutes after the end of infusion, 2 - 3 hours after the end 
of infusion and 5-7 hours after the end of infusion.  
For enrolled patients with moderate renal impairment one repeat set of 
three PK samples, will be collected in one cycle if during the treatment 
period of the study, the patient’s eGFR falls below 30 mL/min/1.73m2.  
For enrolled patients with severe renal impairment one repeat set of three 
PK samples, will be collected in one cycle if during the treatment period 
of the study, the patient’s eGFR falls below 15 mL/min/1.73m2 and the 
patients is approved for dosing by MM.  
All PK samples must be drawn peripherally and not from the central 
catheter.  Refer to the Laboratory Manual for details on specimen 
collection and processing.  
Safety Assessments: 
• Assessment and grading of AEs 
• Physical examinations with vital signs, neurologic assessment and 
assessment of performance status 
• Routine safety laboratory tests, (complete blood count [CBC] with 
differential and platelets and clinical chemistry) with calculation of 
eGFR by CKD-EPI equation (Appendix G) 
• Pregnancy testing 
• ECGs 
• Chest X-ray 
AEs, including clinical laboratory and vital sign abnormalities, will be 
graded using the National Cancer Institute (NCI)’s Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03  
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 or IgD myeloma); and  


 
 
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Protocol Name 
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- UPEP and urine protein IFE (all using the same 24-hour urine 
collection); and 
- SFLC and SFLC ratio 
• Bone marrow to quantify percent myeloma cell involvement  
• Extramedullary plasmacytoma evaluation (by PE or imaging 
technique) 
• Skeletal X-rays and/or low dose CT scan (same technique used at 
screening and each evaluation) 
Serum calcium (corrected calcium) 
Analysis Sets & 
Statistical methods 
Definition of Analysis Sets: 
PK Analysis Set 
All patients that have received at least one melflufen dose and have 
sufficient PK samples taken after Cycle 1 or 2 infusion.  
Efficacy Analysis 
All patients that complete 2 doses of melflufen and have relevant baseline 
and follow-up disease assessments after the second dose of melflufen.  
Safety Analysis Set 
All patients that receive at least one or partial dose of melflufen or 
dexamethasone.   
Statistical Methods: 
Primary Endpoints: 
PK Analysis 
Melphalan concentration data will be pooled across patients and all 
melflufen studies providing data and evaluated using a population 
approach with nonlinear mixed-effect modeling. Actual time points for 
drug administration and plasma sampling will be used.  
Details on the modeling approach will be described in a separate 
population PK-PD plan which will be developed in parallel with the 
ongoing Phase 3 study OP-103 (OCEAN TRIAL).   
The relationship between melphalan PK parameters and patient factors 
will be assessed, as well as the inter-occasion variability in melphalan 
exposure. 
Safety Analysis 
The number (%) of patients experiencing treatment emergent adverse 
events (TEAEs) will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred 
term (PT).  The denominator for the percentage will be based on the 
number of patients at in the Safety analysis set.  No formal statistical 
analysis will be performed for the safety endpoints. 
 
 


 
 
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Compound Name 
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Protocol Name 
OP-107 
Secondary Endpoints: 
The ORR will be estimated as the proportion of patients with ≥ PR (sCR, 
CR, VGPR and PR) as best response. Clinical benefit response will also 
be assessed in patients who achieve ≥ MR.  
PFS, DOR, duration of clinical benefit, TTR and OS will be analyzed 
using the method by Kaplan-Maier. 
Interim analysis 
An interim analysis for an interim clinical study report (iCSR) is planned 
when patients enrolled in Cohort 1a and 1b have been followed until 
progression or up to at least 6 months after first dose. The objective of 
this interim analysis is to evaluate PK, safety and efficacy in Cohort 1, 
moderately impaired patients, to support regulatory submissions. 
ICH and Ethics 
This clinical study was designed and shall be implemented and reported 
in accordance with the International Conference Harmonization (ICH) 
Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), 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 local ethics committees or Institutional 
Review Boards (IRBs) and patients will sign Informed Consent Forms 
(ICFs) before enrolling to the trial.   
 
List of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine transaminase/Alanine aminotransferase/glutamic pyruvic 
transaminase (SGPT) 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem-cell transplantation 
AST 
Aspartate transaminase/Aspartate aminotransferase/glutamic 
oxaloacetic transaminase (SGOT) 
AUC 
Area under the curve 
BMA 
Bone marrow aspiration 
CB 
Clinical benefit 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
eCRF 
electronic Case Report Form 
CRO 
Clinical Research Organization 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CT 
Computerized tomography 
CTCAE 
Common terminology criteria for adverse events 
DNA 
Deoxyribonucleic acid 


 
 
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DOR 
Duration of response 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EoT 
End of Treatment 
FCBP 
Female of childbearing potential 
FISH 
Fluorescence In Situ Hybridization 
FLC 
Free light chain 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
iCSR 
Interim Clinical Study Report 
IEC 
Independent Ethics Committee 
IFE 
Immunofixation  
Ig 
Immunoglobulin 
IMiD 
Immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISS 
International Staging System 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Myeloma 
MR 
Minimal response 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
OS-FU 
Overall survival follow-up 
PD 
Progressive disease 
PFS 
Progression free survival 
PFS-FU 
Progression free survival follow-up 
PI 
Proteasome Inhibitor 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetics 
POEMS 
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein 
PR 
Partial response 
PT 
Preferred term 
q.d. 
Quaque die/ one a day 


 
 
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RBC 
Red blood cell 
R-ISS 
Revised international staging system 
RRMM 
Relapsed Refractory Multiple Myeloma 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent complete response 
S-Cr 
Serum Creatinine 
SD 
Stable disease 
SFLC 
Serum free light chain 
SOC 
System organ class 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
VGPR 
Very good partial response 
WHO 
World Health Organization 
 
 
 


 
 
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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 30,330 patients with 
myeloma were diagnosed in the United States in 2015 (SEER 2016).  
The disease is characterized by clonal proliferation of plasma cells in the bone marrow and 
the production of excessive amounts of a monoclonal Ig (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 inhibitors (panobinostat), conventional chemotherapy 
(melphalan, cyclophosphamide, doxorubicin), including high dose melphalan with 
autologous stem-cell transplantation (ASCT) and the most recent addition of monoclonal 
antibodies (elotuzumab and daratumumab). The selection of treatment in relapsed/refractory 
multiple myeloma (RRMM) is challenging.  The National Comprehensive Cancer Network 
(NCCN) guidelines (NCCN 2018) and a recent overview published in the Mayo Clinic 
Proceedings (Kumar et al. 2016) detail an array of single agent, doublet and triplet 
combination regimens that can be considered.  Patients for whom stem cells were 
cryopreserved early in the disease course, and who are transplant candidates, may benefit 
from ASCT as salvage therapy (Cavo et al. 2011).  In general, MM patients will receive an 
average of 4 to 8 different treatment regimens during their lifespan.   
1.2 
RENAL IMPAIRMENT IN MULTIPLE MYELOMA 
Renal impairment is a diagnostic feature of the end-organ damage of MM (Dimopoulos et al. 
2016) and one of the most common complications of MM. Approximately 50% of MM 
patients will have some degree of renal impairment at diagnosis and/or during the course of 
disease (Knudsen et al. 2000). The incidence of renal impairment is deﬁned either as serum 
creatinine (S-Cr) above the upper normal limit or > 2 mg/dL or as estimated glomerular 
ﬁltration rate (eGFR) <60 mL/min/1.73 m2 (Riccardi et al. 1991; Abbott et al. 2001; Tsakiris 
et al. 2010) 
Renal impairment in patients with MM is caused mainly by the toxic effects of the 
monoclonal light chains on basement membranes of the glomeruli and/or the renal tubule 
(Dimopoulos et al. 2008). The most common form of renal injury in patients with MM is cast 
nephropathy which often leads to acute kidney injury (Dimopoulos et al. 2008; Hutchison et 
al. 2012; Kastritis et al. 2013).  Cast nephropathy develops when light chain production 
overcomes the capacity of tubular cells to endocytose and to catabolize the ﬁltered free light 
chains. As a result, excess light chains form aggregates and casts with uromodulin in the 


 
 
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distal nephron, leading to tubular obstruction and concomitant inﬂammation (Kastritis et al. 
2013; Huang et al. 1995; Sengul et al. 2002). Hypercalcemia, dehydration, nephrotoxic drugs 
(aminoglycoside antibiotics and/ or nonsteroidal anti-inﬂammatory agents), infection and 
contrast agents contribute to the development of or exacerbate existing renal impairment by 
aggravating the toxic effect of light chains (Dimopoulos M. et al. 2008; Hutchison C. et al. 
2012;  From et al. 2008) In a study evaluating renal impairment in patients with MM, renal 
biopsy indicated in 15% of patients that the renal impairment had no  association with the 
monoclonal gammopathy. Alternate reasons included arterionephrosclerosis (6%), diabetic 
glomerulosclerosis (5%), post infectious glomerulonephritis (2%), or even smoking related 
glomerulopathy (0.5%) (Nasr et al, 2012). The presence of monoclonal immunoglobulin 
deposition disease (MIDD) or amyloidosis may also contribute to renal impairment. All 
patients with symptomatic myeloma should have in their diagnostic work-up serum 
creatinine, electrolytes measurements, and eGFR and also serum free light chain (SFLC) 
measurement and electrophoresis of a sample from a 24-hour urine collection. A 24-hour 
urine protein electrophoresis (UPEP) may reveal patterns of protein excretion that may 
provide clues to the etiology of renal impairment. Predominantly selective proteinuria, 
consisting of light chains, with limited albumin excretion is most likely a result of cast 
nephropathy, whereas larger amounts of albumin or nonselective patterns of proteinuria 
suggest an alternative pathology. (Leung et al. 2012; Dimopoulos et al. 2016). 
Rapid intervention to reverse renal dysfunction is critical for the management of patients 
with renal impairment especially for those with light chain cast nephropathy. Reversal of 
renal dysfunction is possible (Dimopoulos et al, 2008) with reduction of tumor cell mass with 
therapy and with the use of supportive care.   
1.3 
OVERVIEW OF MELFLUFEN 
1.3.1 
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-
1.  The molecular weight 498.4 as free base and 534.9 as the HCl salt.   
 
 
 
 
 
 
 
 
Figure 1-1:   Structure of Melflufen 


 
 
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1.3.2 
Melflufen Scientific Rational 
Melphalan flufenamide (hereinafter referred to as 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 desethylmelflufen, 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; Wickström 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, 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 Area Under the Curve (AUC) after melflufen 
administration is similar to historical data on exposure after melphalan administration (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 (Wickström et al. 2008), which 
is explained by the 50-fold higher intracellular exposure as AUC of alkylating agents 
compared to that observed after an equimolar dose of melphalan (Chauhan et al. 2013).  
Mechanistically-oriented studies have shown that melflufen-induced apoptosis is associated 
with (i) activation of caspases and poly Adenosine diphosphate ribose polymerase cleavage; 
(ii) reactive oxygen species generation; (iii) mitochondrial dysfunction and release of 
cytochrome c; and (iv) induction of DNA damage (Chauhan et al. 2013; Ray et al. 2016).  
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 parental, 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; Wickström et al. 2007; Chauhan et al. 
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1.4 
CLINICAL EXPERIENCE 
1.4.1 
Clinical Experience in RRMM 
Melflufen was 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 Phase 1 design 
with 3 to 6 patients per dose cohort, depending on dose limiting toxicity 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 maximum tolerated dose (MTD) was established as 40 mg of melflufen 
in combination with 40 mg dexamethasone weekly.  Following identification of the MTD, 
the Phase 2a part of the trial was initiated and all subsequently treated patients received a 
starting dose of 40 mg of melflufen (Palumbo et al, 2016).   
1.4.1.1 
Clinical Safety 
As of November 9, 2017, 58 patients had received 284 doses of melflufen 40 mg in trial 
O-12-M1.  The median number of completed cycles was 5.0 (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 the disease of 
MM and of treatment with alkylators.  These events were assessed to be dose-related, 
reversible, monitorable and mechanism-driven. 
Treatment related Grade 3 or 4 adverse events (AEs) were reported in 37 out of 45 patients 
(82%) treated with 40 mg melflufen in combination with 40 mg weekly dexamethasone.  
Those related to melflufen and occurring in ≥ 2 patients are presented in Table 1-1. 
Table 1-1    Summary of Melflufen Treatment-Related Grade 3 or 4 AE in ≥ 2 Patients  
System Organ Class  
(Preferred Term) 
Patients with Grade 3 or 4 AEs  
n (%) 
Patients with Grade 4 AEs 
n (%) 
Any treatment-related event 
37 (82) 
19 (42) 
Blood and lymphatic system disorders 
Thrombocytopenia 
Neutropenia 
Anemia 
Lymphopenia 
Febrile neutropenia 
36 (80) 
26 (58) 
26 (58) 
19 (42) 
3 (7) 
2 (4) 
19 (42) 
17 (38) 
11 (24) 
0 (0) 
1 (2) 
0 (0) 
General disorders and administration 
site conditions 
Asthenia 
Fatigue 
Pyrexia 
7 (16) 
2 (4) 
2 (4) 
2 (4) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 


 
 
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Investigations 
White blood cell count decreased 
5 (11) 
2 (4) 
0 (0)0 (0) 
Infections and infestations 
Pneumonia 
2 (4) 
2 (4) 
0 (0) 
0 (0) 
Continuous review of safety data in the Phase 2a part of the study led 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. 
Even though neutropenia and thrombocytopenia have been common in connection to 
melflufen treatment, few cases have been reported as serious adverse events (SAEs) such as 
febrile neutropenia or bleeding.  Please see the current investigator’s brochure (IB) for 
details. 
1.4.1.2 
Evaluation of QTcF Intervals from Holter Recordings 
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 in Study O-12 M1 for general screening purposes. No patient in the study has 
developed absolute QTcF values that are associated with a meaningful increased risk of 
arrhythmias.  Please see the current IB for details. 
1.4.2 
Safety Summary 
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 pyrexia and asthenia. The incidence of Grade 3 and 4 neutropenia 
and thrombocytopenia after 40 mg doses of melflufen are comparable to the incidence 
observed in studies with low dose melphalan regimens in combination with steroids 
(Richardson et al. 2010). Even though neutropenia and thrombocytopenia have been common 
in connection to melflufen treatment, few cases have been reported as SAEs, as febrile 
neutropenias, or thrombocytopenia associated bleedings.   
Since both the disease of MM as well as treatment with alkylators may cause neutropenia and 
neutropenia may be connected with pneumonia, sepsis or other infections, it is important to 
follow institutional or NCCN guidelines (NCCN 2018) Prevention and treatment of cancer-
related infection for antimicrobial prophylaxis for MM patients. 
Please see the IB for additional information. 
1.5 
CLINICAL EFFICACY 
As of Nov 9, 2017, 34 patients were evaluable for efficacy (patients receiving at least two 
doses of 40 mg melflufen with appropriate follow-up).  Of these 34 patients, 5 achieved very 
good partial response (VGPR), 9 achieved PR and 8 achieved minimal response (MR).  
Eleven patients maintained stable disease (SD) and one had progressive disease (PD) 
(Richardson 2017).  
A total of 45 patients had received at least one dose of melflufen. Median time since initial 
diagnosis was 5.0 years (1-21).  Median number of prior therapies was 4.0 (2-14).  All 
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had been exposed to alkylators.  Of these 45 patients, 39 patients (87%) patients were IMiD-
refractory, 32 (71%) were PI-refractory and 24 (53%) were alkylator refractory.  Thirty out 
of the 45 patients (67%) were double-refractory (IMiDs and PIs) and 18 (40%) were double- 
and alkylator-refractory.  Thirty-nine (87%) were refractory to last line of treatment. 
The median progression free survival (PFS) in the trial has been evaluated both for the 
protocol defined efficacy evaluable patients, (i.e. treated with ≥ 2 doses of melflufen [n=34]) 
and all patients (those evaluable after ≥ 1 dose) of melflufen [N=45]) with baseline and 
appropriate follow-up assessments.  The median PFS for the efficacy evaluable population 
was at the time of data cut-off 8.3 months (95% confidence interval [CI] 4.5 to 9.8 months) 
based on 30 events in 34 patients with available data.  Four 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 5.7 months (95% CI 3.7 to 9.3 months) based on 41 events in 
45 patients with available data.  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. 
1.5.1 
Clinical Pharmacokinetics 
In humans, melflufen is metabolized to desethyl-melflufen, melphalan and the non-alkylating 
para-fluoro-phenylalanin ethyl ester, and this metabolism appears to occur primarily outside 
of the plasma compartment.  PK data for melflufen and melphalan are available from the 
completed clinical trial O-05-001 in patients with solid tumors and from ten MM patients in 
the ongoing clinical trial O-12-M1.   
In clinical trial O-12-M1 in MM patients, PK data from ten patients covering the dose range 
15 mg to 55 mg were available as of 6 February 2017.  In all patients, melflufen plasma 
concentration reached a peak before end of infusion and was eliminated with a half-life of 
1 to 5 minutes as measured from end of infusion.  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 was 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 intravenous infusion. 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, and 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).  Following administration of melflufen, melphalan 
is found in plasma with a peak concentration at 5 to 10 minutes after the end of melflufen 
infusion (PK data from clinical trial O-12-M1).  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 (including any tumor cells present) outside of the plasma compartment. 
Melphalan is predominately formed in these tissues and thereafter distributed back to plasma 
and eliminated primarily by spontaneous hydrolysis to non-alkylating metabolites and with a 
small contribution of direct renal elimination. There is no appreciable active metabolism of 
melphalan mediated by drug metabolic enzymes.  Please see the current IB for details. 


 
 
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1.5.2 
Melflufen and Renal Function 
During treatment with melflufen, the great majority of alkylating activity is expected to occur 
from melflufen instantly reaching cells and tissues outside of the plasma compartment 
(including any tumor cells present) and from the metabolite melphalan that is formed 
intracellularly from melflufen and subsequently is distributed back to plasma. The 
contribution to alkylating activity from melphalan that is again distributed back to cells from 
the bloodstream is therefore likely to be small. Once formed, melphalan is distributed back to 
plasma from the cells, but melphalan in plasma is likely to have only a minor contribution to 
intra-cellular alkylating activity as the initial local concentrations when formed from 
melflufen in cells are much higher than those coming from redistributed melphalan in the 
circulation. Melphalan is eliminated from plasma primarily by spontaneous plasma 
hydrolysis to monohydroxy-melphalan and dihydroxy-melphalan, a process which is 
independent of renal function and hepatic metabolism. In addition, there is a minor 
contribution of direct renal elimination.  
Melflufen is cleared very rapidly from the plasma compartment and completely metabolized 
to melphalan in tissues. Renal function is therefore assessed not to contribute to melflufen 
total clearance. The relationship between glomerular filtration rate (GFR) and melphalan PK 
after administration of melphalan has been evaluated in two studies including 11 and 15 
patients, respectively (Adair et al. 1986; Osterborg et al. 1989), and in a population PK study 
with 100 patients (Nath et al. 2010). The results were consistent across studies and 
demonstrated a slightly less than two-fold increase in melphalan total exposure (AUC) for a 
defined melphalan dose when comparing a GFR of 120 mL/min (normal function) with a 
GFR of 30 mL/min (threshold to severe renal impairment).  To date there have been no 
reports of renal toxicity related to melflufen in completed or ongoing clinical trials evaluating 
melflufen.  
In an investigation in 272 patients with newly diagnosed MM, cycles of melphalan 0.25 
mg/kg once daily orally for four days with no adjustment for renal function were given as 
palliative treatment (Carlson et al. 2005). Patients were categorized according to estimated 
creatinine clearance (CrCl) of >50, 30 to 50, and <30 mL/min and hematological toxicity 
World health organization (WHO) Grades 3-4 after the first course was seen in 18%, 28% 
and 36%, respectively. WHO Grades 3-4 infections occurred in 6% of the total population 
and were not significantly related to renal function.  
A modest prolongation of the melphalan elimination half-life with no change in peak 
concentrations in patients with renal impairment down to a GFR of 30 mL/min is assessed to 
have negligible impact on the efficacy and safety of the melflufen treatment. The long dosing 
intervals will prevent any drug accumulation.  
2 
RATIONALE 
2.1 
STUDY RATIONALE 
Recent improvements in therapies have significantly increased the expected life span for MM 
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 RRMM patients typically respond to any particular treatment and 
ultimately patients relapse from all available options.  In addition, many therapies are not 
well tolerated due to compromise in renal function associated with MM and some drugs have 
restrictions in relation to renal function. Renal impairment has significant implications in 


 
 
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both the toxicity profile, as well as the disease response to treatment and it is therefore 
essential to establish the impact of renal impairment with melflufen therapy. Patients with 
decreased renal function have poorer prognosis compared with patients with normal renal 
function and thus the medical need for these patients is high. 
Melflufen has a different bio distribution and bioavailability profile compared to other 
alkylators.  Melphalan is the most potent existing alkylator for the treatment of MM. Cancer 
cells receive approximately 50 times higher exposure of alkylating moieties after exposure to 
melflufen compared to melphalan.  In the Phase 2a portion of protocol O-12-M1 in heavily 
pretreated RRMM patients (median 4 prior lines of therapy) the median PFS was 5.7 months 
(95% confidence interval 3.7 to 8.5 months) based on 40 events in 45 patients with available 
data.  Of the 34 efficacy evaluable patients the ORR was 41% and 62% of the patients 
reported a best response of MR or better.  
The safety profile of melflufen suggested by preclinical studies is supported by clinical data 
from 45 patients with solid tumors (trial O-05-001) and from a total of 75 patients with 
RRMM in a Phase 1/2a clinical trial O 12 M1 (58 patients dosed at the 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 antitumor 
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. 
This trial will evaluate the relationship between renal function and the PK parameters for the 
metabolite melphalan during treatment with melflufen, as well as the safety and efficacy of 
melflufen treatment in patients with impaired renal function. 
2.2 
RATIONALE FOR PATIENT SELECTION AND PK SAMPLING 
SCHEDULE  
The proposed trial will be conducted in relapsed or RRMM patients who have received 2 to 4 
prior lines of therapy, and with moderate and severe renal impairment. In the previous 
melflufen study O-12-M1 with rich PK sampling the evaluation demonstrated a consistent 
delay in the achievement of peak concentrations for melphalan by 5-10 minutes after end of 
melflufen infusion. Thereafter the decrease in melphalan plasma concentrations followed a 
first-order process. Using non-compartmental methods, a comparison was performed 
between the results in O-12-M1 with rich sampling and an assumed reduced sampling 
according to the schedule planned for the present OP-107 study. The average deviation for 
AUCinf and Cmax did not exceed 5% and the highest individual deviation was 11%. It was 
therefore demonstrated that the reduced sampling in OP-107 (3 samples collected after the 
start of infusion) will provide PK estimates of sufficient accuracy.  A separate population 
PK-PD plan will be developed for a combined analysis from this study and the OP-103 
Ocean study, where patients with normal or limited renal impairment are included. The OP-
12-M1 trial as well as the ongoing OP-103 and OP-106 trials required patients to have a 
baseline CrCl of ≥ 45 mL/min based on Cockcroft Gault formula (Cockcroft 1976) combined 
with a S-Cr of ≤ 2.0 mg/dL. In this trial, by using the CKD-EPI formula (Appendix G) we 
will include one cohort of MM patients with an eGFR of ≥ 30 mL/min/1.73m2 to < 45 
mL/min/1.73m2 corresponding to a moderate decrease in GFR and a second cohort with an 
eGFR of ≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2 corresponding to a severe decrease in 
GFR.  


