Clinical trial NCT03151811
Conditions: Multiple Myeloma
Keywords: Refractory Multiple Myeloma Relapsed Multiple Myeloma Melphalan flufenamide (Melflufen) Pomalidomide Dexamethasone
Sponsor: Oncopeptides AB
Start date: 2017-06-12; Completion date: 2023-02-03
Enrollment: 495 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melflufen+dex or pomalidomide+dex.

Detailed description:
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide.

Patients were randomized to either one of two arms:

Arm A: Melphalan flufenamide (Melflufen) 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.

Arm B: Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.

Patients ≥ 75 years of age received a reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22 for both Arm A and Arm B.

Patients were to receive treatment until such time as there was documented disease progression, unacceptable toxicity, or the patient/treating physician determined it was not in the patient's best interest to continue.

Dose modifications and delays in therapy may have been implemented based on patient tolerability as detailed in the protocol. In the event of a cycle delay, unrelated to dexamethasone toxicity, it was recommended to continue dexamethasone weekly.

Arms: arm 1: Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue. arm 2: Pomalidomide 4 mg orally daily on Days 1 to 21 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue.
Interventions: intervention 1: Melflufen intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Oral capsules intervention 3: Oral tablets

Protocol documents:
Prot_002.pdf: 
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Protocol No. OP-103 
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Protocol: Version 6.1: April 20, 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. 
 
Clinical Development Protocol 
OP-103 OCEAN Trial 
A Randomized, Controlled, Open-Label, Phase 3 Study of 
Melflufen/Dexamethasone Compared with Pomalidomide/ 
Dexamethasone for Patients with Relapsed Refractory Multiple 
Myeloma who are Refractory to Lenalidomide 
 
 
Investigational Product 
Study Sponsor 
Melflufen 
Oncopeptides AB 
Västra Trädgårdsgatan 15 
SE-111 53 Stockholm, Sweden 
 
Protocol Number 
OP-103 
Eudract number 
2016-003517-95 
Investigational New Drug Number 
Clinical Research Organization (CRO) 
 
116362 
 
Precision Oncology and PSI CRO 
200 Route 31 North 
Suite 102 
Flemington, NJ 08822 
USA 
Development phase 
Phase 3 
Document status 
Version 1.1: December 7, 2016 
Version 2.0: June 29, 2017 
Version 3.0: May 30, 2018 
Version 4.0: November 20, 2018 
Version 4.1: May 24, 2019 
Version 5.0: March 24, 2020 
Version 6.0: May 08, 2020 
Version 6.1: Apr 20, 2021 
 




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Protocol Acceptance Page 
 
Protocol Number: OP-103: OCEAN TRIAL 
 
Protocol Title: A Randomized, Controlled, Open-Label, Phase 3 Study of Melflufen/ 
Dexamethasone Compared with Pomalidomide/Dexamethasone for 
Patients with Relapsed Refractory Multiple Myeloma who are 
Refractory to Lenalidomide 
 
 
Protocol Date: Version 1.1: December 7, 2016 
Version 2.0: June 29, 2017 
Version 3.0: May 30, 2018 
Version 4.0: November 20, 2018 
Version 4.1: May 24, 2019 
Version 5.0: March 24, 2020 
Version 6.0: May 08, 2020 
Version 6.1: April 20, 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 
 
 
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, with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles 
laid down in the Declaration of Helsinki. 
 
The study protocol and any amendments are to be reviewed by an Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) before implementation. 
 
Confidential information contained in this document will not be used for any purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent 
of Oncopeptides AB. 


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TABLE OF CONTENTS 
List of Figures ......................................................................................................... 7 
List of Tables .......................................................................................................... 7 
List of Abbreviations ............................................................................................ 20 
1 
Background ........................................................................................................... 22 
1.1 
Overview of Multiple Myeloma ................................................................ 23 
1.2 
Overview of Melflufen .............................................................................. 24 
1.2.1 
Melflufen Description ............................................................... 24 
1.2.2 
Melflufen Scientific Rationale .................................................. 24 
1.3 
Clinical Experience ................................................................................... 25 
1.3.1 
Clinical Experience in RRMM ................................................. 25 
1.3.2 
Evaluation of QTcF Intervals from Holter Recordings ............ 26 
1.3.3 
Safety Summary ....................................................................... 27 
1.4 
Clinical Efficacy ....................................................................................... 27 
1.4.1 
Clinical Pharmacokinetics ........................................................ 27 
1.5 
Overview of Pomalidomide ...................................................................... 28 
2 
Rationale ............................................................................................................... 29 
2.1 
Rationale for the Selected Patient Population ........................................... 29 
2.2 
Rationale for Dose Selection ..................................................................... 29 
2.3 
Rationale for Patient Reported Outcomes ................................................. 30 
3 
Objectives and Endpoints ..................................................................................... 30 
3.1 
Primary Objectives .................................................................................... 30 
3.2 
Secondary Objectives ................................................................................ 30 
3.2.1 
Key Secondary Objectives* ...................................................... 30 
3.2.2 
Other Secondary Objectives* ................................................... 31 
3.3 
Explorative Objectives .............................................................................. 31 
4 
Study Design ......................................................................................................... 31 
4.1 
Description of Study Design ..................................................................... 31 
5 
Patient Population ................................................................................................. 32 
5.1 
Patient Screening ....................................................................................... 32 
5.1.1 
Screening Failures .................................................................... 32 
5.2 
Patient Eligibility ...................................................................................... 32 
5.3 
Inclusion Criteria ....................................................................................... 32 
5.4 
Exclusion Criteria ..................................................................................... 34 
6 
Patient Enrollment ................................................................................................ 36 
6.1 
Enrollment Procedure ............................................................................... 36 
6.2 
Patient Numbering .................................................................................... 36 
6.3 
Randomization .......................................................................................... 36 
6.4 
Replacement Policy .................................................................................. 36 


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7 
Treatment .............................................................................................................. 36 
7.1 
Study Treatment ........................................................................................ 36 
7.2 
Initiation of Therapy ................................................................................. 37 
7.3 
Melflufen ................................................................................................... 38 
7.3.1 
Melflufen Packaging and Labeling ........................................... 38 
7.3.2 
Melflufen Storage ..................................................................... 38 
7.3.3 
Preparation of Melflufen Solution for Infusion ........................ 38 
7.3.4 
Melflufen Administration (Arm A) .......................................... 39 
7.4 
Dexamethasone ......................................................................................... 39 
7.4.1 
Dexamethasone Packaging and Labeling ................................. 39 
7.4.2 
Dexamethasone Storage ........................................................... 39 
7.4.3 
Dexamethasone Administration (Arm A and Arm B) .............. 39 
7.5 
Pomalidomide ........................................................................................... 40 
7.5.1 
Pomalidomide Supply USA and Canada Sites ......................... 40 
7.5.2 
Pomalidomide Supply for non-USA/Canada Sites ................... 40 
7.5.3 
Special Handling Instructions ................................................... 40 
7.5.4 
Pomalidomide Administration (Arm B only) ............................. 40 
7.6 
Study Drug Compliance and Accountability ............................................. 41 
7.6.1 
Study Drug Compliance ........................................................... 41 
7.6.2 
Study Drug Accountability ....................................................... 41 
7.7 
Concomitant Therapy ................................................................................ 41 
7.7.1 
Required Concomitant Therapy ............................................... 41 
7.7.2 
Recommended Concomitant Therapy ...................................... 42 
7.7.3 
Contraindicated Concomitant Therapy..................................... 43 
7.8 
Dose Modifications ................................................................................... 44 
7.8.1 
Dose Modification Guidelines for Melflufen (Arm A) ............ 44 
7.8.2 
Dose Modification Guidelines for Pomalidomide (Arm B) ..... 47 
7.8.3 
Dose Modification Guidelines for Dexamethasone .................. 49 
7.9 
Treatment Duration ................................................................................... 50 
8 
Visit Schedule and Assessments ........................................................................... 50 
8.1 
Study Flow and Visit Schedule ................................................................. 50 
8.2 
Study Assessments .................................................................................... 56 
8.2.1 
Screening Disease Assessments ............................................... 56 
8.2.2 
Efficacy Assessments ............................................................... 56 
8.2.3 
Safety and Tolerability Assessments ........................................ 58 
8.2.4 
Electrocardiogram Assessments ............................................... 58 
8.2.5 
Patient Reported Outcome Assessments .................................. 58 
8.2.6 
Pharmacokinetic Assessments .................................................. 58 
8.2.7 
End of Treatment ...................................................................... 59 