 
 
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2.3 
RATIONALE FOR DOSE SELECTION 
The dose and schedule of melflufen was established in the Phase 1/2 trial (O-12-M1) with 
melflufen in combination with weekly dexamethasone in RRMM patients as 40 mg on Day 1 
of a 28-day cycle. In study O-12-M1 and in the ongoing trial OP-106 (melflufen and 
dexamethasone in pomalidomide- and/or daratumumab-refractory patients), hematologic 
toxicity is the most common AE reported, with thrombocytopenia being the most clinically 
important AE. This trial will establish the safety of melflufen given at the established 
recommended Phase 2 dose (RP2D) of 40 mg on Day 1 of a 28-day cycle in patients with 
moderate or severe renal dysfunction. Available data indicate that renal impairment with 
GFR down to 45 mL/min will not have a clinically meaningful effect on melflufen or 
melphalan PK. 
Following PK evaluations from 9 patients enrolled in this study, 6 patients with eGFR ≥ 30  - 
< 45 mL/min/1.73m2, and 3 patients with eGFR > 45 mL/min/1.73m2, it was observed that 
Melphalan AUC increases with decreasing eGFR and this was linked to an increased 
myelotoxicity with lower nadir in platelets and neutrophils. DSMC recommended on 10 
September 2019 further evaluation of melflufen 30 mg as the starting dose for patients with 
eGFR ≥ 30 - < 45 with a minimum of 6 additional patients in cohort 1 (Cohort 1b).  
Following PK evaluation from 19 patients enrolled in this study, DSMC recommended on 15 
December 2020 melflufen 20 mg as the starting dose for patients with eGFR ≥ 15 - < 30. A 
melflufen dose of 20 mg is predicted to be adequate for an eGFR of 15-29 mL/min/1.73 m2 
based on melphalan AUC. 
2.4 
RATIONALE FOR AMENDMENT 1 
Amendment 1 will include a potential cohort of at least 6 patients with severe renal 
impairment. This cohort is added after recommendation by the FDA since it would be 
beneficial to allow clinical use of melflufen also in patients with severe renal impairment and 
since there are no unacceptable safety concerns with use of melphalan in patients with renal 
impairment, even after high dose treatment with melphalan 200 mg/m2 (Sweiss 2016).  
Cohort 2 will only be initiated following DSMC review of the pharmacokinetic and safety 
profile of at least 6 patients in cohort 1. If the DSMC advises to proceed with Cohort 2, at 
least 6 patients with eGFR of ≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2 will be enrolled 
and analyzed for safety and pharmacokinetics data. 
Since scientific data show that the Cockcroft-Gault formula is unreliable for patients with 
low CrCl (Michels 2010), guidelines advise not to use the Cockcroft-Gault formula for 
patients with CrCl of 30 mL/min or lower (Levey 2009, Tattersall 2011, KDIGO 2013). The 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Appendix G), 
which estimates GFR, has better reliability especially at low CrCl value (Levey 2009, 
Michels 2010, KDIGO 2013, Levey 2017) and will therefore be used in the present study for 
all patients following approval of Amendment 1.  
The FDA also recommended evaluating patients in later lines of therapy limited to those who 
have received 2 – 4 prior lines, as the treatment paradigm for multiple myeloma (MM) has 
shifted as there are approved therapies with known clinical benefit in the first 2 lines of 
therapy.  Therefore, we will enroll only those patients that have received 2 – 4 lines of 
therapy.  


 
 
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2.5 
RATIONALE FOR AMENDMENT 2 
The current protocol does not allow Cycle 1 Day 1 to start at any other dose than 40 mg of 
melflufen. Data from the PK and safety analysis of the first 9 patients indicates that the AUC 
increases with decreasing eGFR and that this was linked to an increased myelotoxicity with 
lower nadir in platelets and neutrophils. However, there was no increased incidence of 
clinically important bleedings or infections. As a result, the DSMC recommends further 
evaluation of melflufen with a reduced starting dose of 30 mg in 6 additional patients in 
Cohort 1. Cohort 1 will then consist of two groups: cohort 1a with a starting dose of 40 mg 
and 1b with a starting dose of 30 mg melflufen.  Following approval of amendment 2, cohort 
1a will close for enrollment and cohort 1b will open. 
The opening and starting dose for Cohort 2 will be decided following review of available 
data from cohort 1a+1b and recommendation of the DSMC. 
2.6 
RATIONALE FOR AMENDMENT 3 
The current protocol requires all patients to have weekly CBC assessments. From cycle 3 
onwards they can be done at a local laboratory close to the patient, and not necessarily at the 
clinic. Patients with good tolerability will no longer require all weekly CBC assessments. 
Specifically, if patient’s 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. 
For patients not visiting the site weekly, they should still be contacted weekly by phone to 
follow up on AE/SAEs and dexamethasone compliance. 
2.7 
RATIONAL FOR AMENDMENT 4 
To update the CSP with the by DSMC confirmed starting dose for Cohort 2a of 20 mg 
melflufen, including dose reductions steps for this cohort, Table 6.1 updated.  
Cohort 2 will consist of two groups.  
• Cohort 2a, evaluating patients with eGFR of ≥ 15 mL/min/1.73m2 to < 30 
mL/min/1.73m2 with a starting dose of 20 mg melflufen.  
• Cohort 2b, evaluating patients with eGFR of ≥ 15 mL/min/1.73m2 to < 30 
mL/min/1.73m2 with a starting dose of 30 mg melflufen.  
Cohort 2b will only open if recommended by DSMC after evaluating data from Cohort 1a, 1b 
and Cohort 2a. 
This amendment also includes adding an interim analysis for an iCSR, to conclude the results 
from Cohort 1, patients with eGFR ≥ 30 - < 45 mL/min/1.73m2.  
As more cohorts are added the number of PK evaluable patients have increased from 25 to 
approximately 35. 
2.8 
RATIONAL FOR AMENDMENT 5 
Due to difficulties in recruiting eligible patients for Cohort 2a and b an updated feasibility assessment 
was performed alongside discussions with the investigators to identify potential eligibility hurdles in 
the current design of the protocol. The most frequent reasons for pre-screened patients not being 
eligible for screening was that they had received more than 4 prior lines of therapy (inclusion criteria 
no 3) or had deteriorating kidney function (inclusion criteria no 10). The protocol is therefore updated 


 
 
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to allow at least 2 prior lines of therapy with no upper limit and a wider eGFR window for patients to 
proceed from Screening 1 to Screening 2. 
SAE reporting details have been updated to reflect the change of safety CRO from PSI PVG Unit to 
TFS. SAE reporting email address updated to 
.  
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES 
3.1.1 
Primary Objectives 
• To evaluate the relationship between renal function and the PK parameters for 
melphalan during treatment with melflufen  
• To assess the safety and tolerability of melflufen in patients with moderate (Cohort 
1a and 1b) and severe (Cohort 2a and 2b) renal impairment 
3.2 
SECONDARY OBJECTIVES 
• To assess the best tumor response as well as overall response rate (ORR) 
• To assess the PFS 
• To assess duration of response (DOR) in patients with ≥ PR (stringent complete 
response (sCR), CR, VGPR, PR) as best response  
• To assess clinical benefit rate (CBR) and duration of clinical benefit (i.e., 
proportion of patients with ≥ MR) as best response  
• To assess time to response (TTR) in patients with a PR or better and time to CB for 
patients with MR or better. 
• Overall Survival (OS) 
All tumor response and progression-depended objectives are assessed by investigators 
according to the International Myeloma Working Group Uniform Response Criteria (IMWG-
URC) (Rajkumar et al. 2011, Appendix C) unless otherwise specified. 
 
3.3 
EXPLORATORY OBJECTIVE 
• To assess changes in renal function 
4 
STUDY DESIGN 
4.1 
DESCRIPTION OF STUDY DESIGN 
This multicenter study will enroll patients with RRMM who have received at least 2 lines of 
prior therapy.  
Patients will be treated with melflufen 10-40 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 reduced 
dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22. 
Patients will be assessed for response after each cycle according to the IMWG-URC 
(Rajkumar et al. 2011, Appendix C). Patients may continue treatment until there is 


 
 
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documented disease progression, unacceptable toxicity or the patient/treating physician 
determines 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.  In the event of a cycle delay, unrelated to dexamethasone toxicity, 
it is recommended to continue dexamethasone weekly.   
A Schedule of Events for the study is outlined in Section 8, Table 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.  Patients must meet all the entry criteria detailed in Section 5.2.1 
and Section 5.2.2.  After informed consent is obtained, the screening assessments will be 
performed as detailed in Section 8 of the protocol.  Table 8-1, Schedule of Events, 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.  
Patients who complete the screening process for study OP-103 (OCEAN) but fail to meet the 
required estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min for OP-103 
may consent for OP-107.  In this case, the screening assessments performed for OP-103 that 
are required in OP-107 do not need to be repeated provided that the assessments are 
performed as required and within the specified timeframe required for OP-107.    
5.1.1 
Screening Failures 
Patients who sign an informed consent but fail to be enrolled for any reason, e.g. do not 
fulfill eligibility criteria below, will be considered screen failures.  Patients may be re-
screened following all the same criteria in the event a screening evaluation changes.  
Rescreened participants should be assigned the same participant number as for the initial 
screening. 
A minimal set of screen failure information is required to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE) that occurs during the screening period. 
5.2 
PATIENT ELIGIBILITY 
The Investigator must ensure that patients meet all the following inclusion and exclusion 
criteria.  
5.2.1 
Inclusion Criteria 
Patients will be considered eligible for inclusion in this study only if they meet all of the 
following criteria: 
1. Male or female, age 18 years or older, at the time of signing the informed consent;  
2. A prior diagnosis of MM with documented disease progression in need of treatment at 
time of screening; 


 
 
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3. Received at least 2 prior lines of therapy. (Appendix D); 
4. Measurable disease defined as any of the following: 
a. Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis 
(SPEP) 
b.  ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine 
electrophoresis (UPEP) 
c. SFLC ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain 
ratio; 
5. Life expectancy of ≥ 6 months; 
6. ECOG performance status ≤ 2. (Patients with lower performance status based solely 
on bone pain secondary to MM may be eligible following consultation and approval 
of the medical monitor) (Appendix A); 
7. Patient is a female of childbearing potential (FCBP)* with a negative serum or urine 
pregnancy test prior to initiation of therapy and agrees to practice appropriate 
methods of birth control, or the patient is male and agrees to practice appropriate 
methods of birth control (Section 7.1); 
8. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent; 
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula 
(QTcF) interval of ≤ 470 msec (Appendix H);  
10. Renal function: Estimated GFR by CKD-EPI formula (Appendix G) on 2 consecutive 
screening evaluations. Patients meeting criteria for Screening 1, must also meet 
criteria for Screening 2 following optimal hydration (as determined by the 
investigator). Screening 2 must be on or as close as possible to treatment start date 
(preferably < 24-48 hours) but cannot exceed 72 hours.  
Cohort 1 (a and b): 
Screening 1: eGFR between ≥25mL/min/1.73m2 to <45 mL/min/1.73m2.  
Screening 2: eGFR between ≥30 mL/min/1.73m2 to < 45 mL/min/1.73m2.   
 
Cohort 2 (a and b):  
Screening 1: eGFR between ≥10 mL/min/1.73m2 to < 35 mL/min/1.73m2.   
Screening 2: eGFR between ≥15 mL/min/1.73m2 to < 30 mL/min/1.73m2. 
 
Cohort 2b will only be enrolled following approval of DSMC after evaluating data 
from Cohort 1a, 1b and 2a. 
 
Patients with fluctuating values of eGFR may be eligible following consideration of 
additional assessments in consultation with the medical monitor.  
 
11. The following laboratory results must be met during screening (within 21 days) and 
immediately before study drug administration on Cycle 1 Day 1: 


 
 
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• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth 
factors cannot be used within 10 days [14 days for pegfilgrastim] prior to 
initiation of therapy) 
• Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions 
during the 10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dl (red blood cell [RBC] transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or higher in patients 
diagnosed with Gilbert’s syndrome, that have been reviewed and approved by 
the medical monitor 
• Aspartate transaminase / Serum glutamic oxaloacetic transaminase (AST / 
SGOT) and alanine transaminase / Serum glutamic pyruvic transaminase 
(ALT / SGPT) ≤ 3.0 x ULN; 
12. Must have, or be willing to have, an acceptable central catheter. (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. 
5.2.2 
Exclusion Criteria 
Patients will be ineligible for this study if they meet any one of the following criteria: 
1. Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy); 
2. Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory 
(platelet count fails to increase by > 10,000 cells/mm3 [10.0 x 109/L] after transfusion 
of an appropriate dose of platelets); 
3. Any medical conditions that, in the Investigator’s opinion, would impose excessive 
risk to the patient or would adversely affect his/her participating in this study. 
Examples of such conditions are: a significant history of cardiovascular disease (e.g., 
myocardial infarction, significant conduction system abnormalities, uncontrolled 
hypertension, ≥ Grade 3 thromboembolic event in the last 6 months); 
4. Known active infection requiring parenteral or oral anti-infective treatment within 14 
days of initiation of 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 or very low and low risk prostate cancer in 
active surveillance;  
6. Pregnant or breast-feeding females; 
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse compliance or follow-up evaluation; 
8. Known human immunodeficiency virus or active hepatitis B or C viral infection; 
9. Concurrent symptomatic amyloidosis or plasma cell leukemia; 


 
 
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10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for MM 
within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. The use of live 
vaccines within 30 days before initiation of therapy.  IMiDs, PIs and or corticosteroids 
within 2 weeks prior to initiation of therapy. Other investigational therapies and 
monoclonal antibodies (mAb) within 4 weeks of initiation of therapy. Prednisone up to 
but no more than 10 mg orally once daily (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; 
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 peripheral stem cell transplant within 12 weeks of initiation of therapy; 
14. Prior allogeneic stem cell transplantation with active graft-versus-host- disease; 
15. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of 
study therapy this does not include limited course of radiation used for management of 
bone pain to be completed within 7 days of initiation of study therapy. Plasmapheresis 
is not permitted within 14 days of initiation of therapy; 
16. Known intolerance to steroid therapy; 
17. Prior renal transplant; 
18. Currently in need of renal dialysis. 
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 these regimens in subsets defined by race, gender, or ethnicity, and there is no 
reason to expect such differences to exist.  Investigators are encouraged to recruit a diverse 
population. 
5.3 
PATIENT ENROLLMENT 
5.3.1 
Enrollment Procedure 
Sites must be formally notified of activation before patients can be consented at that site. An 
IRB/EC approved Informed consent form (ICF) must be signed by the patient before any 
study-specific tests may be performed.  
Complete details on patient enrollment procedures are provided in the Investigator Site File 
(ISF) at each site. Following completion of the ICF process and Screening activities the site 
will complete a patient enrollment form and submit along with the required documentation to 
the Medical Monitor for approval. Once eligibility is confirmed by the medical monitor, the 
patient will be considered enrolled into the study.   
Patients that do not meet all the eligibility criteria will be considered screen failures and will 
not be enrolled. 
5.3.2 
Patient Numbering 
A unique patient number will be assigned at the time of signing of consent.   


 
 
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5.3.3 
Replacement Policy  
If a patient discontinues therapy prior to completing sufficient PK sampling and is not 
evaluable for PK analysis the patient may be replaced.  (See Section 12.4.1.2) 
6 
STUDY TREATMENT 
Treatment may be given in an outpatient treatment setting in cycles.  Each cycle is 28 days. 
Pretreatment tests/procedures and timelines are detailed in Table 8-1 Schedule of Events.  All 
evaluations must be complete prior to enrollment and initiation of treatment.   
6.1 
INITIATION OF THERAPY (CYCLE 1 DAY 1) 
Prior to initiation of therapy, patients must continue to meet eligibility criteria including 
ECOG performance status of ≤ 2 and the Cycle 1 Day 1 laboratory results must also meet the 
entry criteria noted below: Screening 2 must be on or as close as possible to treatment start 
date (preferably < 24-48 hours) but cannot exceed 72 hours. 
• ANC ≥ 1,000 cells/ mm3 (1.0 x 109/L) (Growth factors cannot be used within 
10 days [14 days for pegfilgrastim] prior to initiation of therapy) 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusion during the 
previous 10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dl (RBC transfusions are permitted)  
• Total Bilirubin ≤ 1.5 x ULN, except patients diagnosed with Gilbert’s syndrome 
that have been reviewed and approved by the medical monitor 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN 
See Section 7 for required, recommended and prohibited concomitant medications. Dose 
modifications and delays may be implemented based on patient tolerance as detailed in 
Section 6.4.  
6.2 
STUDY DRUG ADMINISTRATION 
Refer to Section 9 and Pharmacy Manual for supply, storage, preparation and accountability 
of study drugs. 
6.2.1 
Melflufen Administration 
Prophylactic treatment with anti-emetic drug(s) prior to melflufen administration is 
recommended. Subsequent anti-emetic drugs against delayed emesis should be administered 
at the discretion of the investigator. Concomitant medication shall be documented in the 
concomitant medication page in the electronic case report form (eCRF). 
 
The study treatment should be administered through a central catheter, which should 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 Section 9.1.5 and the Pharmacy Manual for 
complete instructions on melflufen preparation for infusion.  
 
Before infusion: 
• Document vital signs prior to start of infusion. 