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8.2.8 
Follow Up Assessments ............................................................ 59 
8.2.9 
Lost to Follow-Up .................................................................... 60 
8.2.10 
Criteria for Premature Patient Withdrawal ............................... 60 
9 
Safety Monitoring and Reporting ......................................................................... 60 
9.1 
Adverse Events ......................................................................................... 60 
9.1.1 
Definitions ................................................................................ 60 
9.1.2 
Grading of severity ................................................................... 61 
9.1.3 
Causality ................................................................................... 61 
9.1.4 
Adverse Event Reporting.......................................................... 62 
9.1.5 
Laboratory Test Abnormalities ................................................. 62 
9.2 
Serious Adverse Events ............................................................................ 63 
9.2.1 
Definitions ................................................................................ 63 
9.2.2 
Serious Adverse Event Reporting ............................................. 64 
9.3 
Pregnancy .................................................................................................. 65 
10 Data Collection and Management ......................................................................... 65 
10.1 
Data Confidentiality .................................................................................. 65 
10.2 
Site Monitoring ......................................................................................... 66 
10.3 
Data Collection.......................................................................................... 66 
10.4 
Database Management and Quality Control ............................................. 67 
11 Statistical Methods and Data Analysis .................................................................. 67 
11.1 
Study Endpoints ........................................................................................ 67 
11.1.1 
Primary Endpoint ...................................................................... 67 
11.1.2 
Secondary Endpoints ................................................................ 67 
11.2 
Sample Size Calculation ........................................................................... 68 
11.3 
Statistical Methods .................................................................................... 69 
11.3.1 
General Considerations for the Statistical Analyses ................. 69 
11.3.2 
Analysis Populations ................................................................ 69 
11.3.3 
Analysis of Efficacy Endpoints ................................................ 70 
11.3.4 
Analysis of Safety Endpoints .................................................... 72 
11.3.5 
Analysis of Patient Reported Outcomes ................................... 73 
11.4 
Handling of Drop-outs and Missing Data ................................................. 73 
11.5 
Interim Analysis ........................................................................................ 73 
11.6 
Non-inferiority analysis and Choice of Non-Inferiority Margin ............... 73 
11.7 
Pharmacokinetic Analysis ......................................................................... 74 
11.8 
Exposure-response analyses ...................................................................... 74 
12 Ethical Considerations and Administrative Procedures ........................................ 75 
12.1 
Regulatory and Ethical Compliance .......................................................... 75 
12.2 
Data Monitoring Committee ..................................................................... 75 
12.3 
Independent Review Committee ............................................................... 75 