 
 
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• Prepare the central catheter by flushing with approximately 20 mL of the same type 
of solution (5% glucose or 0.9% saline) that is used for dilution of the melflufen in 
the 250 mL bag. The maximum time from dilution to infusion is obtained if the final 
dilution is performed with 0.9% saline (cold). See the Pharmacy Manual for 
recommended storage times.    
Infusion: 
• The melflufen should be administered as a 30-minute intravenous infusion. 
• Record start and stop time of infusion 
 
After infusion: 
• Document vital signs at the end of the infusion. 
• First flush the central catheter with approximately 20 mL of the same type of solution 
(5% glucose or 0.9% saline) that is used for dilution of the melflufen in the 250 mL 
bag. Then follow with additional flushing as per institutional guidelines if necessary.  
The planned and actual administered dose as well as the start and stop clock time for the 
infusion, should be documented in the source documents and on the appropriate eCRF page. 
Refer to Section 9 for melflufen supply, storage and accountability. Refer to the Pharmacy 
Manual for details on melflufen preparation and administration and a Pharmacy Worksheet 
for recording drug preparation times.   
6.2.2 
Dexamethasone Administration 
Dexamethasone 40 mg (20 mg for patients ≥ 75 years) should be administered orally on Day 
1, 8, 15 and 22. Dexamethasone is best administered prior to melflufen when both drugs are 
given on the same day (Day 1 of each cycle).  
Dexamethasone may be given even if the melflufen is held (continued weekly during cycle 
delays, at the investigator’s discretion).  
6.3 
INITIATION OF A NEW CYCLE OF THERAPY 
The following guidelines apply to all cycles following Cycle 1.  Patients should be assessed 
at the beginning of each cycle according to the tests and evaluations outlined on Day 1 of 
each cycle in Table 8-1: Schedule of Events.  Refer to Section 6.4 for dose modifications 
related to toxicity. To begin a new cycle of treatment, the following criteria must be met. 
Criteria for Initiation of a New Cycle of Therapy  
• ANC must be ≥ 1,000 cell/mm3 (1.0 x109/L) 
• Platelet count must be ≥ 50,000 cell/mm3 (50.0 x 109/L) (platelet transfusions not 
recommended within ≤ 5 days of dosing [See Section 7.3) 
• eGFR ≥ 15 mL/min/1.73m2. Melflufen dosing of patients with eGFR below 15 
mL/min/1.73m2 is not acceptable, unless in the best interest of the patient as 
assessed by the investigator and in consultation with the medical 
monitor.  Melflufen dosing in patients in need of dialysis is also not acceptable and 
may only be considered in required consultation with the medical monitor on a 
case-by-case basis (Also see section 7.3). 


 
 
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All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except peripheral 
neuropathy Grade 2 without pain, alopecia any grade and fatigue ≤ Grade 2). If these criteria 
are not met on the scheduled Day 1, the new cycle should be held, and patients should be re-
evaluated weekly. Refer to Section 6.4 for guidelines on dose modification due to drug 
related toxicity.  
The maximum amount of time for which study therapy 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 
benefiting from therapy, the patient may be able to continue treatment at the Investigator’s 
discretion and in consultation with the medical monitor, after resolution of the AE.  
6.4 
DOSE MODIFICATIONS 
Dose modifications are permitted according to guidelines described in this section.  Toxicity 
should be assessed using the common terminology criteria for adverse events (CTCAE) 
version 4.03 (Appendix B).  All dose modifications should be based on the worst preceding 
toxicity.  Each AE should be attributed to a specific drug (melflufen or dexamethasone), if 
possible, so that the dose modifications can be made accordingly.  No dose escalations are 
permitted in any given patient once a dose level has been reduced. 
Dose modifications different from those stated in the protocol should only be made in 
consultation with the medical monitor or Sponsor; unless required for immediate patient 
safety.   
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. 
6.4.1 
Dose Reduction Steps 
6.4.1.1 
Dose Reduction Steps for Melflufen 
Dose modifications of melflufen for drug related toxicity are permitted. Multiple dose 
reductions are permitted, however, the lowest dose permitted is 10 mg.  If a patient is unable 
to tolerate the lowest dose of melflufen due to drug related toxicity the patient must be 
withdrawn from treatment.  Prior to each cycle of melflufen the criteria for initiation of 
therapy must be met (See Section 6.3).  Table 6-1 describes the dose reduction steps for 
melflufen.  
Table 6-1    Dose Reduction Steps for Melflufen 
 
Cohort 
Starting dose 
Dose reduction 
Step - 1 
Dose reduction 
Step - 2 
Dose reduction 
Step - 3 
Cohort 1a 
40 mg 
30 mg 
20 mg 
15mg 
Cohort 1b 
30 mg 
20 mg 
15 mg 
10 mg 
Cohort 2a 
20 mg 
15 mg 
10 mg 
N/A 
Cohort 2b 
30 mg 
20 mg 
15 mg 
10 mg 


 
 
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6.4.1.2 
Dose Reduction Steps for Dexamethasone 
Table 6-2 outlines the dose reduction steps for dexamethasone.  Dose reductions of 
dexamethasone other than those listed in Table 6-2 or discontinuation may be considered in 
consultation with the medical monitor. 
Table 6-2    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 
4 mg 
* (20 mg is the starting dose for patients ≥ 75 years).  **If dexamethasone is not tolerated, alternate steroids 
may be considered at the at the investigator’s discretion in consultation with medical monitor. 
6.4.2 
Dose Modification Guidelines Based on Toxicity 
Melflufen is a potent myelosuppressive agent, therefore it is essential that careful attention be 
paid to the monitoring of blood counts.  General supportive measures, together with 
appropriate RBC and platelet transfusions and hematological growth factors, should be 
instituted as necessary (See Section 7.0).  It is recommended, at the investigator’s discretion, 
that platelet transfusion should be avoided ≤ 5 days of the next dose of melflufen in order to 
assess endogenous platelet recovery and avoid the possibility of excessive myelosuppression. 
Please note: The guidelines in Table 6-3 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 sequential 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 6-3    Dose Modification Guidelines 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 one level dose reduction 
• Optional to hold one week (to Day 36) 
Hold dose.  
Evaluate in one week (to Day 36) 
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) 


 
 
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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 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 investigators 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, such as directly to 20 mg) 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 AE including abnormal laboratory 
value must be followed as described in Section 8.2.5 and 8.2.6.   
6.4.2.1 Dose Modifications for Non-Hematologic Toxicity  
In order to start a new cycle of therapy the resolution of all non-hematologic toxicity must be 
to ≤ Grade 1 or baseline except peripheral neuropathy Grade 2 without pain, alopecia any 
grade and fatigue ≤ Grade 2. Melflufen dosing of patients with eGFR below 15 
mL/min/1.73m2 is not acceptable, unless in the best interest of the patient as assessed by the 
investigator and in consultation with the medical monitor.  Melflufen dosing in patients in 
need of dialysis is also not acceptable and may only be considered in required consultation 
with the medical monitor on a case-by-case basis (Also see section 6.3). The following 
guidelines should be followed:   
• If the criteria for initiation of a new cycle of therapy are not met on Day 29 (the 
next scheduled Day 1 of any given cycle), dose should not be given, and the patient 
should be re-evaluated weekly. 
• If cycle prolongation of more than 14 days is needed to meet the criteria for 
initiation of a new cycle, a one-step dose reduction is necessary. 
• The option to “hold one week” for further resolution of toxicity is permitted at the 
investigator’s discretion based on the timelines in Table 6-3 above.  
• If cycle prolongation of more than 28 days (beyond Day 57) is needed, study 


 
 
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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. 
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 AE including abnormal laboratory 
value must be followed as described in Section 8.2.5 and 8.2.6.   
6.4.3 
Dose Modifications for Dexamethasone 
Dose modifications for dexamethasone are permitted. If a patient is unable to tolerate 
dexamethasone due to dexamethasone related toxicity, dexamethasone may be further 
reduced or discontinued following consultation with the medical monitor.  In the event of a 
cycle delay, unrelated to dexamethasone toxicity, dexamethasone may be continued weekly 
at the investigators’ discretion.  
Table 6-4    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 one 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 one dose level; if 
edema persists despite above measures, 
decrease dose another dose level. 


 
 
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Body System 
Symptom 
Recommended Action 
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 dose level until levels are satisfactory. 
Alternate dose modification may be considered in discussion with the medical monitor or the 
Sponsor.  
6.5 
TREATMENT DURATION 
Patients will receive treatment until there is documented PD, according to the IMWG-URC 
guidelines (Rajkumar et al. 2011, Appendix C), 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.  
7 
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 physical 
therapy, herbal/natural medications and blood transfusions) administered during the study 
must be listed on the Concomitant Medications page of the eCRF.  
7.1 
REQUIRED CONCOMITANT THERAPY 
• Contraceptive measures 
Males and females of child-bearing potential shall be required to use effective 
contraceptive methods (or abstinence) prior to initiation of study drug, while on therapy 
and for 28 days after last dose of melflufen for females, and for 3 months after the last 
dose of melflufen for males.  The best method should be determined in consultation 
with the Investigator. 
Females: 
Birth control methods that are considered as highly effective include: tubal ligation, 
Intrauterine device (IUD), 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, 


 
 
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unless due to hysterectomy. 
Males: 
Males must use a condom during any sexual contact with females of child-bearing 
potential during therapy and for three months after the last dose of study drug, 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.   
7.2 
RECOMMENDED CONCOMITANT THERAPY 
• Pneumocystis prophylaxis  
o All patients are recommended to receive pneumocystis prophylaxis 
concomitant treatment according to the NCCN or institutional guidelines: 
o http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf 
o Trimethoprim/sulfamethoxazole – Prophylaxis: single or double strength daily 
or double strength 3 x per week.  May require adjustment for renal 
insufficiency. 
o Patients who are found to be intolerant of pneumocystis prophylaxis while on 
study may continue on study at the discretion of the investigator.   
• Patients enrolled in the trial may be vaccinated in accordance with the advice of 
their treating physician and continue study participation, and allowed vaccines must 
have local approval and not be live vaccines. 
• 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.  
• Patients should receive full supportive care, including transfusions of blood and 
blood products (with the limitations of prophylactic use noted below), antibiotics, 
antidiarrheals, analgesics, etc. and prophylactic treatment for tumor lysis syndrome 
when appropriate.  
• Other prophylactic treatment for patient related concomitant conditions or risks may 
be considered. 
• Bisphosphonate therapy intravenously or oral should be administered if indicated in 
accordance with institutional guidelines. 
• Thrombocytopenia and neutropenia are known consequences of MM but also the 
most common expected AEs associated with melflufen.  Careful attention is to be 
paid to the monitoring of blood counts.  General supportive measures, together with 
appropriate blood and platelet transfusions and hematological growth factors should 
be instituted if necessary.  It is recommended, at the investigator’s discretion, that 
platelet transfusion should be avoided within ≤ 5 days of the next dose in order to 
assess endogenous platelet recovery and avoid the possibility of excessive 
myelosuppression (Excluding Cycle 1, Day 1 which adheres to the guidelines in 
Section 6.1 for use of growth factors and platelet transfusions prior to the first dose 
of therapy). 


 
 
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• Recommended Antimicrobial prophylaxis   
o For patients with history of cytomegalovirus (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 
prophylaxis throughout the treatment period per NCCN or institutional 
guidelines. http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf  
or NCCN.org 
7.3 
PROHIBITED CONCOMITANT THERAPY 
• Concurrent therapy with any approved or investigative anticancer therapeutic drug 
with activity against MM, including alpha interferon and/or chronic use of 
clarithromycin, is not allowed.  
• Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel 
disease) prednisone > 10 mg/day (or its equivalent) are not permitted.  
• Other investigative agents should not be used during the study 
• Radiation therapy to a limited area for bone pain to a pre-existing lesion may be 
considered in consultation with the medical monitor and approval of the sponsor. 
• The use of live vaccines is prohibited during the study and for 30 days after last 
dose of study drug. 
• 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 
inclusion criteria Section 5.2.1. Other limitations are detailed in Section 6.3 and 
Section 7.2. 
• Plasmapheresis is not permitted on study or within 14 days of initiation of therapy. 
• Patients on renal dialysis are not permitted to enter the study, however, if renal 
dialysis is needed during the course of therapy in a patient that is benefitting from 
therapy, it must be discussed with the medical monitor and approved by the 
sponsor.   
8 
VISIT SCHEDULE AND ASSESSMENTS 
8.1 
STUDY FLOW AND VISIT SCHEDULE 
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 
indicated.  All data obtained from these assessments must be supported in the patient’s 
source documentation.  
 


 
 
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Table 8-1    Schedule of Events 
 
 
Evaluation 
Screening 
Days  
-21 to -1 
 
All Cycles s 
End of 
Treatment p 
PFS -
FUq 
OS-FUr 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
Informed consent a 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria and review on day 1 
X 
X 
 
 
 
 
 
 
Medical and disease history b 
X 
 
 
 
 
 
 
 
Physical examination/symptom assessment c  
X 
X 
(X) 
(X) 
(X) 
X 
 
 
Vital signsd and weight 
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  
(X)t 
X 
(X)t 
X 
 
 
Blood chemistries h 
X/X 
X  
 
 
 
X 
(X) r 
 
Urinalysis  
X 
 
 
 
 
 
 
 
Bone marrow aspiration i 
X 
(X) 
 
 
 
(X) 
(X)r 
 
M protein assessments (SPEP/UPEP, IFE, SFLC) j 
X 
X  
 
 
 
X 
(X)r 
 
Serum β2-microglobulin  
X 
 
 
 
 
 
 
 
Assessment of extramedullary plasmacytoma k 
X 
(X) 
 
 
 
(X) 
(X)r 
 
Skeletal survey or CT scan l 
X 
(X) 
 
 
 
(X) 
(X)r 
 
Pharmacokinetic samples m  
 
(X) 
 
 
 
 
 
 
Melflufen administration n 
 
X 
 
 
 
 
 
 
Dexamethasone administration n and review of patient 
compliance 
 
X 
 
Xt 
 
X 
Xt 
 
 
 
Concomitant medications o 
X 
 
X 
 
 
AE monitoring u 
 
 
X 
 
 
Follow-up (PFS, OS) 
 
 
 
Xq, 
X 
(X) Only if indicated 
a) All patients must sign an Independent Ethics Committee (IEC)-approved ICF within 28 days 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, 
International staging system (ISS) and cytogenetics at diagnosis (if previously evaluated).  ISS and revised international staging system (R-ISS) stage (Appendix I) at 
time of study entry.  Prior surgery and/or radiation and anticancer therapy, including start and stop dates, documentation of best response, date of PD and relapsed or 
refractory status (Appendix E).   


 
 
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c) A complete physical exam, including height (screening only) and weight, neurologic assessment and assessment for extramedullary myeloma (if present on physical 
exam) will be conducted at screening, Day 1 of each cycle and End of Treatment (EoT) visit.  A symptom directed physical examination will be conducted as needed 
during a cycle.  Extramedullary Plasmacytomas that can be followed by physical exam 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 and as clinically indicated and at 
End of treatment visit. Weight to be recorded on Day 1 of each cycle. 
e) All FCBP must have a medically supervised negative serum or urine pregnancy test prior to the initiation of therapy and on day 1 of each cycle.   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 will be performed on all patients at screening and at end of treatment, and as clinically indicated.  Q-Tc interval to be assessed by Fridericia formula 
(Appendix H). 
g) Hematology: Complete Blood Count (CBC) with differential, and platelet count. CBC required at screening and may need to be repeated prior to enrollment for patients 
with borderline evaluations if requested by the medical monitor.   Patients are required to have all laboratory evaluations completed at the study center during Cycles 1 
and 2.  Starting with Cycle 3, 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 and reduced frequency of CBC evaluations may be made only in consultation with the medical monitor.  
All CBC values collected in addition to protocol specified time points must be recorded in the eCRF.  See Section 10.1.5 for reporting requirements of scheduled and 
unscheduled results of thrombocytopenia and neutropenia.   
h) Blood chemistry: sodium, chloride, potassium, blood urea nitrogen [BUN] or urea, glucose (fasting at baseline), ALT/AST (SGPT/SGOT), alkaline phosphatase, total 
protein, total bilirubin, albumin, serum creatinine, and eGFR by CKD-EPI Formula (two consecutive screening evaluations for eGFR) (Appendix G) calcium and lactate 
dehydrogenase (LDH).  Patients are required to have all evaluations completed at the treatment center during Cycles 1 and 2.  Starting with Cycle 3, 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.  
i) 
BMA to be collected at screening for % plasma cells, morphology, and cytogenetics by Fluorescence In Situ Hybridization (FISH). Minimum FISH probes include 
t(4;14), t(14;16), t(14;20), del(17/17p), gain(1q). (Sonneveld et al. 2016). If a BMA and/or biopsy has been collected within 28 days, with the appropriate evaluations, 
prior to initiation of therapy, it does not need to be repeated. A repeat BMA is required to confirm a suspected CR. Refer to Laboratory manual. 
j) 
SPEP and UPEP and serum and urine IFE (if SPEP and UPEP are not detectable and to confirm a CR), quantitative immunoglobulins (Ig) per routine lab practice and 
SFLC assay (only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hours and SPEP is < 0.5 g/dL]) are to be conducted at screening, Cycle 1 Day 1 
and prior to each cycle even if treatment is delayed and to confirm sCR. Quantitative Ig only need to be repeated for patients with IgA or IgD myeloma.  All assessment 
of SPEP, UPEP, IFE and free light chain (FLC) must be completed in the same laboratory for a given patient.  In the event treatment is delayed, ≥ 6 weeks (beyond Day 
43), MM disease response assessments are required to be repeated on the day the new cycle starts (Day 50 or 57 of the previous cycle). If treatment is discontinued 
beyond Day 43 the response assessments should be repeated on the day of that determination (or as soon as possible) after last dose of melflufen as part of the EoT visit.  


 
 
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k) Known or suspected extramedullary plasmacytomas are to be assessed at screening, as clinically indicated and to confirm response or progression. The same method of 
evaluation should be used throughout the study (e.g., Computerized tomography [CT]/ magnetic resonance imaging [MRI]/ positron emission tomography [PET]). All 
imaging assessments should be documented in the eCRF. Imaging assessments at screening do not need to be repeated if completed within 28 days of initiation of 
therapy.  
l) 
Skeletal survey includes x-rays of 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. Low dose CT scan may be used in addition or in place of conventional X-ray with the same technique to be used with each 
evaluation.  Bone imaging assessments at screening do not need to be repeated if completed within 6 weeks of initiation of therapy. Required at any time when clinically 
indicated.  Limited X-rays may be performed as clinically indicated to confirm PD. 
m) PK samples: Three plasma samples for determination of melphalan concentrations will be drawn in connection to the first two melflufen treatment cycles (Cycle 1 and 2); 
5-10 minutes after the end of infusion, 2 - 3 hours after the end of infusion and 5-7 hours after the end of infusion, if PK sampling is missed during Cycle 1 or 2 it may be 
taken at a later cycle. For enrolled patients with moderate renal impairment one repeat set of three PK samples, will be drawn in one cycle, if during the treatment period, 
the patient’s eGFR falls below 30 mL/min/1.73m2. For enrolled patients with severe renal impairment one repeat set of three PK samples, will be drawn in one cycle, if 
during the treatment period, the patient’s eGFR falls below 15 mL/min/1.73m2 and dosing is approved by MM.  All PK samples must be drawn peripherally and not from 
the central catheter.  Refer to the Laboratory Manual for details on specimen collection and processing.  
n) See Section 6 in the protocol for complete details on study drug administration, dose modifications, start of a new cycle of therapy. See Section 9 for study drug supply, 
storage, preparation and accountability and compliance.   
o) Concomitant medications and procedures: - all blood products and medications within 21 days prior to first dose until the EoT Visit. 
p) 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 (such as in the case of a prolonged cycle) with evaluation of safety variables including recording of new and ongoing AEs, review 
of concomitant medications and any other new disease related therapy.  If a new treatment for MM is to be introduced sooner than 30 days after last dose of study drug 
the EoT visit should occur as close as possible before the first dose of the new drug.  Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EoT visit are to 
be followed until resolution (≤ Grade 2) or initiation of subsequent therapy.  SAEs should be followed until resolution or stabilization with no expected resolution.   
q) PFS-FU: 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. Schedule the first assessment 4 weeks after the EoT visit.  Confirmed PD 
should be verified by medical monitor prior to discontinuation of therapy. If PD has not been confirmed prior to the initiation of subsequent therapy the reason for the 
subsequent therapy should be documented. Documentation of the date and regimen of the first subsequent therapy is required. Serum calcium and albumin (corrected 
calcium) required only if evidence of PD. *Patients unwilling or unable to return to the site for PFS evaluations may have the lab evaluations done locally following 
approval by the medical monitor. 
r) 
Overall Survival Follow-up (OS-FU):  Following confirmed disease progression or initiation of subsequent therapy, FU for OS status and second primary malignancies 
will take place every three months +/- 7 days.  Following completion of the last patient in PFS-FU, OS-FU will end.  However, in the event that Oncopeptides AB would 
like to determine the status of patients following this time point, patients will consent to one or more inquiries to their health status.  This information may be collected 


 
 
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outside of the eCRF established for this study.  Documentation of the date and regimen of the first subsequent therapy should be done if it occurs during OS -FU.  
Follow-up may be completed by phone contact.  SAEs 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.  
s) +/- 3 day window permitted (Except Cycle 1 Day 1) for holidays/administrative reasons. 
t) 
 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.  
For patients not visiting the site weekly they should still be contacted weekly by phone to follow up on AE/SAEs and dexamethasone compliance.  
u) SAEs will be collected from signing of the ICF until 30 days after last dose of study treatment. Any SAE that occurs after this timepoint and is considered related to 
melflufen or study participation in the opinion of the investigator will also be collected. 
      


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8.2 
STUDY ASSESSMENTS 
Refer to the Table 8-1; Schedule of Events for details and timelines and explanation of all 
study assessments.  Adherence to the study design requirements, including those specified in 
Table 8-1, is essential and required for study conduct. Procedures conducted as part of the 
participant’s routine clinical management (eg, blood count) and obtained before signing of the 
ICF may be utilized for screening or baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within the time frame defined in Table 8-1. 
Refer to the Laboratory Guidance Document for details on lab testing requirements.  
8.2.1 
Screening Disease Assessments 
• M-protein determination using the following procedures  
o SPEP and serum protein IFE with quantitative Ig;  
• 
Quantitative Ig evaluation may be based on regional availability of the test. 
• 
IFE 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) 
• 
IFE of urine is required at screening if M protein by UPEP 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 and morphology, cytogenetics 
by FISH. 
• Extramedullary plasmacytoma evaluation of known or suspected lesions (by 
physical examination 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. Low dose CT scan may be used in addition or in place 
of conventional X-ray (with the same technique to be used with each evaluation)   
• Beta2 microglobulin 
• LDH  
• ISS staging score and revised R-ISS (Appendix I) 
8.2.2 
Efficacy Assessments  
M-protein determination using the following procedures (also refer to footnote j on Table 8-
1): 
• SPEP and serum protein IFE with quantitative Ig (For patients with IgA and IgD 


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myeloma);  
o Immunofixation (IFE) of serum is required at any time when M protein by 
SPEP becomes non-detectable* and to confirm a CR. 
• UPEP and urine protein IFE (all using the same 24-hour urine collection); and  
o IFE of urine is required at any time when M protein by UPEP becomes not 
detectable* and to confirm a CR. 
*IFE is not required on one (serum or urine) if the other remains detectable. 
• SFLC and SFLC ratio 
o 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), 
o 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 IFE and FLC evaluations when required, to enable response 
assessments according to IMWG criteria (Rajkumar et al. 2011, Appendix C). 
• Extramedullary plasmacytoma evaluation with the same technique to be used with 
each evaluation 
• BMA to quantify percent myeloma cell involvement  
• Skeletal X-rays and/or CT scans 
• Serum calcium (corrected calcium) 
BMA to be collected at screening for % plasma cells, morphology, and cytogenetics by 
Fluorescence In Situ Hybridization (FISH). Minimum FISH probes include t(4;14), t(14;16), 
t(14;20), del(17/17p), gain(1q). (Sonneveld et al. 2016).  If a BMA and/or biopsy has been 
collected within 28 days, with the appropriate evaluations, prior to initiation of therapy, it 
does not need to be repeated. A repeat BMA is required to confirm a suspected CR. Refer to 
Laboratory manual. 
SPEP and UPEP and serum and urine IFE (if SPEP and UPEP are not detectable and to 
confirm a CR), quantitative immunoglobulins (Ig) per routine lab practice and SFLC assay 
(only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hours and SPEP 
is < 0.5 g/dL]) are to be conducted at screening, Cycle 1 Day 1 and prior to each cycle even if 
treatment is delayed and to confirm sCR. Quantitative Ig only need to be repeated for patients 
with IgA or IgD myeloma.  All assessment of SPEP, UPEP, IFE and SFLC must be 
completed in the same laboratory for a given patient.  In the event treatment is delayed, ≥ 6 
weeks (beyond Day 43), MM disease response assessments are required to be repeated on the 
day the new cycle starts (Day 50 or 57 of the previous cycle). If treatment is discontinued 
beyond Day 43 the response assessments should be repeated on the day of that determination 
(or as soon as possible) after last dose of melflufen as part of the EoT visit.  
Known or suspected extramedullary plasmacytomas are to be assessed at screening, as 
clinically indicated and to confirm response or progression. The same method of evaluation 
should be used throughout the study (e.g., Computerized tomography [CT]/ magnetic 


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resonance imaging [MRI]/ positron emission tomography [PET]). All imaging assessments 
should be documented in the eCRF. Imaging assessments at screening do not need to be 
repeated if completed within 28 days of initiation of therapy.  
Skeletal survey includes x-rays of 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. Low dose CT scan may be used in addition or in place of conventional 
X-ray with the same technique to be used with each evaluation.  Bone imaging assessments at 
screening do not need to be repeated if completed within 6 weeks of initiation of therapy. 
Required at any time when clinically indicated.  Limited X-rays may be performed as 
clinically indicated to confirm PD. 
8.2.3 
Safety and Tolerability Assessments 
Safety Assessments: 
• Assessment and grading of AE 
• Physical examination with vital signs, weight, neurologic assessment and assessment 
of performance status 
• Routine safety laboratory tests (CBC with differential and platelets; clinical 
chemistry, and urinalysis) with calculation of the eGFR according to the CKD-EPI 
formula. (Appendix G) 
• Chest X-ray (postero-anterior/lateral) 
• Pregnancy testing  
• ECG - Q-Tc interval to be assessed by Fridericia formula (Appendix H)  
AEs, 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 any 
dose of study treatment. 
The investigator must review the laboratory report and document abnormal laboratory results 
as an AE according to the guidelines in Section 10.1.5. The laboratory reports must be filed 
with the source documents.  
8.2.4 
Pharmacokinetic Assessments 
Three plasma samples for determination of melphalan concentrations will be drawn in 
connection to the first two melflufen treatment cycles (Cycle 1 and 2); 5-10 minutes after the 
end of infusion, 2 - 3 hours after the end of infusion and 5-7 hours after the end of infusion. If 
PK sampling is missed during Cycle 1 or 2 it may be taken at a later cycle. For enrolled 
patients with moderate renal impairment one repeat set of three PK samples, will be drawn in 
one cycle if during the treatment period the patient’s eGFR falls below 30 mL/min/1.73m2. 
For enrolled patients with severe renal impairment one repeat set of three PK samples, will be 
collected in one cycle if during the treatment period of the study, the patient’s eGFR falls 
below 15 mL/min/1.73m2 and the patients is approved for dosing by MM. All PK samples 
must be drawn peripherally and not from the central catheter.  Refer to the Laboratory Manual 
for details on specimen collection and processing.   


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8.2.5 
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 the patient from therapy occurs later 
than 30 days after last dose (e.g. in the case of prolonged cycle).  At the EoT visit evaluation 
of safety including recording of new and ongoing AEs, review of concomitant medications 
and any other new disease related therapy should be done.  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 MM is to be 
introduced sooner than 30 days after last dose of study drug, the EoT visit should occur as 
close as possible before the first dose of the new drug.  If PD has not been confirmed prior to 
the initiation of subsequent therapy the reason for the subsequent therapy should be 
documented.  Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EoT visit are to be 
followed until resolution (≤ Grade 2), or initiation of subsequent therapy.  Ongoing SAE’s 
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.   
8.2.6 
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.  Discontinuation 
from treatment 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.  Schedule the first assessment 4 weeks after the EoT visit.  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 it occurs during PFS-FU.  
8.2.6.2 
Overall Survival Follow-up 
Following confirmed disease progression, or initiation of subsequent therapy, patients will be 
followed for OS-FU. Follow-up for overall survival (OS) status, second primary malignancies 
and first subsequent therapy will take place every three months +/- 7 days.  Following 
completion of the last patient in PFS-FU OS-FU will end.  However, in the event that 
Oncopeptides AB would like to determine the status of patients following this time point, 
patients will consent to one or more inquiries to their health status.  This information may be 
collected 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 
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.). 


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8.2.7 
Criteria for Premature Patient Withdrawal 
Patients may be withdrawn from treatment if any of the following occur: 
• Documented confirmed disease progression verified by the medical monitor 
(2 consecutive evaluations)  
• Patients may choose to withdraw from the study treatment at any time and continue 
in follow-up 
• AEs that, in the judgment of the investigator, may cause severe or permanent harm 
or which require study drug discontinuation (See Sections 6.4.2 and 6.4.3). 
• 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 
• Requiring other anti-neoplastic therapies 
• Requiring renal dialysis not approved by the sponsor 
• Major deviation of the study protocol (i.e., unable to adhere to study schedule) 
• Confirmed pregnancy 
• Lost to follow-up 
Patients may be withdrawn from the study if any of the following occur: 
• Withdrawal of consent for study participation 
• Death 
• Lost to follow-up 
• Discontinuation of the study by Oncopeptides AB 
• Completed OS-FU per protocol 
The reason(s) for withdrawal of study 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 
STUDY DRUG SUPPLY AND HANDLING 
9.1 
MELFLUFEN 
9.1.1 
Melflufen Packaging and Labeling 
Melflufen is formulated as a sterile lyophilized powder for solution for infusion (containing 
melflufen and the excipient sucrose).  The drug product, melflufen powder for solution for 
infusion, is filled in 50 mL glass vials with grey rubber stoppers and flip-off seals.  Each 
vial contains 20 mg of melflufen.  These will be delivered in paper boxes containing 
enough vials for several administrations.  


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Please refer to the Pharmacy Manual for further details on packaging and labeling. 
9.1.2 
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 to +8°C (refrigerated).   
9.1.3 
Melflufen Supply 
Melflufen will be provided by Oncopeptides AB free of charge. 
9.1.4 
Melflufen Special Handling 
Melflufen is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and 
handling melflufen solutions. The use of gloves and other appropriate protective clothing is 
recommended.  In case of skin contact, wash the affected area immediately and thoroughly 
with soap and water for at least 15 minutes.  If product contacts eye, immediately flush eye 
thoroughly with water for at least 15 minutes.  Always contact a physician after any form 
of body contact.  All materials that have been used for preparation should be disposed of 
according to standard practices. 
9.1.5 
Melflufen Drug Preparation 
Melflufen powder for solution for infusion is prepared by reconstitution with 5% glucose 
solution and then further diluted in a 250 mL infusion bag of either 5% glucose (ambient or 
cold) or 0.9% saline (cold). The i.v. 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 
degrades in solutions*.  The maximum time from dilution to infusion is obtained if the 
final dilution is performed with 0.9% saline (cold). See the Pharmacy Manual for 
recommended storage times.   
Time to infusion requirements: 
• 250 mL bag of 5% glucose:   
o Ambient: the 250 mL bag of 5% glucose should be at room temperature prior to 
adding melflufen. The maximum allowed time from start of reconstitution until 
the start of iv infusion is 30 minutes, 
o Pre-cooled: the 250 mL bag of 5% glucose should be pre-cooled prior to adding 
melflufen. The maximum allowed time from start of reconstitution until the start 
of iv infusion is 45 minutes,  
• 250 mL bag of 0.9% saline 
o The 250 mL bag of saline 0.9% should be pre-cooled prior to adding melflufen.  
The infusion bag may be stored at 2-8o C before use (See the Pharmacy Manual 
for recommended storage times).   


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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 a Pharmacy Worksheet to 
record drug preparation time points). 
9.2 
DEXAMETHASONE 
9.2.1 
Dexamethasone Packaging and Labeling 
Dexamethasone will be labeled for investigational use for sites. 
9.2.2 
Dexamethasone Storage 
Dexamethasone is to be stored at controlled room temperature.  Consult the summary of 
product characteristics (SmPC) for dexamethasone for additional storage and usage 
instructions. Upon receipt, the temperature log should be checked, and notice given to 
supplier of the condition of the shipment.    
9.2.3 
Dexamethasone Supply 
Oral dexamethasone will be supplied by Oncopeptides AB.  
9.3 
STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
9.3.1 
Study Drug Compliance 
Compliance will be assured by administration of the study treatment under the supervision of 
the investigator or his/her designee and should be documented in the study drug 
administration and accountability records.   
9.3.2 
Study Drug Accountability 
All study drugs must be stored by the sites in a secure facility with limited access. The 
investigator or designee must maintain an accurate record of the shipment and dispensing of 
study treatment supplied to the site by the Sponsor in a drug accountability log.  Drug 
accountability will be reviewed by the Clinical Research Organization (CRO) monitor during 
site visits and at the completion of the study.  
At study close-out, and as appropriate during the course of the study, all unused study drug 
packaging and any associated supplies should be discarded according to the site drug 
destruction policy following review and approval of the site CRO monitor.  A copy of the 
drug destruction policy and the completed drug accountability log should be provided to the 
CRO monitor.  
10 
SAFETY MONITORING AND REPORTING 
10.1 
ADVERSE EVENTS 
10.1.1 
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 the use of a medicinal product, whether or not 


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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 side effect, 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 or prescribing information for a marketed compound.  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”.    
10.1.2 
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 event representing a change in the 
CTCAE Grade need to be reported on the AE eCRF.  This includes any abnormal laboratory 
values that the investigator considers clinically significant (Section 10.1.5).  
For AEs not adequately addressed in the CTCAE, the severity in Table10-1 may be used: 
Table 10-1  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 
10.1.3 
Causality 
The assessment of causality should 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 


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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.  
Only if an abnormal laboratory result is considered clinically significant, should it be reported 
as a TEAE. (See Section 10.1.5.1). 
10.1.4 
Adverse Event Reporting 
All AEs 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 AE 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); 
5. Whether medication or therapy was given (e.g., concomitant medication or procedure); 
6. Outcome (e.g., not resolved, resolved, resolved with sequalae, fatal, unknown); 
7. Whether it is a SAE as defined in Section 10.2.1. 
All AEs should be treated appropriately.  If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the eCRF. 
Any AE (e.g., 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 AE on the appropriate page(s) of the eCRF.  Should a patient discontinue from 
treatment and commence subsequent anticancer therapy within 30 days of the last study drug 
administration, AEs attributable to this subsequent therapy should not be recorded.   
10.1.5 
Laboratory Test Abnormalities 
10.1.5.1 Definitions and Reporting 
Laboratory abnormalities are usually not recorded as AEs; 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 AE’s (or serious AE’s) if they meet the definition of an AE as described in 
Section 10.1 or 10.2.  In addition, laboratory abnormalities assessed as clinically significant 
should also be recorded as AEs.  The Investigator will record the grade of the clinically 
significant laboratory abnormality and will evaluate its relationship to the study drug and 
clinical condition.  Laboratory AEs should be recorded using only one event term per event 
such as thrombocytopenia for low platelet count but not as both (thrombocytopenia and low 
platelet count). 
Clinically significant laboratory abnormalities are those that: 


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• Induce clinical signs and symptoms (Note: The sign/symptom should be recorded as 
an AE, not the lab abnormality) 
• Require concomitant therapy  
• Require change in study treatment 
• Investigator considers clinically significant for any reason 
• Additional Laboratory Reporting Guidelines All platelet and neutrophil 
laboratory values collected during the course of the study should be reported 
including protocol specified time points and any additional time points (unscheduled 
assessment).  
• Ongoing Grade 3 and 4 platelet and ANC values at the time of the EoT visit are to 
be followed until resolution (≤ Grade 2), or stabilization, or initiation of a 
subsequent therapy;  
• All neutrophil and platelet laboratory values associated with an 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 Granulocyte colony-stimulating 
factor (G-CSF) given for AEs or prophylactic reasons must be reported in the eCRF 
and if applicable also in the SAE report. 
10.2 
SERIOUS ADVERSE EVENTS 
10.2.1 
Definitions 
A SAE is defined as any AE, occurring at any dose that meets any one or more of the 
following criteria (see the ICH Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting): 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant; 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,  
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 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). 
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 


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rather than disease progression to the extent possible (e.g. “respiratory failure” or “renal 
failure” due to progressive MM)  
Note that in-patient hospitalizations for the following reasons should not be reported as 
SAE’s: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition including 
• 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 and/or administrative 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 SAE 
10.2.2 
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 Sponsor, within 24 hours of the onset or after the 
investigator became aware of the SAE. 
 
An SAE reporting form must be filled out and emailed to Oncopeptides safety report mailbox:  
.   
 
A fax number can be found in the Investigator Site File and is only to be used as a back-up if 
emailing report is not possible. 
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 SAE.  The investigator’s initial causality assessment must also be 
included if available. 
Each recurrence, 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. 
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 10.2.2.1).   


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SAEs should be followed until resolution, or stabilization with no anticipation of resolution 
regardless of 30-days reporting timeline 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 IECs in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.  For the 
purpose of SUSAR reporting, only possibly or probably related SAEs (i.e. there is a 
reasonable possibility of causality) will be considered serious adverse drug reactions.   
10.2.2.1 Reporting of Death 
• Death is an outcome of a SAE and not a SAE in itself.  When death is an outcome, 
the event(s) resulting in death should be reported (e.g., “pulmonary embolism” with 
a fatal outcome).  The appropriate diagnosis or term should be recorded and assigned 
severity Grade 5; 
• In instances of death due to “Disease Progression” the cause of death should be 
indicated as the event or condition resulting in death to the extent possible (e.g., 
“respiratory failure” due to progressive MM);   
• Adverse events resulting in death 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. 
10.3 
PREGNANCY 
All instances of pregnancy occurring in a patient or partner of a patient taking study 
therapy must be reported within 24 hours of awareness of the pregnancy.    
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 emailed to Oncopeptides safety report 
mailbox:  
   
 
A fax number can be found in the Investigator Site File and is only to be used as a back-up if 
emailing reports is not possible. 
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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10.4 
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 lead investigator, the 
CRO global medical monitor, Sponsor representative(s) and headed by an independent 
chairperson.  All activities and processes surrounding the DSMC will be outlined in the 
DSMC Charter. Refer also to Section 12.5.2. 
11 
DATA COLLECTION AND MANAGEMENT 
11.1 
DATA CONFIDENTIALITY 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations.  Those regulations require a signed informed consent document 
informing the patient of the following: 
• What personal identifying and health information 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 personal 
and health information 
In the event that a patient revokes authorization to collect or use personal identifying and 
health information, 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 personal identifying and health information, attempts 
should be made to obtain permission to collect follow-up safety information. 
Access to the data collection system will be controlled by user identification codes and 
passwords, made available only to authorized personnel who have completed prerequisite 
training. 
11.2 
SITE MONITORING 
Before study initiation, at a site initiation visit and/or at an investigator’s meeting, 
Oncopeptides AB staff (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 and to GCP, 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, ECGs, 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 ICF (a signed copy is given to the patient). 


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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. 
11.3 
DATA COLLECTION 
An 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. 
11.4 
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 changes to the 
data. 
12 
STATISTICAL METHODS AND DATA ANALYSIS 
12.1 
STUDY ENDPOINTS  
12.1.1 
Primary Endpoints 
• PK parameters of melphalan  
• Frequency and grade of AE’s.  
12.1.2 
Secondary Endpoints 
ORR: Proportion of patients with ≥ PR (sCR, CR, VGPR and PR) as best response  
CBR: Proportion of patients with ≥ MR (sCR, CR, VGPR, PR and MR) as best response  
PFS: defined as time (months) from date of initiation of therapy to the earlier of confirmed 
disease progression or death due to any cause.  


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DOR: defined as the time from the first evidence of confirmed assessment of sCR, CR, 
VGPR, or PR to first confirmed disease progression, or to death due to any cause.  DOR is 
defined only for patients with a confirmed PR or better. Duration of clinical benefit, for 
patients with a confirmed MR, or better will also be evaluated. 
TTR: Time from first dose or therapy to first documented confirmed response.  
Best response during the study (sCR, CR, VGPR, PR, MR, SD or PD). 
OS: defined as time (months) from date of initiation of therapy 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. 
12.2 
EXPLORATORY ENDPOINT 
Renal function: The level of eGFR determined at baseline and the start of each cycle.  
12.3 
SAMPLE SIZE  
Enrollment of approximately 35 PK evaluable patients is considered sufficient for a reliable 
assessment of the PK parameters, at least 6 patients per cohort. 
12.4 
GENERAL CONSIDERATIONS FOR THE STATISTICAL ANALYSES 
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, 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 eCRFs and 
any derived data will be presented by group and patient in data listings. 
12.4.1 
Analysis Populations 
12.4.1.1 Safety Analysis Set 
The Safety analysis set is defined as all patients who received at least one or partial dose of 
melflufen or dexamethasone. The Safety analysis set will be the primary population for the 
summaries of all exposure, efficacy and safety data.  
12.4.1.2 PK Analysis Set 
All patients that have received at least one melflufen dose and have sufficient PK samples 
taken after this infusion (three samples as scheduled post infusion). This analysis set will be 
used for the PK analysis. 
12.4.1.3 Efficacy Analysis Set 
All patients that complete 2 doses of melflufen and have relevant baseline and follow-up 
disease assessments after the second dose of melflufen. This population may be used for 
assessment of select secondary analysis endpoints as defined in the SAP. 