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12.4 
Responsibilities of the Investigator and IRB/IEC/REB ............................ 75 
12.5 
Informed Consent Procedures ................................................................... 75 
12.6 
Discontinuation of the Study .................................................................... 76 
12.7 
Publication of Study Protocol and Results ................................................ 76 
12.8 
Study Documentation, Record Keeping and Retention of Documents ..... 76 
12.9 
Confidentiality of Study Documents and Patient Records ........................ 77 
12.10 Audits and Inspections .............................................................................. 77 
12.11 Financial Disclosures ................................................................................ 77 
13 Protocol Adherence ............................................................................................... 77 
13.1 
Amendments to the Protocol ..................................................................... 78 
14 References ............................................................................................................. 79 
15 Appendices ............................................................................................................ 81 
Appendix A. Eastern Cooperative Oncology Group (ECOG) Performance Scale ...... 81 
Appendix B. National Cancer Institute CTCAE Version 4.03 .................................... 81 
Appendix C. IMWG Uniform Response Criteria ........................................................ 82 
Appendix D. Line of Therapy Definition .................................................................... 84 
Appendix E. Definition of Relapsed Disease .............................................................. 85 
Appendix F. Declaration of Helsinki .......................................................................... 85 
Appendix G. Estimated Creatinine Clearance rate using Cockcroft-Gault Formula . 85 
Appendix H. Assessment of QTC Interval ................................................................. 86 
Appendix I. 
ISS and R-ISS Score ............................................................................. 86 
Appendix J. 
Pomalidomide Pregnancy Prevention Plan. .......................................... 87 
List of Figures 
Figure 1-1: Structure of Melflufen ............................................................................... 23 
List of Tables 
Table 7-1 
Dose Reduction Steps for Melflufen ........................................................ 43 
Table 7-2 
Melflufen Hematologic Toxicity Dose Adjustment Guidelines: .............. 45 
Table 7-3 
Dose Reduction Steps for Pomalidomide ................................................. 47 
Table 7-4 
Pomalidomide Dose Modification during a Cycle of Therapy ................. 47 
Table 7-5 
Dose Reduction Steps for Dexamethasone ............................................... 49 
Table 7-6 
Dose Modifications for Toxicity Related to Dexamethasone ................... 49 
Table 8–1 
Schedule of Events .................................................................................. 51 
Table 9-1 
Adverse Event Severity ............................................................................ 61 
Table 11-1 Conventions for Censoring for PFS ........................................................... 70 


























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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 aspirate 
BUN 
Blood urea nitrogen 
CA 
Chromosomal abnormalities 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CMV 
Cytomegalovirus 
CRF/eCRF 
Case Report Form/electronic Case Report Form 
CRO 
Contract Research Organization 
CR 
Complete Response 
CT 
Computerized tomography 
CTCAE 
Common terminology criteria for adverse events 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
EQ-5D-3L 
EuroQol-5 Dimensions 3 Level 
FCBP 
Female of child bearing potential 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
FLC 
Free light chain 
FU 
Follow-up 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
HBV 
Hepatitis B virus 
HRQol 
Health related quality of life 
IB 
Investigator’s brochure 
ICH 
International Conference of Harmonization 
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 
IRC 
Independent Review Committee 
INR 
International normalized ratio 
IRT 
Interactive response technology 
ISF 
Investigator Site File 
ISS 
International Staging System 


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IUD 
Intrauterine device 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Myeloma 
MR 
Minimal response 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK 
Natural killer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PI 
Proteasome Inhibitor 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetics 
p.o. 
Per os/by mouth/orally 
POEMS 
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein 
PPP 
Pregnancy Prevention Plan 
PR 
Partial response 
PRO 
Patient reported outcomes 
q.d. 
Quaque die/ one a day 
QLQ-C30 
Quality of life questionnaire Core 30 
QLQ-MY20 
Quality of life questionnaire Myeloma 20 
RBC 
Red blood count 
REB 
Regulatory Ethics Board 
REMS 
Risk Evaluation and Mitigation Strategy 
RRMM 
Relapsed Refractory Multiple Myeloma 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SFLC 
Serum free light chain 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TTP 
Time to Progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
VAS 
Visual analogue scale 
VGPR 
Very good partial response 