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12.5 
ANALYSIS OF PRIMARY ENDPOINTS 
12.5.1 
Pharmacokinetic Analysis 
12.5.1.1 Pharmacokinetic methods  
Three plasma samples for determination of melphalan concentrations will be drawn in 
connection to the first two melflufen treatment cycles (Cycle 1 and 2), 5 – 10 minutes after the 
end of infusion, 2 - 3 hours after the end of infusion and 5-7 hours after the end of infusion.  
For enrolled patients with moderate renal impairment one repeat set of three PK samples, will 
be drawn in one cycle if during the treatment period the patient’s eGFR falls below 30 
mL/min/1.73m2. 
For enrolled patients with severe renal impairment one repeat set of three PK samples will be 
drawn in one cycle, if during the treatment period of the study the patient’s eGFR falls below 
15 mL/min/1.73m2 and the patients is approved for dosing by MM. 
In the previous melflufen study O-12-M1 with rich PK sampling the evaluation demonstrated 
a consistent delay in the achievement of peak concentrations for melphalan by 5-10 minutes 
after end of melflufen infusion. Thereafter the decrease in melphalan plasma concentrations 
followed a first-order process. Using non-compartmental methods, a comparison was 
performed between the results in O-12-M1 with rich sampling and an assumed reduced 
sampling according to the schedule planned for the present OP-107 study. The average 
deviation for AUCinf and Cmax did not exceed 5% and the highest individual deviation was 
11%. It was therefore demonstrated that the reduced sampling in OP-107 will provide PK 
estimates of sufficient accuracy.  
12.5.1.2 Individual PK modeling 
For all concentration-time profiles with 3 measurable melphalan concentrations PK 
parameters will be evaluated by non-compartmental methods using the software WinNonlin 
Professional Version 7.0 (Pharsight Corporation). Actual time points for drug administration 
and plasma sampling will be used.  
The following PK parameters will be assessed:  
• Time of maximum observed concentration (tmax)  
• Maximum observed concentration (Cmax)  
• Area under the concentration versus time curve between 0h and time of last 
measured concentration (AUC0-t)  
• Area under the concentration versus time curve from 0h to infinity (AUCinf)  
• Elimination phase half-life (t½)  
12.5.1.3 Population PK modeling 
Melphalan concentration data will be pooled across patients and all melflufen studies 
providing data and evaluated using a population approach with nonlinear mixed-effect 
modeling. Actual time points for drug administration and plasma sampling will be used.  


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Details on the modeling approach will be described in a separate population 
pharmacokinetics-Pharmacodynamic plan which will be developed in parallel with the 
ongoing Phase 3 study OP-103 (OCEAN TRIAL).   
The relationship between melphalan PK parameters and patient factors will be assessed on the 
pooled data, as well as the inter-occasion variability in melphalan exposure. 
12.5.1.4 Statistical methods for PK parameters from the individual modeling 
Descriptive statistics including mean, geometric mean, median, minimum, maximum, 
standard deviation, and percent coefficient of variation (CV%) for the obtained PK parameters 
will be calculated.  
Results for estimated PK parameters will be tabulated using 3 significant figures. Exceptions 
are values 1000 or higher where no rounding will be performed. For descriptive statistics 
mean, geometric mean and median values are shown with 4 significant figures, and standard 
deviation and CV% with 3 significant figures. In the statistical calculations data will be used 
as provided by the input files and by the PK modeling software, without rounding.  
12.5.2 
Analysis of Safety Endpoints 
The number (%) of patients experiencing TEAEs will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT).  The 
denominator for the percentage will be based on the number of patients at in the Safety 
analysis set.   
No formal statistical analysis will be performed for the safety endpoints.  The summaries of 
AEs will be based on TEAEs.  TEAEs are defined as AEs that start on or after the first day of 
study treatment 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 
Safety analysis set.  A patient reporting the same AE more than once will be counted only 
once when calculating incidence 1) within a given SOC, and 2) within a given SOC and PT 
combination.  For such cases, the maximum CTCAE toxicity grade and strongest causal 
relationship to study treatment for the event will be used in the incidence calculations.  
Treatment-related AEs, defined as AEs with a relationship of possibly or probably related will 
be summarized in the same way. 
Summaries of TEAEs and treatment-related AEs will be provided according to maximum 
toxicity grade.  Grade 3 or higher TEAEs and treatment-related AEs, SAEs, and TEAEs 
resulting in permanent discontinuation of study treatment will be provided.  Grade 3 and 4 
thrombocytopenia and neutropenia will be evaluated to determine their frequency, duration, 
relationship to treatment, associated clinical consequences/medical management and 
associated significant AEs. 
A DSMC will assess the benefit/risk profile of the study. All reported Grade 3-4 treatment-
related non-hematological AEs, as well as all SAEs, and any treatment-related deaths due to 


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hematologic or non-hematologic AEs as well as efficacy and PK data will then be presented 
to the DSMC.   
Cohort 2 was initiated following DSMC review of the pharmacokinetic and safety profile of 
31 patients in Cohort 1, of which 19 patients were evaluable for PK. The DSMC advised that 
Cohort 2 should continue as planned and recommended the starting dose to be 20 mg 
melflufen with dose modifications according to Table 6-1. At least 6 patients with eGFR ≥ 15 
mL/min/1.73m2 to < 30 mL/min/1.73m2 will be enrolled and analyzed for safety and 
pharmacokinetics data. 
Cohort 2 will have two parts, Cohort 2a and 2b. After at least 6 patients in Cohort 2a with 
eGFR ≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2 have been evaluated, the DSMC may 
advise if a higher starting dose (Cohort 2b, 30 mg melflufen) should be investigated. 
If the DSMC considers the benefit/risk profile different from previous knowledge of efficacy 
and safety the DSMC may recommend change to the protocol, additional safety monitoring or 
stopping further recruitment. 
12.6 
ANALYSIS OF SECONDARY ENDPOINTS 
ORR: The ORR will be estimated as the proportion of patients who achieve a confirmed 
response of sCR, CR, VGPR, or PR as their best response in the safety evaluable population. 
The exact binomial 95% CI for ORR will be calculated. 
CBR: The CBR will be estimated as the proportion of patients who achieve a confirmed 
response of sCR, CR, VGPR, PR, or MR as their best response in the safety population. The 
exact binomial 95% CI for CBR will be calculated. 
PFS: PFS is measured from the date of initiation of therapy to the date of documented disease 
progression or death in efficacy analysis set as well as the safety analysis set.  PFS will be 
right-censored for patients who meet 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 Food and Drug Administration (FDA) 
Guidance for Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics’.  
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm071590.pdf) 
For such patients, the primary analysis of PFS will be right-censored according to the 
conventions described in Table 12-1. 


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Table 12-1 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 initiation of therapy 
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 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
The distribution of PFS will be summarized using the Kaplan-Meier (K-M) method.  The 
median PFS will be estimated from the 50th percentile of the corresponding K-M estimates.  
The 95% CI for median PFS will be constructed using the method of Brookmeyer 
(Brookmeyer and Crowley, 1982).   
DOR: The DOR will be calculated for patients who achieve a confirmed response of PR or 
better. The DOR is defined as the time from first documentation of response to disease 
progression or death due to any cause.  Dates of progression and censoring will be determined 
as described for the analysis of PFS.  
Duration of clinical benefit will be calculated for patients who achieve a confirmed response 
of MR or better. The duration of clinical benefit is defined as the time from first 
documentation of response ≥ MR to disease progression or death due to any cause.  Dates of 
progression and censoring will be determined as described for the analysis of PFS. 
TTR: TTR will be presented using descriptive statistics. TTR is defined as time from first 
dose of study drug until documentation of a disease response. The TTR will be calculated for 
patients who achieve a confirmed response of PR or better. Time to CB will be presented for 
confirmed response of MR or better.  
12.7 
ANALYSIS OF EXPLORATORY OBJECTIVES 
Renal function will be assessed over the duration of the trial to observe patterns and potential 
correlation with various parameters such as co-morbid conditions, concomitant medications, 
tolerability and MM disease status. 
12.8 
HANDLING OF DROP-OUTS AND MISSING DATA 
The SAP describes how drop-outs 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 


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(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. 
12.9 
INTERIM ANALYSIS 
An interim analysis for an interim clinical study report (iCSR) is planned when patients 
enrolled in Cohort 1a and 1b have been followed until progression or up to at least 6 months 
after first dose. The objective of this interim analysis is to evaluate PK, safety and efficacy in 
Cohort 1, moderately impaired patients, to support regulatory submissions. 
As no inferential statistical analyses are planned at the interim analysis, the interim has no 
impact on the statistical methods or presentation of data for the final report.  
13 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
13.1 
REGULATORY AND ETHICAL COMPLIANCE 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for GCP, 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. 
13.2 
RESPONSIBILITIES OF THE INVESTIGATOR AND IEC 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IEC before study start.  A signed and dated statement that the protocol and informed consent 
have been approved by the 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, IECs and 
regulatory authorities as required. 
13.3 
INFORMED CONSENT PROCEDURES 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), 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 is obtained will be captured in the eCRFs. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.  Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  A participant who is rescreened is not required to sign 
another ICF if the rescreening occurs within 21 days from the previous ICF signature date. 
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 


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must be agreed to by Oncopeptides AB before submission to the IEC, and a copy of the 
approved version must be provided to the Oncopeptides AB (or designated CRO) monitor 
after IEC approval. 
13.4 
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.  Specific 
conditions for terminating the study at any time for reasonable medical or administrative 
reasons in any single center could be 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 
• An incidence or a seriousness of SAEs in this study or other studies indicating a 
potential danger for the patient’s health caused by the study treatment 
13.5 
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. 
13.6 
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 harmonization 
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. 


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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 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 
Investigational new drug (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. 
13.7 
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 ICFs and patient enrollment log must be kept strictly confidential to enable patient 
identification at the site.  Refer to Section 11.1 for additional details regarding patient 
confidentiality. 
13.8 
AUDITS AND INSPECTIONS 
Source data/documents must be available to inspections by Oncopeptides AB or designee or 
Health Authorities. 
13.9 
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. 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
14 
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 IEC at the 
study site should be informed according to local regulations. 


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14.1 
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, and the IEC before it may be implemented.  Only amendments that are required for 
patient safety may be implemented prior to IEC approval.  
 
 


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15 
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Dimopoulos M, Sonneveld P, Leung N, et al. International Myeloma Working Group 
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Huang ZQ, Sanders PW: Biochemical interaction between Tamm-Horsfall glycoprotein and 
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Kastritis E, Terpos E, Dimopoulos MA: Current treatments for renal failure due to multiple 
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181. 
Kumar S, Rajkumar SV, Dispenzieri A, et al.  Improved Survival in Multiple Myeloma and 
the Impact of Novel Therapies. Blood. 2008; 111(5):2516-2520. 
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Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma. The 
Lancet Oncology. 2016; 17(8):e328-e346 
Leung N, Gertz M, Kyle RA, et al: Urinary albumin excretion patterns of patients with cast 
nephropathy and other monoclonal gammopathy related kidney diseases. Clin J Am Soc 
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Levey A, Stevens L, Schmid C et al.  A new equation to estimate glomerular filtration rate.  
Ann Intern Med. 2009; 150(9):604-612. 
Levey A, Inker L.  Assessment of Glomerular Filtration Rate in Health and Disease: A State 
of the Art Review. Clin Pharmacol Ther. 2017; 102(3):405-419. 
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and new CKD-EPI formulas in relation to GFR, age, and body size. Clin J Am Soc Nephrol. 
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Over a 24-hour Period, in Patients with Advanced Malignancies. Cancer Chemother 
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Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6):649-655. 
Osterborg A, Ehrsson H, Eksborg S, et al. Pharmacokinetics of oral melphalan in relation to 
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and Dexamethasone in Combination for Patients with Relapsed and Relapsed-Refractory 
Multiple Myeloma (RRMM).  Blood. 2014; 124(21):2123. 
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Multiple Myeloma: A Report from International Myeloma Working Group. Journal of 
Clinical Oncology. 2015; 33:26, 2863-2869  
Palumbo A, Magarotto V, Sonneveld P, et al. Final Phase 2 Study Data of Melflufen and 
Dexamethasone for Patients with Relapsed-Refractory Multiple Myeloma (RRMM) EHA 
2016. Abstract P281.   
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Improved Progression Free Survival (PFS) in a Completed Phase 2a Study of Melflufen in 
Advanced Relapsed Refractory Multiple Myeloma (RRMM) Blood. 2017; 130:3150. 
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Uniform Reporting of Clinical Trials: Report of the International Myeloma Workshop 
Consensus Panel 1.  Blood. 2011; 117(18):4691-4695. 
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Prior Lines of Therapy in Multiple Myeloma.  Blood. 2015; 126:921-922. 
Ray A, Ravillah D,1, Das D, et al. A novel alkylating agent Melﬂufen induces irreversible 
DNA damage and cytotoxicity in multiple myeloma cells. British Journal of Haematology, 
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Sengul S, Zwizinski C, Simon EE, et al: Endocytosis of light chains induces cytokines 
through activation of NF-kappaB in human proximal tubule cells. Kidney Int. 2002; 62:1977-
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high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 
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Sweiss K et al. Melphalan 200 mg/m2 in patients with renal impairment is associated with 
increased short-term toxicity but improved response and longer treatment free survival. Bone 
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Tsakiris DJ, Stel VS, Finne P, et al: Incidence and outcome of patients starting renal 
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deposit disease: An ERAEDTA Registry study. Nephrol Dial Transplant. 2010; 25:1200-
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Wickström M, Johnsen JI, Ponthan F, et al. The Novel Melphalan Prodrug J1 Inhibits 
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16 
APPENDICES 
Appendix A.  Eastern Cooperative Oncology Group (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 
  Source: Oken MM, et al. 1982.   
 
 
 
 
Appendix B.  National Cancer Institute 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 Uniform Response Criteria  
 
Response 
IMWG criteria (Rajkumar 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, 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 measurable, > 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  
(MR) 
EBMT 
Criteria 
•  ≥ 25% but ≤ 49% reduction of serum M protein and reduction in 
24-hour urine M protein by 50 – 89%, which still exceeds 200 
mg/24 hours. 
• In addition to above; if present at baseline, 25-49% reduction in 
the size of soft tissue plasmacytomas is also required 


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• No increase in size or number of lytic bone lesions (development 
of compression fractures does not exclude response) 
Stable 
Disease (SD) 
• Not meeting criteria for CR, VGPR, PR, MR or progressive 
disease 
Progressive 
Disease 
(PD) 
Increase of > 25% from lowest response value in any one or more of the 
following: 
• Serum M-component (the absolute increase must be > 0.5 g/dL) 
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 
levels 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; all response 
categories and SD 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 ≥ 0.5 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, 2011, Rajkumar 2015), a line of therapy consists of at least 1 or more cycles of a 
planned treatment regimen.  This may consist of single-agent or combination therapy or a 
sequence of treatments administered in a planned manner.   For example, a planned induction, 
followed by ASCT followed by maintenance is considered one line of therapy.  A new line of 
therapy starts when a planned course is modified to include other treatment agents as a result 
of progression, relapse or toxicity or when a planned period of observation is interrupted by 
the need for additional treatment of the disease.    
Modification of drug doses or resuming therapy after holding will not be considered a new 
line of therapy provided that there was no evidence of progression of disease as defined in the 
IMWG-URC. 
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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Protocol: Version 6.0: April 30, 2021 
Appendix E.  Definition of Relapsed 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/ 
 
 
Appendix G.  Estimated Glomerular Filtration Rate (eGFR) by  CKD-EPI equation 
CKD-EPI equation calculator:  
An online calculator for estimating eGFR may be accessed at the following link: 
 
https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr 
 
CKD-EPI equation: 
 
GFR = 141 * min(Scr/κ,1)α * max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if 
black] 
 
*Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for 


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Protocol: Version 6.0: April 30, 2021 
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, et al 2017) 
 
Appendix H.  Assessment of QTC Interval  
QTc Fridericia Formula  
 
 
 
(Fridericia, 1920) 
 
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 (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 
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 of III 
Stage III 
ISS stage III and either high risk CA by iFISH or 
high LDH 
(Palumbo et al. 2015) 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Version 2.0, 20 July 2021 
 
Protocol OP-107 
 
Protocol Title: A Study of the Pharmacokinetics of Melphalan During Treatment 
with Melflufen and Dexamethasone in Patients with Relapsed Refractory Multiple 
Myeloma and Impaired Renal Function 
 
 
National Clinical Trial number: NCT03639610 


Oncopeptides AB 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL OP-107 
 
A Study of the Pharmacokinetics of Melphalan During Treatment with Melflufen and 
Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma and Impaired Renal 
Function  
 
 
 
 
Protocol code:  
OP-107 
SAP Version:  
FINAL v2.0 
SAP Date:  
20JUL2021 
Author:  
 Senior Statistician, PSI CRO 
 
 
 


Statistical Analysis Plan: OP-107 
Review Status: FINAL 
 
Version: 2.0 
 
Version Date: 20JUL2021 
 
 
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DOCUMENT HISTORY 
VERSION HISTORY 
Version # 
Version Date 
V1.0 
21APR2021 
V2.0 
20JUL2021 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
V1.0 
N/A 
Initial release 
N/A 
V2.0 
7.9.3 
Laboratory 
Data 
Added “Lipegfilgrastim” in the 
list of coded preferred term for 
defining G-CSF for analysis. 
The coded preferred term, 
“Lipegfilgrastim” should be 
considered G-CSF for analysis. 
 
 
Added eGFR for analysis using 
toxicity grades. 
This is to summarize eGFR 
toxicity grade data available. 
 
7.9.2 Adverse 
Events 
Remove the clause regarding 
death before the start of 
subsequent anticancer 
treatment for the summary of 
death. 
This is to summarize all death 
in a table regardless of the 
timing of the subsequent 
anticancer treatment started. 
 
7.9.7 Chest 
x-ray 
Added a section of chest x-ray.  This is to document chest x-ray 
data by a listing. 
 
 
 
 


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APPROVAL SIGNATURES 
STUDY TITLE: A Study of the Pharmacokinetics of Melphalan During Treatment with 
Melflufen and Dexamethasone in Patients with Relapsed Refractory Multiple Myeloma and 
Impaired Renal Function 
 
 
PROTOCOL NUMBER: OP-107 v.5.0. (Amendment 4 dated January 22, 2021) 
SAP FINAL v2.0, July 20, 2021 
 
PSI 
Author: 
 Senior Statistician 
Signature: 
................................................................ 
Date: ...................... 
 
Peer-reviewer Statistician: 
 Senior Group Leader Biostatistics 
Signature: 
............................................................... 
Date: ...................... 
 
Project Manager: 
 
Signature: 
................................................................ 
Date: ...................... 
 
Medical Writer: 
 
Signature: 
........... .................................................... 
Date: ...................... 
 
Oncopeptides AB 
Study Statistician: 
 
Signature: 
................................................................ 
Date: ...................... 
 
Clinical Study Physician:  
 
Signature: 
................................................................ 
Date: ...................... 
 
Head of Clinical Pharmacology and Translational Science: 
 
Signature: 
................................................................ 
Date: ...................... 
 


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TABLE OF CONTENTS 
 
Contents 
LIST OF ABBREVIATIONS ....................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................................. 8 
2. 
STUDY OBJECTIVE ....................................................................................................... 8 
2.1 
Primary Objectives ...................................................................................................... 8 
2.2 
Secondary Objectives ................................................................................................. 8 
2.3 
Exploratory Objectives ................................................................................................ 9 
3. 
STUDY DESCRIPTION .................................................................................................... 9 
3.1 
Study Design .............................................................................................................. 9 
3.2 
Study Treatment ......................................................................................................... 9 
3.3 
Data and Safety Monitoring Committee ...................................................................... 10 
4. 
SAMPLE SIZE AND POWER CALCULATION ................................................................. 11 
5. 
ANALYSIS ENDPOINTS ................................................................................................ 11 
5.1 
Primary Endpoints .................................................................................................... 11 
5.2 
Secondary Endpoints ................................................................................................ 11 
5.3 
Exploratory Endpoints ............................................................................................... 11 
6. 
ANALYSIS POPULATIONS ........................................................................................... 12 
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS ....................................................... 12 
7.1 
General Conventions and Statistical Considerations ................................................... 12 
7.2 
Definition of Baseline, Study Visits, and Visit Windows ................................................ 13 
7.3 
Handling of Missing Data ........................................................................................... 14 
7.4 
Patient Disposition .................................................................................................... 16 
7.5 
Protocol Deviations ................................................................................................... 17 
7.6 
Patient Characteristics .............................................................................................. 17 
7.6.1 
Baseline and Demographic Characteristics ....................................................... 17 
7.6.2 
Medical History and Current Medical Conditions ............................................... 17 
7.6.3 
Multiple Myeloma Disease History ..................................................................... 17 
7.6.4 
Prior MM Therapies ............................................................................................ 21 
7.6.5 
Prior and Concomitant Medication ..................................................................... 23 
7.7 
Pharmacokinetics Analysis ........................................................................................ 24 
7.8 
Efficacy Endpoints and Analysis ................................................................................ 27 
7.8.1 
Response Rates ................................................................................................. 27 
7.8.2 
Time to Event Parameters ................................................................................. 28 
7.8.3 
Efficacy Assessments ........................................................................................ 30 
7.9 
Safety Endpoints and Analysis ................................................................................... 31 
7.9.1 
Exposure to Study Treatment ............................................................................ 31 
7.9.2 
Adverse Events .................................................................................................. 32 
7.9.3 
Laboratory Data ................................................................................................. 35 
7.9.4 
Vital Signs .......................................................................................................... 37 
7.9.5 
Physical Examination ......................................................................................... 38 


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7.9.6 
12-lead Electrocardiogram (ECG) ...................................................................... 38 
7.9.7 
Chest X-Ray ....................................................................................................... 38 
7.10 Other Endpoints and Analysis .................................................................................... 38 
7.10.1 
ECOG ................................................................................................................. 38 
7.10.2 
eGFR .................................................................................................................. 38 
8. 
INTERIM ANALYSIS ..................................................................................................... 39 
9. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE PROTOCOL ............................. 39 
10. 
PROGRAMMING SPECIFICATION ................................................................................. 39 
11. 
REFERENCES ............................................................................................................. 39 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under curve 
AUC(0-∞) 
area under the concentration-time profile from 0 hours to infinity 
AUC(0-t) 
area under the concentration-time profile from 0 hours to the last 
measurable concentration 
CB 
clinical benefit 
CBR 
clinical benefit rate 
CKD-EPI 
chronic kidney disease epidemiology collaboration 
CI 
confidence interval 
cm 
centimeters 
CR 
complete response 
CTCAE 
common terminology criteria for adverse events 
CV% 
coefficient of variation 
DOCB 
duration of clinical benefit 
DOR 
duration of response 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EMD 
extramedullary disease 
EOT 
end of treatment 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 
ICH 
International Council for Harmonisation 
IFE 
immunofixation  
Ig 
immunoglobulin 
IMiD 
immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
ISS 
International Staging System 
K-M 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
mAb 
monoclonal antibodies 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
ml 
milliliter 
MM 
multiple myeloma 


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MR 
minimal response 
NCA 
non-compartmental analysis 
NCI 
 
National Cancer Institute 
NDA 
New drug application 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
F-U 
follow-up 
PI 
proteasome inhibitor 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred Term 
R-ISS 
revised international staging system 
RRMM 
relapsed refractory multiple myeloma 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
S-Cr 
serum creatinine 
SD 
standard deviation; stable disease (depending on context)  
SDG 
standardized drug groupings 
SDTM 
study data tabulation model 
SFLC 
serum free light chain 
SMQ 
standardized MedDRA query 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
t½ 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TTR 
time to response 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
WBC 
white blood cells 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
 


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1. 
INTRODUCTION 
 
This statistical analysis plan (SAP) describes the statistical analysis and reporting for the study 
protocol OP-107 v.5.0. (Amendment 4 dated January 22, 2021) entitled; A Study of the 
Pharmacokinetics of Melphalan During Treatment with Melflufen and Dexamethasone in Patients 
with Relapsed Refractory Multiple Myeloma and Impaired Renal Function. The purpose of the 
plan is to outline the types of analyses and data presentations that will address the study objectives 
outlined in the protocol, and to explain in detail how the data will be handled and analyzed, 
adhering to commonly accepted standards and practices of biostatistical analysis in the 
pharmaceutical industry. If the protocol is amended, this SAP will be revised as required. The plan 
will be finalized before the study database is locked. 
The statistical principles applied in the design and planned analyses of this study are consistent 
with International Council for Harmonisation (ICH) guidelines E9 (Statistical Principles for 
Clinical Trials). 
This SAP does not include the description of the population pharmacokinetic (PK) modeling 
analysis, which is described in a separate analysis plan. 
 
2. 
STUDY OBJECTIVE 
2.1 
PRIMARY OBJECTIVES 
 
 To evaluate the relationship between renal function and the PK parameters for melphalan 
during treatment with melflufen  
 To assess the safety and tolerability of melflufen in patients with moderate (Cohort 1a and 
1b) and severe (Cohort 2a and 2b) renal impairment 
 
2.2 
SECONDARY OBJECTIVES 
 
 To assess the best tumor response as well as overall response rate (ORR) 
 To assess the progression free survival (PFS) 
 To assess duration of response (DOR) in patients with ≥ partial response (PR) (stringent 
complete response (sCR), complete response (CR), very good partial response (VGPR), 
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 To assess clinical benefit rate (CBR) and duration of clinical benefit (DOCB) (i.e., 
proportion of patients with ≥ minimal response (MR)) as best response  
 To assess time to response (TTR) in patients with a PR or better and time to clinical benefit 
(CB) for patients with MR or better 
 Overall Survival (OS) 
 
2.3 
EXPLORATORY OBJECTIVES 
 
 To assess changes in renal function 
 
3. 
STUDY DESCRIPTION 
3.1 
STUDY DESIGN 
 
This multicenter study will enroll patients with relapsed refractory multiple myeloma (RRMM) 
following 2-4 lines of prior therapy.  
Patients will be treated with melflufen 10-40 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 reduced dose of 
dexamethasone of 20 mg on Days 1, 8, 15 and 22.  
 
3.2 
STUDY TREATMENT 
 
There are four Cohorts in the study: 1a, 1b, 2a and 2b. 
 Cohort 1a (estimated glomerular filtration rate [eGFR] of ≥ 30 ml/min to < 45 ml/min): 
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. 
Following approval of Amendment 2, Cohort 1a will close for enrollment and Cohort 1b will open 
for a minimum of 6 additional patients. 
 Cohort 1b (eGFR of ≥ 30 ml/min to < 45 ml/min): Patients will be treated with Melflufen 
30 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. 
Cohort 2a will only open if recommended by Data Safety Monitoring Committee (DSMC) after 
evaluating data from Cohort 1a and 1b. 


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 Cohort 2a (eGFR of ≥ 15 ml/min to < 30 ml/min): Patients will be treated with melflufen 
20 mg (recommended dose by DSMC) on Day 1 and dexamethasone 40 mg on Days 1, 8, 
15 and 22 of each 28-day cycle. 
Cohort 2b will only open if recommended by DSMC after evaluating data from Cohort 1a, 1b and 
2a. 
 Cohort 2b (eGFR of ≥ 15 ml/min to < 30 ml/min): Patients will be treated with melflufen 
30 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 reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 
and 22. Patients will be assessed for response after each cycle according to the International 
Myeloma Working Group Uniform Response Criteria (IMWG-URC) (Rajkumar, 2011). Patients 
may continue treatment until there is documented disease progression, unacceptable toxicity or the 
patient/treating physician determines 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.  In the event of a cycle delay, unrelated to dexamethasone toxicity, it is 
recommended to continue dexamethasone weekly. 
 
3.3 
DATA AND SAFETY MONITORING COMMITTEE  
 
An independent DSMC will perform surveillance of efficacy/safety balance at regular intervals 
and on as needed basis during the study and assess the benefit/risk profile of the study, to safeguard 
the interest of study participants. The DSMC will consist of lead CRO global medical monitor 
investigator and Sponsor representative(s) and headed by an independent chairperson.  
All reported grade 3-4 treatment-related non-hematological adverse events (AEs), as well as all 
serious adverse events (SAEs), and any treatment-related deaths due to hematologic or non-
hematologic AEs, as well as efficacy and PK data will then be presented to the DSMC.   
Cohort 2 will only be initiated following DSMC review of the PK and safety profile of at least 6 
patients in Cohort 1. If the DSMC advises to proceed with Cohort 2, at least 6 patients with eGFR 
≥ 15 ml/min to < 30 ml/min will be enrolled and analyzed for safety and PK data. The DSMC will 
advise if Cohort 2 should continue as planned. Cohort 2 will have two parts, Cohort 2a and 2b. 
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the DSMC may advise if a higher starting dose (Cohort 2b, 30 mg melflufen) should be 
investigated. 
If the DSMC considers the benefit/risk profile different from previous knowledge of efficacy and 
safety the DSMC may recommend change to the protocol, additional safety monitoring or stopping 
further recruitment. 
All activities and processes surrounding the DSMC will be outlined in the DSMC charter. 
 
4. 
SAMPLE SIZE AND POWER CALCULATION 
 
Enrollment of approximately 35 PK evaluable patients is considered sufficient for a reliable 
assessment of the PK parameters, at least 6 patients per cohort.  
 
5. 
ANALYSIS ENDPOINTS 
5.1 
PRIMARY ENDPOINTS 
 
 PK parameters of melphalan  
 Frequency and grade of AE’s 
 
5.2 
SECONDARY ENDPOINTS 
 
 ORR 
 CBR 
 PFS 
 DOR   
 DOCB 
 TTR 
 Best response during the study (sCR, CR, VGPR, PR, MR, stable disease (SD) or 
progressive disease (PD)) 
 OS 
 
5.3 
EXPLORATORY ENDPOINTS  
 


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 Renal function: The level of eGFR determined at baseline and the start of each cycle 
 
6. 
ANALYSIS POPULATIONS 
 
Safety Analysis Set 
The safety analysis set is defined as all patients who received at least one or partial dose of 
melflufen or dexamethasone. The safety analysis set will be the primary population for the 
summaries of all exposure, efficacy and safety data. Demographics and disposition data will also 
be summarized based on the safety analysis set. 
All listings will be presented based on the safety analysis set. 
 
PK Analysis Set 
All patients that have received at least one melflufen dose and have sufficient PK samples taken 
after this infusion (three samples as scheduled post-infusion), i.e. patients with at least one 
treatment cycle with three measurable melphalan concentrations within the same cycle. 
This analysis set will be used for the PK analysis. 
 
Efficacy Analysis Set 
All patients that complete 2 doses of melflufen and have relevant baseline and follow-up disease 
assessments after the second dose of melflufen.  This analysis set will be used for sensitivity 
analysis of all the efficacy parameters.  
Relevant disease assessments: Serum protein electrophoresis (SPEP), urine protein electrophoresis 
(UPEP), serum free light chain (SFLC), and immunofixation (IFE) in serum and urine. 
Note: All of these relevant lab parameters at different timepoints will be considered for follow-up 
disease assessments as long as taken after the second dose of melflufen.  
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS 
7.1 
GENERAL CONVENTIONS AND STATISTICAL CONSIDERATIONS 
 
All statistical analyses will be performed using SAS statistical analysis software (SAS, 
SAS/GRAPH and SAS/STAT; version 9.4 or higher of SAS for Windows [SAS Institute Inc.; 
Cary, NC, USA]).  


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Descriptive statistics for continuous variables will include the number of patients with non-missing 
data (n), arithmetic mean, standard deviation (SD), median, minimum and maximum. Summary 
statistics for categorical variables will contain count and percentage based on the number of 
patients in the selected analysis population. Percentages will be presented to one decimal, except 
for zero and one hundred percent, which will be presented as 0% and 100% respectively.  
For descriptive statistics of continuous variables, the accuracy of the minimum and maximum and 
should match the original data, for the mean and median one more decimal point in addition to the 
original data will be presented, and for SD two more decimal points in addition to the original data 
will be presented. For the derived variables (e.g., time since diagnosis) minimum and maximum 
will be presented with one decimal after point; mean, median and SD will be applied following 
the rule above. Presented decimal places should however not be greater than 4. 
For PK descriptive statistics significant figures will be used for precision: mean, geometric mean 
and median values are shown with 4 significant figures, and standard deviation and CV% with 3 
significant figures. 
Any data categorization will be done based on the original data, before rounding is applied. 
Unless otherwise specified, the denominators for the percentages will be based on the number of 
patients with non-missing data in the population used in each column. For the summaries presented 
by time points, the denominator will be the number of patients with non-missing data at each time 
point. A “missing” category will be included for any parameter for which information is missing, 
without a percentage. 
By default the data collected in the electronic case report form (eCRF) and by external vendors 
will be used for analysis unless it is specified that additional derivation is required. 
There will be no formal statistical analysis in this study. Results will be presented using descriptive 
statistics by cohort (Cohort 1a, Cohort 1b, Cohort 2a and Cohort 2b) and overall. 
For treated patients all data collected will be presented in the listings. Some derived parameters 
will also be presented in the listings: i.e. derived international staging system (ISS) and revised 
international staging system (R-ISS), cytogenetics abnormalities risk-level, best confirmed 
response during the study, and PK parameters.  
 
7.2 
DEFINITION OF BASELINE, STUDY VISITS, AND VISIT WINDOWS 
 


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In general the baseline is the last available assessment prior to the first dose of study drug (the 
earliest of melflufen and dexamethasone start date). 
Where assessments are made on the day of first treatment and the time is available for comparison, 
the time should be used to recognize whether or not the assessment was prior to the first treatment 
and thus should be used as a baseline.  If only the date is in place and time is not available, for 
assessments on the day of first treatment that are per protocol scheduled to take place prior to 
treatment, it will be assumed that the assessment is pre-dose, and is a valid baseline assessment. 
Refer to the protocol for the study visit schedule. 
Note that for this study there is no study day 0, so the day immediately prior to study day 1 is study 
day -1. For any events on or after the first dose of study drug, study day is calculated as: event date 
– date of first administration of study treatment + 1. As such, the first dose date was study day 1.  
For any events before the first dose date, study day is calculated as: event date – date of first 
administration of study treatment. As such, one day before first dose date was study day -1.  
Because unscheduled assessments are not associated with any scheduled time point, they are 
excluded from all summaries by time point. Unscheduled visits will be considered for the baseline 
values derivations.  Unscheduled assessments will be considered when deriving myeloma response 
parameters as described in the Section 7.7 and for analysis of laboratory parameters by worst 
toxicity grade as specified in the Section 7.8.3 of this SAP. All unscheduled assessments will be 
presented in the respective listings. 
The data will be analyzed according to the visits recorded in the eCRF and no analysis windows 
will be applied. 
7.3 
HANDLING OF MISSING DATA 
 
If only a partial date is available and is required for a calculation (e.g., time since diagnosis, time 
since most recent relapse, determination of whether a medication is concomitant or an AE is 
treatment-emergent), the following standards will be applied: 
 Start dates (e.g., AE onset date or start date of medication, date of diagnosis, date of 
relapse). For missing start day only - day will be imputed as the first day of the month (i.e., 
1) with the following exception: if the partial date falls in the same month and year as the 
date being used in the calculation (e.g., first dose date, informed consent date), then the 


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partial date will be imputed to equal the date being used for the calculation, unless there is 
a complete end date which is earlier. 
 For missing start day and month - day and month will be imputed as the first day of the 
year (i.e., 01 January) with the following exception: if the partial date falls in the same year 
as the date being used in the calculation (e.g., first dose date, informed consent date), then 
the partial date will be imputed to equal the date being used for the calculation, unless there 
is a complete end date which is earlier. 
 Stop dates (e.g., AE resolution date or stop date of medication). For missing stop day only 
- day will be imputed as the last day of the month (i.e., 28, 29, 30, or 31). 
 For missing stop day and month - day and month will be imputed as the last day of the year 
(i.e., 31 December). 
 
Any partial dates will be displayed in data listings without imputation of missing days and/or 
months (e.g., MAR2011, 2009).  
In case of incomplete date of relapse, for the purpose of calculation of the time since most recent 
relapse, the rules mentioned above for the partial start date will be used. However, for the date of 
frontline transplant in calculation of time since frontline transplant   to relapse and for the date of 
relapse in derivation of refractory status, the simplified approach of assigning first day of a month 
in case of missing day and 01 January in case of missing month and day will be used.  This simple 
approach will be also applied to impute the partial date of relapse in the calculation of time since 
the frontline transplant to relapse with the following exception in order to avoid yielding a negative 
duration due to imputation: The partial date of relapse will be imputed to the date of frontline 
transplant in case the partial date falls in the same month and year (if only day is missing) or in the 
same year (if day and month are missing). 
If time is not available but is required for a calculation (e.g., timing of AE vs study drug 
administration), the most conservative approach should be used, i.e. assuming that the time of AE 
was after study drug administration or that the time of concomitant medication was after AE. 
AEs with missing relationship are considered related for the purposes of summaries. In case of 
multiple cases, the information regarding the number of imputed relationships will be provided in 
the footnote of the respective summaries. 
AEs with missing severity are considered severe (grade 3) for the purposes of summaries. Imputed 


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relationship and severity will not be included in the listings. 
eGFR will be derived using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula (See Section 7.6.3) if eGFR is not reported but serum creatinine is available for the 
corresponding visit. 
The handling of dropouts and missing disease status assessments for the efficacy variables is 
described in their definitions in the relevant sections.   
7.4 
PATIENT DISPOSITION 
 
Disposition summary will be based on the safety analysis set and presented by cohort and overall. 
The disposition of patients includes: 
 Number (%) of patients in safety, PK and efficacy analysis sets 
 Number (%) of patients permanently discontinued from the treatment along with the 
primary reasons for permanent treatment discontinuation 
 Number (%) of death reported up to the end of treatment visit  
 Number (%) of patients who had PFS follow-up (F-U) and by the following categories 
using counts and percentages based on the number of patients who had PFS F-U 
o Progressive disease (PD) and confirmed PD 
o Diagnosed with a second primary malignancy 
o Started subsequent therapy  
 Number (%) of patients who had OS F-U and by the following categories using counts and 
percentages based on the number of patients who had OS F-U 
o Diagnosed with a second primary malignancy 
o Started subsequent therapy 
o Survival status at the last OS-FU 
 Number (%) of patients discontinued from the study and reasons for study discontinuation 
Treatment discontinuations due to AE specific to COVID-19 or other pandemic-related reasons 
will be presented separately. 
All patient disposition information will be presented in the respective listings.  
 


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7.5 
PROTOCOL DEVIATIONS 
 
Major protocol deviations will be summarized by the deviation type for the safety analysis set by 
cohort and overall. All protocol deviations will also be provided in a listing. Separate listings for 
major protocol deviations, COVID-19 pandemic-related protocol deviations, and major COVID-
19 pandemic-related protocol deviations will also be provided. 
7.6 
PATIENT CHARACTERISTICS 
7.6.1 BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
 
The following demographic and baseline characteristics will be summarized descriptively for the 
safety analysis set by cohort and overall: 
 Age (years) 
 Age categories (<65, ≥ 65 to ≤75, >75) 
 Sex 
 Race 
 Ethnicity 
 Baseline fertility status 
 Baseline height (cm) 
 Baseline weight (kg) 
 Baseline Eastern Cooperative Oncology Group (ECOG) performance status 
A listing will be provided for patient’s demographic and baseline characteristics. 
Separate listings will be provided for pregnancy test and ECOG results.  
7.6.2 MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
 
Medical history will be summarized by Medical Dictionary of Regulatory Activities (MedDRA) 
(version 24.0 or higher), System Organ Class (SOC) and preferred term (PT) using number (n) and 
percentage (%) of patients having at least one occurrence of a disease for the safety analysis set by 
cohort and overall. Any medical history of COVID-19 will be presented as separate PTs specific 
to COVID-19 or SARS-CoV-2. 
A listing will be provided for patient medical history. 
7.6.3 MULTIPLE MYELOMA DISEASE HISTORY 
 
The following disease characteristics at diagnosis will be summarized descriptively for the safety 
analysis set by cohort and overall: 


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 Stage of disease (ISS and R-ISS) 
 Heavy chain and light chain subtypes 
 Evidence of lytic bone disease 
 Evidence of extramedullary disease (EMD) 
 
The following disease characteristics at baseline/study entry will be summarized descriptively for 
the safety analysis set by cohort and overall: 
 Stage of disease (ISS and R-ISS), eCRF reported and derived (see Table 1.) 
 Heavy chain and light chain subtypes 
 Evidence of lytic bone disease 
 Evidence of EMD 
 Disease status 
 Time since diagnosis in years (calculated as [date of first dose of study drugs (the earliest 
of melflufen and dexamethasone first dose) – date of diagnosis+1]/365.25). Partial dates 
will be imputed according to the section 7.3 of this SAP 
 Time since most recent relapse/progression in months (calculated as [date of first dose of 
study drugs (the earliest of melflufen and dexamethasone first dose)  – date of most 
recent relapse/progression+1]/30.4375) 
 Baseline SPEP, UPEP, kappa/lambda values; For descriptive statistics, in case of the 
second SPEP value being available as >0 g/L, the SPEP value will be derived as follows; 
Otherwise, in case of the second SPEP value being 0 g/L or not available, descriptive 
statistics will be produced without considering the second SPEP. 
o If there are more than one heavy chain subtypes (IgG, IgA, IgD, IgE, IgM) at 
study entry, the worst/higher values between the two available SPEP values will 
be used for descriptive statistics. 
o 
If there is only one heavy chain subtype (IgG, IgA, IgD, IgE, IgM) at study entry, 
the sum of the two available SPEP values will be used for descriptive statistics.  
 Baseline maximum bone marrow plasma cells involvement (%) as values and by 
categories (<30%, ≥30 to <60%, ≥60%) (Note: The maximum bone marrow plasma cells 
involvement will be defined as the highest value amongst any of the available test results 
from the following bone marrow lab parameters: plasma cells ratio from bone marrow 
test, immature plasma cells/total cells based on bone marrow biopsy test or bone marrow 
aspiration/differential test.) 
 Laboratory assessments 
o Baseline β2 microglobulin (mg/L) as continuous values and categories (< 3.5, ≥3.5 to 
≤5.5 and > 5.5) 


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o Baseline platelet count (10^9/L) as continuous values and categories (<75, ≥75 to ≤ 
100, >100 to ≤ 150, >150) 
o Baseline absolute neutrophil count (ANC) (10^9/L) as continuous values and 
categories (<1.0, ≥1.0 to ≤1.5, and >1.5) 
o Baseline hemoglobin (g/L) as continuous values and categories (<80, ≥80 to ≤100, 
>100) 
o Baseline lactate dehydrogenase (LDH) (u/L) as continuous values and categories 
(<1.5xULN and ≥1.5xULN) 
o Baseline albumin (g/L) as continuous values and categories (<35, ≥35) 
o Baseline creatinine as continuous values 
o Baseline eGFR (mL/min/1.73m2) as continuous values and categories (< 15, ≥15 to 
<30 , ≥30 to <45, ≥45)  
o Screening eGFR (mL/min/1.73m2) as continuous values and categories (< 15, ≥15 to 
<30 , ≥30 to <45, ≥45) (Note: The latest available screening value (including 
unscheduled if available) will be used for analysis.) 
o Baseline corrected calcium as continuous values 
 
For patients for whom only creatinine clearance was calculated at baseline as a basis for 
enrolment values for renal function will be recalculated as eGFR using CKD-EPI formula: 
 
eGFR = 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. 
In addition to the above, ISS Stage and Revised ISS (R-ISS) Stage will be derived at study entry 
[Palumbo, 2015], (see Table 1). 
ISS will be derived from screening serum β2 microglobulin and screening albumin. This derived 
ISS will in turn be used with screening serum LDH and high-risk cytogenetics at study entry as 
defined by the R-ISS guidelines to derive R-ISS. Derived ISS and R-ISS will be referred as 
“Derived ISS” and “Derived R-ISS” respectively. (Note: This derivation will consider the latest 
available screening value for β2 microglobulin, albumin, and serum LDH (including 
unscheduled if available). 


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Table 1: Standard Risk Factors for MM and the Revised ISS (R-ISS)  
Standard Risk Factors for MM and the Revised -ISS (R-ISS)  
Prognostic Factor  
Criteria  
ISS Stage  
Stage I  Serum B2-microglobulin < 3.5 mg/L, serum albumin ≥ 3.5 g/dL  
Stage II  Not ISS stage I or III  
Stage III  Serum B2-microglobulin ≥ 5.5 mg/L  
Chromosomal abnormalities (CA) by interphase florescent in situ hybridization (iFISH)  
High-Risk  Presence of del(17p) and/or translocation of t(4:14) and/or translocation of t(14:16)  
Standard-Risk  No high-risk CA  
Lactate Dehydrogenase (LDH) 
Normal  Serum LDH =< upper limit of normal (ULN)  
High  Serum LDH > ULN  
A new model for risk stratification of MM R-ISS  
Stage I  ISS stage I and standard-risk CA by iFISH and normal LDH  
Stage II  Not R-ISS stage I or III  
Stage III  ISS stage III and either high-risk CA by iFISH or LDH  
 
A separate summary dedicated to cytogenetics investigations at diagnosis and study entry will be 
presented, including type of cytogenetic analysis (iFISH, karyotype), and the number and 
percentage of patients having particular types of cytogenetic abnormalities. Cytogenetics 
abnormalities at study entry will also be pooled by risk level (high-risk, standard-risk and 
unknown) as follows depending on the type of cytogenetic analysis:  
 High-risk based on iFISH is defined in case the following abnormalities were found: 
deletion (17p), gain 1q (+1q), gain (1q21); t (4;14), t(4;14) (p16;q32), t (14;16), t (14;16) 
(q32;q23), t(14;20), t(14;20) (q32;q11).  
 Standard-risk based on iFISH consists of patients who have a genetic subtype recorded but 
none of the genetic subtypes categorized as high-risk based on iFISH. 
 Unknown: consists of patients for whom the iFISH procedure was not done or unevaluable. 
 High-risk based on karyotype is defined in case the following abnormalities were found: 
deletion (13) or deletion (13q).  
 Standard-risk based on karyotype consists of patients who have a genetic subtype recorded 
but none of the genetic subtypes categorized as high-risk based on karyotype. 


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 Unknown: consists of patients for whom the karyotype procedure was not done or 
unevaluable. 
Bone lesion assessments at screening will be analyzed descriptively with the number and percent 
of patients, including the number and percent of patients for whom skeletal survey was performed, 
method of skeletal survey, result of exam, bone lesions locations. The same information will be 
presented for the other imaging procedures. 
Listings will be provided for MM history, bone lesion assessments and bone marrow aspirate. 
 
7.6.4 PRIOR MM THERAPIES 
 
The following information related to prior MM therapies will be summarized for the safety 
analysis set by cohort and overall: 
 Number and percentage of patients who had a transplant. 
 Number of patients who had a salvage transplant (defined as any transplant where the 
patient has already had one or more transplants in earlier lines). Planned tandem autologous 
or autologous-allogeneic are considered as one transplant. 
 Frontline transplant type (allogeneic or autologous); Frontline transplant is the first 
transplant per patient irrespective in which therapy line it was applied. The number and 
percentage of patients having frontline transplant per prior therapy line will be presented.  
 Number and percentage of patients with the tandem transplant.  
 Number and percentage of patients with at least one prior autologous transplant, and 
number and percentage of patients with two or more prior autologous transplants 
 Number of prior autologous transplants 
 Time from frontline transplant to the earliest relapse following frontline transplant (not 
necessarily after the prior therapy line when frontline transplant occurred) in years (as 
continuous variable as well as per categories < 1 year, ≥1 year to <1.5 years, ≥1.5 years to 
≤2 years, >2 years; To be calculated as [date of earliest relapse following the frontline 
transplant – date of frontline transplant +1]/365.25. Partial dates will be imputed according 
to the section 7.3 of this SAP)  
 Number of prior systemic therapy lines 
 Best response to the last prior line of systemic therapy 


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 Refractory status to the last prior line of systemic therapy 
 Number and percentage of patients with any prior lines including: immunomodulatory 
drugs (IMiD’s), proteasome inhibitors (PI’s), alkylators,  anti-CD38 monoclonal antibodies 
(mAb), other mAb and others 
 Number and percentage of patients receiving any of above agents in the last prior line. 
 The number and percentage of patients refractory to any of the above agents in at least one 
prior regimen 
  The number and percentages patients refractory to any of the above agents in the last prior 
line 
 Number and percentage of patients who received IMiD and PI (double-class) in any of 
prior lines of therapies  
 Number and percentage of patients, double refractory to PI and IMiD in any of prior lines 
of therapies);  
 Number and percentage of patients who received IMiD, PI, and anti-CD38 mAb (triple-
class) in any of prior lines of therapies 
 Number and percentage of patients, that are refractory and/or intolerant to a PI, an IMiD, 
and an Anti-CD38 mAb (Triple class refractory) in any of prior lines of therapies. 
Intolerance is defined when a patient stopped treatment due to toxicity, and as well as did 
not receive a drug in the same therapeutic drug class again prior to entering the current 
study.   
 Number and percentage of patients with prior radiotherapy 
The next list of drugs is associated with each drug class using World Health Organization Drug 
Dictionary (WHODD) version March 2021 or higher: 
 IMiD is defined as WHODD Standardized Drug Groupings (SDG) “Antineoplastic 
thalidomide analogues”  
 PI is defined as WHODD SDG “Antineoplastic proteasome inhibitors” 
 Alkylators is defined as WHODD SDG “Antineoplastic alkylating drugs” 
 Anti-CD38 mAb is defined as WHODD SDG “Antineoplastic CD38 antigen inhibitors” 
 Other mAb is defined as WHODD SDG “Monoclonal antibodies – antineoplastics” 
excluding SDG “Antineoplastic CD38 antigen inhibitors” 


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 Other antineoplastic drugs for the treatment of MM will be referred to as ‘Other”. Will be 
identified by manual review of the drugs not included into the categories above. 
Refractory is defined as non-responsive disease (achieving SD or PD as the best response) while 
on therapy, or reason for termination was PD, or relapse/progression within 60 days after stop date 
of treatment.  A patient is to be deemed as refractory to a therapy line in case of refractory to at 
least one of the agents in the therapy line whereas a patient is deemed as non-refractory to a therapy 
line in case of non-refractory to all of agents in the therapy line. Otherwise, a patient’s refractory 
status to the therapy line will be considered unknown. 
All patient details of prior MM therapies will be presented in the respective listings. 
 
7.6.5 PRIOR AND CONCOMITANT MEDICATION 
 
All concomitant medications will be coded using the WHODD version March 2021 or higher.   
A medication is considered prior if stopped before the date of the first dose of study drug (the 
earliest of melflufen and dexamethasone start date). Concomitant medications are defined as 
medications with start date or end date on or after the date of first dose of study drug and start date 
within 30 days after the date of the last dose of study drug (the latest of melflufen and 
dexamethasone end date) or are ongoing at the time of first dose of study drug.   
The number and percentages of patients with at least one concomitant medication will be 
summarized by the Anatomical Therapeutic Chemical (ATC) class (ATC 2 and ATC 4) and 
preferred name. Summaries will be presented by safety analysis set by cohort and overall. Patients 
may have more than one medication per ATC class and preferred name.  At each level of patient 
summarization, a patient is counted once if he/she reported one or more medications at that level.  
The summaries will be ordered by descending frequency of ATC class and preferred name within 
each ATC class in the total group. Prior medications will be presented separately in the same way.  
Separate summaries will be provided for the number and percentage of patients with the following 
medication categories: “Haemapoetic growth factors” (WHODD SDG “Colony stimulating 
factors”) and by preferred terms, as well as “Transfusions” (including next PTs: “Platelets”, 
“Erythrocytes”). 
A listing of prior and concomitant medications will be provided. 
All prior and concomitant surgical/medical procedures performed within 21 days of study entry 
until the EOT visit will be listed. 


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7.7 
PHARMACOKINETICS ANALYSIS 
 
 
PK parameters will be calculated and provided by the Sponsor using Non-Compartmental Analysis 
(NCA) and the software Phoenix WinNonlin® version 8.2 or later (Certara L.P., U.S.A.). The 
following PK parameters will be assessed for melphalan. 
 
 Maximum drug concentration (Cmax) 
 
Cmax is defined as the maximum drug concentration observed in plasma per treatment cycles 
with PK sampling.  
 
 Time of maximum concentration (Tmax) 
 
Time of maximum plasma concentration (Tmax) is defined as the time at which the Cmax occurs.  
 
 Area under the concentration-time profile from 0 hours to the last measurable concentration 
(AUC(0-t)) 
 
AUC(0-t) is defined as the area under the concentration-time curve from start of dosing (time 0) 
to the time of the last measured concentration. AUC(0-t) will be estimated using the Linear Up 
Log Down calculation method. 
  
 Area under the concentration-time profile from 0 hours to infinity (AUC(0-∞)) 
 
AUC(0-∞) is defined as the total area under the concentration-time curve from start of infusion 
(time 0) to the limit as the end time becomes arbitrarily large.  
 
 Half-life (t½) 
 
The apparent t½ is defined as the time required for the drug concentration to decrease by a 
factor of one-half in the terminal phase. t½ will be estimated as ln(2) / Ke, Ke referring to 
terminal phase elimination rate constant of the apparent log-linear decrease as defined by 3 data 
points. 
 
Blood samples for PK analysis of melphalan concentrations in plasma, will be collected at the 
following time points: 


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Table 4. PK sampling schedule 
 
 
Cycle 1 and 2 
Sample 1, time point 
5-10 minutes after the end of 
melflufen infusion   
Sample 2, time point 
2-3 hour after the end of 
melflufen infusion 
Sample 3 time point 
5-7 hours after the end of 
melflufen infusion 
 
 
Date and time of sample collection or reason for not being collected will be recorded in the 
eCRF. Concentrations and corresponding PK parameters will be provided as external files and 
appended to the study database.  
Actual time points relative to start of melflufen infusion in minutes will be derived and used by 
the Pharmacokinetist for calculating parameters. Actual time in minutes will be calculated as 
datetime of blood sampling minus datetime of start of infusion.  
All PK parameters to be calculated for melphalan are listed in Table 5. The derivation of PK 
parameters is done by the Pharmacokineticist. All parameters will be presented in a listing in 
minimum.  
Table 5. PK parameters to be calculated 
Phoenix WinNonLin ID 
Unit 
Parameter code 
CDISC submission value 
Rsq 
R2 
R Squared 
Rsq_adjusted 
R2ADJ 
R Squared Adjusted 
Corr_XY 
CORRXY 
Correlation Between TimeX and Log ConcY 
No_points_lambda_z 
LAMZNPT 
Number of Points for Lambda z 
Lambda_z 
min 
LAMZ 
Lambda z 
Lambda_z_int 
ng/mL 
LAMZINT 
Lambda z Intercept  
Lambda_z_lower 
min 
LAMZLL 
Lambda z Lower Limit 
Lambda_z_upper 
min 
LAMZUL 
Lambda z Upper Limit 
Lambda_z_span 
min 
LAMZSPN 
Lambda z Span  
*HL_Lambda_z 
min 
LAMZHL 
Half-Life Lambda z 
*Tmax 
min 
TMAX 
Time of Cmax 
*Cmax 
ng/mL 
CMAX 
Max Conc 
Cmax_D 
ng/mL/mg 
CMAXD 
Max Conc Norm by Dose 


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Tlast 
min 
TLST 
Time of Last Nonzero Conc 
Clast 
ng/mL 
CLST 
Last Nonzero Conc 
Clast_pred 
ng/mL 
CLSTP 
Last Nonzero Conc Pred  
*AUClast 
min*ng/mL 
AUCLST 
AUC to Last Nonzero Conc 
AUClast_D 
min*ng/mL 
AUCLSTD 
AUC to Last Nonzero Conc Norm by Dose  
AUCall 
min*ng/mL 
AUCALL 
AUC All 
*AUCINF_obs 
min*ng/mL 
AUCIFO 
AUC Infinity Obs 
AUCINF_D_obs 
min*ng/mL/mg 
AUCIFOD 
AUC Infinity Obs Norm by Dose 
AUC_%Extrap_obs 
% 
AUCPEO 
AUC %Extrapolation Obs 
Vss_obs 
L 
VSSO 
Vol Dist Steady State Obs  
Vz_obs 
L 
VZO 
Vz Obs  
AUCINF_pred 
min*ng/mL 
AUCIFP 
AUC Infinity Pred 
AUCINF_D_pred 
min*ng/mL/mg 
AUCIFPD 
AUC Infinity Pred Norm by Dose 
AUC_%Extrap_pred 
% 
AUCPEP 
AUC %Extrapolation Pred 
Vss_pred 
L 
VSSP 
Vol Dist Steady State Pred  
Vz_pred 
L 
VZP 
Vz Pred  
Cl_pred 
L/min 
CLP 
Total CL Pred 
AUMClast 
min*min*ng/mL 
AUMCLST 
AUMC to Last Nonzero Conc 
AUMCINF_obs 
min*min*ng/mL 
AUMCIFO 
AUMC Infinity Obs 
AUMC_%Extrap_obs 
% 
AUMCPEO 
AUMC % Extrapolation Obs 
AUMCINF_pred 
min*min*ng/mL 
AUMCIFP 
AUMC Infinity Pred 
AUMC_%Extrap_pred 
% 
AUMCPEP 
AUMC % Extrapolation Pred 
MRTlast 
min 
MRTIVLST 
MRT Intravasc to Last Nonzero Conc 
MRTINF_obs 
min 
MRTIVIFO 
MRT Intravasc Infinity Obs 
 MRTINF_pred 
min 
MRTIVIFP 
MRT Intravasc Infinity Pred 
* Summarized with descriptive statistics as continuous variables and with the geometric mean and geometric coefficient of 
variation. 
 
Cmax and Tmax will be presented with the same number of decimals as the concentration 
measurements and time points, while the derived PK variables will be presented with an 
appropriate number of significant digits based on the general practice.  
It may be necessary to exclude individual PK profiles because they are erroneous or abnormal, 
e.g. protocol violation, documented sample handling errors etc. Such data will not be used for 
analysis and any excluded data should be flagged in the listings and the reason for exclusion 
should be documented. 
 


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Statistical methods 
 
Descriptive statistics (arithmetic mean with corresponding SD, geometric mean with 
corresponding SD , geometric coefficient of variation (CV%), median with minimum and 
maximum) for drug concentrations by time point and PK variables will be provided for 
melphalan. 
 
Geometric mean and geometric CV% will be calculated as follows: 
𝐺𝑒𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝑚𝑒𝑎𝑛= GeoMean =  𝑒𝑥𝑝[{𝑙𝑛(𝑦1) + ⋯+ 𝑙𝑛(𝑦𝑛)} 𝑛
⁄ ] , 
𝐺𝑒𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑑𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛= 𝐺𝑒𝑜𝑆𝐷=  𝑒𝑥𝑝[𝑆𝐷{𝑙𝑛(𝑦1), … , 𝑙𝑛(𝑦𝑛)}] , and 
𝐺𝑒𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝐶𝑉 (%) = 𝐺𝑒𝑜𝐶𝑉=  100 × √𝑒𝑥𝑝{𝑙𝑛(𝐺𝑒𝑜𝑆𝐷)}2 −1 , 
 
where SD is the arithmetic standard deviation. 
 
7.8 
EFFICACY ENDPOINTS AND ANALYSIS 
 
All efficacy analyses will be produced on the safety analysis set and efficacy analysis set by cohort 
and overall. 
All tumor response and progression-depended objectives are assessed by investigators according 
to the IMWG-URC (Rajkumar, 2011). 
7.8.1 RESPONSE RATES 
 
For analysis of response rates, all percentages calculations will be based on the respective analysis 
set. For analysis of the best confirmed response rates, a category of ‘non-evaluable’ will be added 
and included in the percentage calculation for patients who cannot be categorized for the best 
confirmed response (as described below). For analysis of the best unconfirmed response rates, the 
same approach will be used.   
 
Best Overall Confirmed Response  
Best overall confirmed response during the study, including follow-up tumor response assessments 
(sCR, CR, VGPR, PR, MR, SD or PD), collected prior to the new therapy initiation, and assessed 
by the investigator according to IMWG-URC, will be summarized descriptively.  
 
Confirmed response: Two consecutive assessments with the same response result made at any 
time. In case at the second consecutive assessment (made at any time) the response is higher than 


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the previous one, then confirmed response (linked to the first assessment visit) will be the first one 
(e.g., PR – VGPR consecutive pair will lead to a PR confirmed response at the first visit). In case 
the second consecutive response is lower than the first one, then confirmed response (linked to the 
first assessment visit) will be the second one (e.g. CR-VGPR consecutive pair will lead to a VGPR 
confirmed response at the first visit). 
 
Best Unconfirmed Response 
Defined as the best response achieved on study, i.e. a response may not be confirmed by a 
consecutive assessment.   Will be presented similarly to best overall confirmed response.   
 
Overall Response Rate  
 
The ORR will be estimated as the proportion of patients who achieve a confirmed response of 
sCR, CR, VGPR, or PR as their best response, as assessed by the investigator. The denominator is 
the number of patients in the analysis population for particular cohort. The exact binomial two-
sided 95% confidence interval (CI) for ORR will be calculated.   
 
Clinical Benefit Rate  
The CBR is the proportion of patients who achieve a confirmed minimal response or better (sCR, 
CR, VGPR, PR and MR) as their best response, as assessed by the investigator.  CBR will be 
summarized using the same method as for ORR. 
All the details of myeloma response assessment will be presented in a listing. 
7.8.2 TIME TO EVENT PARAMETERS 
 
Progression-Free Survival  
The PFS is defined as the time from the date of first study drug (the earliest of melflufen and 
dexamethasone start date) initiation to the date of first documentation of confirmed PD or death 
due to any cause, whichever occurs first. PFS time, in months, is calculated as (PFS date – date of 
first study drug initiation +1)/30.4375. 
Additional conventions for the PFS date derivation and censoring are defined in the Table 2 below: 
 


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        Table 2. Conventions for PFS date derivation and censoring 
Situation 
Date of Progression or Censoring 
Outcome 
No post-baseline response 
assessments, except in the case of 
death 
Date of initiation of therapy (the 
earliest of melflufen and 
dexamethasone start date) 
Censored 
New 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 immediately after 
more than 1 consecutively missed 
response assessment visit* 
Date of last response assessment 
visit 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 planned 
response assessments 
Date of death or first response 
assessment showing PD, 
whichever occurs first 
Progressed 
Death before first response 
assessment 
Date of death 
Progressed 
*unless there was an unscheduled visit showing absence of PD between the last scheduled missing response   
assessment and date of PD identification 
The distribution of PFS will be summarized using the Kaplan-Meier (K-M) method.  The median 
PFS will be estimated from the 50th percentile of the corresponding K-M estimates. The 95% CI 
for median PFS will be constructed using the method of Brookmeyer (Brookmeyer, 1982).   
 K-M plots will also be produced. 
A patient data listing will be provided for PFS follow-up. 
 
Duration of Response (DOR) 
DOR is defined as the time in months 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. 
DOR is to be censored and summarized using the same methods as for PFS. 
DOR will be derived as (DOR date – date of first documented confirmed response (≥PR) + 
1)/30.4375.   


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Duration of Clinical Benefit (DOCB) 
DOCB will be calculated as time in months from the first evidence of confirmed assessment of 
sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause. 
Duration of clinical benefit is defined only for patients with a confirmed MR or better. DOCB will 
be censored and summarized using the same method as for PFS. 
DOCB will be derived as (DOCB date – date of first documented confirmed response (≥MR) + 
1)/30.4375. 
 
Time to Response (TTR) 
TTR will be calculated as time in months from first dose of study drug to first documented 
confirmed response in a patient that has responded with PR or better. TTR will be presented 
descriptively for patients with a response. Will be derived as (date of first documented confirmed 
response (≥PR) – date of study drug initiation +1)/30.4375. 
Time to CB will be presented for confirmed response of MR or better and analyzed similarly to 
TTR. 
 
Overall Survival (OS) 
OS defined as time in months from date of study drug  initiation to death due to any cause.  Patients 
still alive at the end of study, or lost to follow-up, will be censored at last day known alive. Will 
be derived as (OS date – date of study drug initiation +1)/30.4375. 
A patient data listing will be provided for overall survival follow-up. 
7.8.3 EFFICACY ASSESSMENTS 
 
Myeloma specific laboratory tests results, including SPEP, UPEP, serum and urine IFE, and SFLC 
will be summarized descriptively by assessment visit, and this will include change from baseline 
summary using descriptive statistics for continuous variables. In case the second SPEP value is 
available as >0 g/L at a given time point, see the section 7.6.3 for the derivation. 
 
All the myeloma specific laboratory tests results and other efficacy assessments (i.e. 
extramedullary plasmacytoma assessment) will be presented in the listings.  


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7.9 
SAFETY ENDPOINTS AND ANALYSIS 
 
All analyses of safety will be based on the safety analysis set.   
 
7.9.1 EXPOSURE TO STUDY TREATMENT 
 
Exposure analysis will be based on the safety analysis set by cohort and overall.   
 
Duration of melflufen treatment in weeks is defined as (date of last dose – date of first dose + 29 
days) divided by 7. 
If a patient discontinued from treatment and the end of treatment (EOT) visit happened prior to 29 
days after last dose, then the duration of melflufen is defined as (date of EOT – date of first dose 
+1) divided by 7. 
If a patient died prior to 29 days after last dose, then the duration of melflufen is defined as (date 
of death – date of first dose +1) divided by 7. 
Duration of dexamethasone treatment in weeks is defined as (date of last dose – date of first 
dose + 1) divided by 7. 
Overall duration of treatment with study drug in weeks is defined as the longest duration of 
dexamethasone or melflufen treatment. 
The duration of study treatment exposure will be summarized descriptively and presented for 
overall treatment duration and also separately for melflufen and dexamethasone and will include: 
treatment duration in weeks, number of cycles received (and also additionally number of doses for 
dexamethasone), cumulative dose (in mg) of study drug received per patient, average dose of study 
drug (mg/week for melflufen and mg/week for dexamethasone), the total number and percentage 
of patients receiving a dose per cycle (for overall treatment and melflufen), average duration of 
infusion (min) for melflufen. Patients who received only a partial dose of melflufen for a given 
cycle will be considered as having received treatment for that cycle. 
Average dose of melflufen in mg/week is defined as the cumulative dose divided by the duration 
of melflufen treatment (the same for dexamethasone).  
Dose modification information will be summarized descriptively for any drug (melflufen and/or 
dexamethasone) for overall and then also separately for melflufen and dexamethasone by cycle. 
The number of patients with each action by frequency will be presented based on the 
melflufen/dexamethasone administration eCRF page.  
A dose delay is defined as a consecutive dose of melflufen administered on day 33 or later 


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following a preceding dose of melflufen (day at the moment of melflufen administration is defined 
as a difference between Cycle X Day 1 (CXD1) date and C(X-1)D1 date +1). Dose delays will be 
categorized as delays in weeks as 1 (day 33 to 39), 2 (day 40 to 46), 3 (day 47 to 53), 4 (day 54 to 
60), and >4 weeks (day 61 or later) for each cycle.  
A separate table will present the number and percentage of patients with delayed  cycles for post-
cycle 1 (those with day 33 and later at the moment of melflufen administration following a 
preceding dose of melflufen) as well as the number of delayed cycles by delay categories (1 week, 
2 weeks, 3 weeks, 4 weeks and >4 weeks).  
Number of patients with a dose delay due to COVID-19 pandemic will be summarized. 
All melflufen and dexamethasone administration details will be presented in the respective listings.  
7.9.2 ADVERSE EVENTS 
 
All AE summaries will be presented based on the safety analysis set by cohort and overall.   
All AEs will be coded using the MedDRA (version 24.0 or higher), for toxicity assessment the 
National Cancer Institute Common Toxicity Criteria Adverse Event (NCI CTCAE) version 4.03 
will be used.  
The summaries of AEs will be based on treatment-emergent adverse events (TEAEs).  
TEAEs are defined as AEs that start on or after the first day of study treatment (the earliest of 
melflufen and dexamethasone start date) administration and within 30 days after the last 
administration of study treatment (the latest of melflufen and dexamethasone end date), or before 
start of subsequent anticancer treatment (whichever occurs first) or that worsen on or after the first 
day of study treatment.    
An overall summary of AEs will be presented. It will include the number and percentage of patients 
(as well as total event count) with at least one pre-treatment condition (started prior to the first 
dose of melflufen and/or dexamethasone), patients with at least one TEAE, patients with at least 
one grade 3, grade 4 and grade 3/4 TEAE, patients with at least one serious TEAE, and patients 
with TEAEs leading to death.  
The overall summary will include the treatment related TEAEs analyzed separately for treatment 
related TEAEs (melflufen and/or dexamethasone related), melflufen related TEAEs, and 
dexamethasone related TEAE.  It will include the number and percentage of patients (as well as 
total event count) with each corresponding treatment related TEAEs; patients with grade 3, grade 


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4 and grade 3/4 TEAEs; This summary will include the number (%) of patients with study 
treatment related serious TEAEs as well as melflufen-related serious TEAEs, and dexamethasone 
related serious TEAE separately along with the number (%) of patients with respective treatment 
related TEAEs leading to death. In addition the number and percentage of patients with TEAEs 
leading to dose reduction, dose held and dose discontinuation will be presented for overall 
(melflufen and/or dexamethasone), and separately for melflufen and dexamethasone.  
The number and percentage of patients experiencing TEAEs, as well as total event count (except 
for summaries by toxicity grade), will be summarized by MedDRA SOC and PT for:  
 TEAEs 
 Non-serious TEAEs 
 Treatment-related (related to melflufen and/or dexamethasone) TEAEs 
 Melflufen-related TEAEs 
 Dexamethasone-related TEAEs 
 Serious TEAEs 
 Treatment-related serious TEAEs 
 Melflufen-related serious TEAEs 
 Dexamethasone-related serious TEAEs 
 TEAEs by CTCAE toxicity grade 
 Treatment related (related to melflufen and/or dexamethasone) TEAEs by CTCAE toxicity 
grade 
 Melflufen-related TEAEs by CTCAE toxicity grade 
 Dexamethasone-related TEAEs by CTCAE toxicity grade 
 Serious TEAEs by CTCAE toxicity grade 
 Treatment-related serious TEAEs by CTCAE toxicity grade 
 Melflufen-related serious TEAEs by CTCAE toxicity grade 
 Dexamethasone-related serious TEAEs by CTCAE toxicity grade 
 TEAEs resulting in any treatment modification (hold, reduction, delay, interruption and 
discontinuation) for any study drug and also separately for melflufen and dexamethasone 
The number and percentage of patients with grouped AEs – TEAEs defined as follows: 
 Thrombocytopenia (SMQ “Haematopoietic thrombocytopenia” – Broad scope) 


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 Neutropenia (PTs: “Neutropenia”, “Febrile neutropenia”, “Neutrophil count decreased”, 
“Neutropenic sepsis”, “Neutropenic infection”, “Cyclic neutropenia”, “Band neutrophil 
count decreased”, “Band neutrophil percentage decreased”, “Neutrophil percentage 
decreased”, “Agranulocytosis”, “Granulocyte count decreased”, “Granulocytopenia”) 
 Anemia (standardized MedDRA query (SMQ) “Haematopoietic erythropenia” – Broad 
scope) 
 Myelodysplastic syndrome (PTs: “5q minus syndrome”, “Chronic myelomonocytic 
leukemia”, “Myelodysplastic syndrome”, “Myelodysplastic syndrome transformation”, 
“Myelodysplastic syndrome unclassifiable”, “Refractory anemia with an excess of blasts”, 
“Refractory anemia with ringed sideroblasts”,”Refractory cytopenia with multilineage 
dysplasia”, “Refractory cytopenia with unilineage dysplasia”, “Sideroblastic anemia”) 
 Second primary malignancies ((SMQ “Malignant or unspecified tumours” and HLT 
“Myelodysplastic syndromes”), excluding HLGT “Plasma cell neoplasms”) 
 Febrile neutropenia (PT “Febrile neutropenia”) 
 Infections ( SOC “Infections and infestations”) 
 Infective pneumonia – broad scope (SMQ “Infective pneumonia”) 
 Infective pneumonia – narrow scope (SMQ “Infective pneumonia” – Narrow terms) 
 Hemorrhage (SMQ “Haemorrhages” - Narrow terms) 
 Thrombocytopenia concomitant to hemorrhage: Hemorrhage with an onset date within ± 7 
days of the onset and/or resolution date of a grade 3 or 4 thrombocytopenia. Grade 3/4 
thrombocytopenia resolution date is to be identified based on the laboratory data as a first 
day when thrombocytopenia assessment is grade 2 or lower (grade ≤ 2 for toxicity “Platelet 
count decreased”). 
 Neutropenia concomitant to infection: Infection with an onset date within ± 7 days of the 
onset and/or resolution date of a grade 3 or 4 neutropenia. Grade 3/4 neutropenia resolution 
date is to be identified based on the laboratory data as a first day when neutropenia 
assessment is grade 2 or lower (grade ≤ 2 for toxicity “Neutrophil count decreased”).  
The groups above will be summarized as a separate summaries for all by SOC, PT and all by SOC, 
PT, CTCAE toxicity grade analyses.  
By SOC, PT grouped AE summaries will also be presented by cycle. 


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For by-cycle reporting, an AE is assigned to particular cycle if started at or after the date and time 
of the study treatment (earliest of melflufen and dexamethasone administration at particular cycle) 
administration at particular cycle and prior to the date of treatment administration in subsequent 
cycle. If a patient discontinued somewhere in between the cycles, the AE is assigned to the cycle 
in which the discontinuation has happened. 
 
A patient reporting the same TEAE more than once will only be counted once when calculating 
incidence:  
 within a given SOC 
 within a given SOC and PT combination or MedDRA SMQ 
The maximum CTCAE toxicity grade and strongest causal relationship to study treatment for the 
event will be used in the incidence calculations.  
TEAEs reported with a causality assessment of “Probably Related” and “Possibly Related” are to 
be considered as “Related” for the analysis purposes. AEs having both onset and end dates missing 
will be considered TEAEs; in case of a missing start date and a complete end date, the AE will be 
considered a TEAE unless the end date is prior to the date of the first dose of study drug. 
A separate summary will present the number and percentage of patients who died during the study 
treatment period (between the first dose of treatment (the earliest of  melflufen and dexamethasone 
start date) and within 30 days after last dose of treatment (the latest of melflufen and 
dexamethasone end date)) and on follow-up (more than 30 days after last treatment dose along 
with the reason for deaths as well as the number of patients died within 60 days after first treatment 
dose.  
Any AEs related to COVID-19 will be presented as separate PTs specific to COVID-19 or 
coronavirus. 
Listings will be provided for patients experiencing AEs, SAEs, AEs resulting in drug withdrawal 
and events with fatal outcome. 
7.9.3 LABORATORY DATA 
 
Laboratory data will be summarized for the safety analysis set by cohort and overall. 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units on Study Data Tabulation Model (SDTM) level. Hematology and 


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chemistry parameters will be summarized descriptively and changes from baseline to post-baseline 
visits for each parameter will be presented. Urinalysis results will only be listed.  
All the data from both scheduled and unscheduled time points will be included in the CTCAE 
grade shift tables. 
Shift tables for the change in CTCAE grade (with separate parts for decreased and increased 
grades) will be constructed for hematology and chemistry laboratory parameters, which have 
corresponding CTCAE grades to tabulate changes in NCI CTCAE (version 4.03) from baseline to 
worst post-baseline on study (up to and including EOT visit) CTCAE grade. Number of patients 
with grade 3 or higher toxicity will be summarized as counts and percentages by cycle.  A separate 
listing of all laboratory results corresponding to grade 3 or 4 will be provided.   
The following list of parameters that will be presented in the toxicity grades laboratory tables: 
  Hematology 
o Hemoglobin (increase, decrease) 
o Platelets (decrease) 
o White blood cells (WBC) (increase, decrease) 
o ANC (decrease) 
o Lymphocyte count (increase, decrease) 
 Serum Chemistry 
o Alanine aminotransferase (ALT) (increase) 
o Aspartate aminotransferase (AST) (increase) 
o Alkaline phosphatase (increase) 
o Total bilirubin (increase) 
o Creatinine (increase) 
o Calcium (increase, decrease) 
o Glucose (increase, decrease) 
o Albumin (decrease) 
o Potassium (increase, decrease) 
o Sodium (increase, decrease) 
o eGFR (decrease) 
 


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For hemoglobin, ANC and platelet counts, CTCAE grade shift tables will also be additionally 
presented by cycles. For this analysis by cycle, the maximum grade within each cycle is used for 
analysis. 
Time from the date of the first study drug dose (earliest of melflufen and dexamethasone 
administration at particular cycle) in a particular cycle until the date of grade 3, grade 4 and grade 
3/4 onset will be presented for each cycle for ANC and platelets. Time to onset of grade 3, grade 
4 and grade 3/4 for ANC and platelets will also be presented overall (duration in days from the 
treatment start until the date of grade 3, grade 4 and grade 3/4 respectively) and for completed 
cycles. 
For laboratory results reported with a prefix, for example "<" or ">", the value derived from the 
reported results without a prefix will be analyzed. 
A separate table will be produced for incidence of grade 4 neutropenia (grade 4 toxicity 
“Neutrophil count decreased”) and thrombocytopenia (grade 4 toxicity “Platelet count decreased”) 
based on laboratory data for completed cycles (cycles having a subsequent cycle available). The 
table will include the number of patients dosed in each cycle, the number of patients dosed in 
completed cycle, the number and percentage of patients with grade 4 neutropenia and grade 4 
thrombocytopenia, number and percentage of patients with G-CSF (concomitant medication with 
PT=”Granulocyte Colony Stimulating Factor”, “Filgrastim”, “Pegfilgrastim”, “Lenograstim”, 
“Lipegfilgrastim”))  in each cycle, the number  and percentage of patients with platelets transfusion 
(concomitant medication with PT=”Platelets”)  and erythrocytes transfusion (concomitant 
medication with PT=”Erythrocytes” and “Red blood cells”) at each cycle.   
Concomitant medication is assigned to the particular cycle if taken between the date of the 
melflufen administration at a particular cycle and date of melflufen administration in subsequent 
cycle. If patient discontinued somewhere in between the cycles concomitant medication is assigned 
to the cycle in which the discontinuation has happened. 
Another table will investigate the occurrence of grade 3 and 4 neutropenia and thrombocytopenia 
leading to melflufen dose reduction per cycle, based on the laboratory data,  
All laboratory data will be listed, including CTCAE toxicity grades and normal ranges. A listing 
will be provided for urine pregnancy tests as well. 
7.9.4 VITAL SIGNS  
 


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Vital signs will be summarized using descriptive statistics for the safety analysis set by cohort and 
overall. 
Results and change from baseline to post-baseline time points for weight, blood pressure, pulse, 
respiratory rate and temperature will be presented. 
A patient data listing will be provided to document height, weight, and vital signs data. 
7.9.5 
PHYSICAL EXAMINATION 
 
Physical examination will only be listed without a summary. 
 
 
ECG data will be summarized for the safety analysis set by cohort and overall. 
ECG data (heart rate, PR interval, QRS interval, QT interval, QTc-Fridericia (QTcF) interval, RR 
interval) will be summarized using descriptive statistics, changes from baseline to EOT visit will 
also be evaluated.  
Shift tables from baseline (Normal/Abnormal-clinically significant/Abnormal – not clinically 
significant) to EOT visit will be summarized for ECG interpretation data.   
All ECG data collected will be presented in the listing. 
7.9.7 
CHEST X-RAY 
 
Chest x-ray data will be listed without a summary. 
7.10 OTHER ENDPOINTS AND ANALYSIS 
7.10.1 ECOG 
 
 ECOG performance status will be summarized as counts and percentages using shift tables of 
baseline versus worst performance status (largest ECOG value) during the study.  Also, the number 
of patients with decrease of ≥1 unit and ≥2 units respectively at the last available visit and at the 
EOT visit will be summarized as counts and percentages to reflect the level of improvement in 
ECOG values. 
7.10.2 EGFR 
 
The eGFR level at the start of each cycle and the changes from baseline over time will be 
presented using descriptive statistics.  
7.9.6 
12-LEAD ELECTROCARDIOGRAM (ECG) 


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A patient data listing will be provided to document eGFR level by cycle. 
8. 
INTERIM ANALYSIS 
 
The interim analysis took place to support accelerated New Drug Application (NDA) submission 
and was described in the separate interim SAP dated 28 June 2019. 
 An interim analysis for an interim clinical study report (iCSR) is planned when patients enrolled 
in Cohort 1a and 1b have been followed until progression or up to at least 6 months after first dose. 
The objective of this interim analysis is to evaluate PK, safety and efficacy in Cohort 1, moderately 
impaired patients, to support regulatory submissions. As no inferential statistical analyses are 
planned at the interim analysis, the interim has no impact on the statistical methods or presentation 
of data for the final report. 
9. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE 
PROTOCOL 
 
There are no deviations from analysis as described in the protocol. 
10. PROGRAMMING SPECIFICATION 
 
All outputs will be produced using SAS version 9.4 or a later version. 
The margins should be at least 1.50 inches for the binding edge and 1.0 inches for all others.  
In the top left portion of each table/listing, the protocol number will be presented. On the next line 
a table/listing number followed by the title of the table/listing and population information will be 
displayed. Horizontal lines will appear after the column heading of the table/listing. Footnotes will 
be put under the main body of text at the bottom of the page. The source listing number will be 
displayed for all tables. The SAS program name will appear bottom left in a string and the page 
number will appear on the bottom right corner of each table/listing. The date and time of creation 
of table/listing will appear bottom left under to the SAS program name line.  
Courier New 8-point bold font will be used for all tables and listings. Usually, a landscape layout 
is suggested for both tables and listings, but it is not mandatory. Any date information in the listing 
will use the date9. format, for example, 07MAY2002. 
Shells for unique tables and listings are provided in a separate Mock-Up TFLs document. 
11. 
REFERENCES 
 


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Rajkumar, S. V., J. L. Harousseau, B. Durie, et al. Consensus Recommendations for the 
Uniform Reporting of Clinical Trials: Report of the International Myeloma Workshop 
Consensus Panel 1. Blood. 2011; 117(18):4691-4695. 
 
Brookmeyer R, Crowley J. A Confidence interval for the median survival time. Biometrics; 
1982; 38: 29-41. 
 
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.