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1 
BACKGROUND 
 
1.1 
OVERVIEW OF MULTIPLE MYELOMA 
Multiple myeloma (MM) is a malignancy of the differentiated plasma cells that affects the 
older patient with a median age at onset of 65 to 70 years and a slight male predominance. 
MM is the second most common hematologic malignancy and nearly 30,330 patients with 
myeloma are 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 immunoglobulin (usually of the IgG 
or IgA type or free urinary light chain [paraprotein, M-protein or M-component]). Patients 
with MM may experience significant decrement to quality of life, including bone pain, bone 
fractures, fatigue, anemia, infections, hypercalcemia, hyperviscosity of the blood and renal 
function compromise (including renal failure). The disease course for MM varies with the 
disease stage at diagnosis, cytogenetic profile, as well as age and patient comorbidities. The 
median survival is approximately 5 to 7 years with some significant variation in survival 
depending on host factors, tumor burden, biology and response to treatment (Kumar et al. 
2008). However, the disease remains ultimately fatal. 
There are currently 6 classes of approved drugs available for the treatment of MM, including 
steroids (prednisone and dexamethasone), immunomodulatory drugs (IMiDs) (thalidomide, 
lenalidomide and pomalidomide), proteasome inhibitors (PIs) (bortezomib, carfilzomib and 
ixazomib), histone deacetylase 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 2016) 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. In many cases, the same agents used as 
induction therapy may be reinstituted for relapsed disease if the disease recurred more than 
6 to 12 months after the last therapy ended. However, if the time to relapse is of shorter 
duration, the patient is refractory to therapy, or the disease is associated with severe 
symptoms like renal failure or hypercalcemia, a regimen with different mechanism of action 
(class switch) is often selected. Patients for whom stem cells were cryopreserved early in 
the disease course, and who are transplant candidates, may benefit from ASCT as salvage 
therapy (Cavo et al. 2011). In general, MM patients will receive an average of 4 to 8 
different treatment regimens during their lifespan. 
Recent improvements in therapies have significantly increased both the expected life span 
and the quality of life for these patients. However, despite the availability of effective 
therapies, the optimal combinations and sequencing of these agents with other therapies and 
with one another is still unclear. Only 20 to 30% of the relapsed-refractory MM patients 
typically respond to any particular treatment and ultimately patients relapse from all 
available options. Given the inevitable relapses seen in these patients, new approaches to 
therapy are clearly still needed. 


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1.2 
OVERVIEW OF MELFLUFEN 
1.2.1 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 
 
1.2.2 Melflufen Scientific Rationale 
Melflufen is a peptidase-potentiated therapy designed for targeted delivery of alkylating 
moieties to tumor cells. In contrast to other alkylating agents that are hydrophilic, the 
lipophilicity of melflufen leads to rapid and extensive distribution into tissues and cells. 
Inside cells, melflufen may directly bind deoxyribonucleic acid (DNA) or is readily 
metabolized by intracellular peptidases into the well-known antitumor compound melphalan 
or by esterases into des-ethylmelflufen, which also has alkylating properties. Due to the 
high activity of peptidases and esterases in human tumor cells, the formation of melflufen’s 
metabolites is rapid in these cells with 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 


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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 ADP 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). 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. 2013). 
The safety profile of melflufen suggested by preclinical studies is supported by clinical data 
from 45 patients with solid tumors and from a total of 57 patients with RRMM in the 
ongoing Phase 1/2a clinical trial O-12-M1 (40 patients dosed at the maximum tolerated dose 
[MTD] of 40 mg of melflufen and 17 patients dosed at other doses in Phase 1 of the trial). 
Taken together, clinical and preclinical data support that melflufen provides peptidase- 
potentiated delivery of alkylating moieties to tumor cells (such as MM cells) and thereby 
exerts a higher anti-tumor activity compared with equimolar administration of melphalan 
but with a seemingly similar safety profile. The efficacy seems to be consistent across MM 
populations including patients who are double-refractory to IMiDs and PIs and refractory to 
alkylators. 
Please see the Investigator’s Brochure (IB) for additional information. 
1.3 
CLINICAL EXPERIENCE 
1.3.1 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 Proteasome Inhibitor (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 I followed the 
standard 3 + 3 modified Fibonacci 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 MTD was established as 40 mg of melflufen in combination with 
40 mg dexamethasone weekly. Following identification of the MTD, the Phase 2 part of the 


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trial was initiated and all subsequently treated patients received a starting dose of 40 mg of 
melflufen. The Phase 2 part of the clinical trial was completed in November 2017 including 
data from 45 patients treated with 40 mg melflufen in combination with weekly 
dexamethasone and 13 patients treated with single agent 40 mg melflufen. 
1.3.1.1 Clinical Safety 
As of November 9, 2017, 58 patients had received 280 doses of melflufen 40 mg. The 
median number of completed cycles was 5.0 (range 1 – 14). 
The most common treatment emergent adverse events (TEAE) 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 and 4 Adverse Events (AE)s were reported in 37 patients out of 
45 patients (82%). Those related to melflufen and occurring in ≥ 5% of the patients are 
presented in Table 1-1. 
Table 1-1   Summary of Melflufen Treatment Related Grade 3 or 4 AE in ≥ 5% of 
45 Patients Dosed with 40 mg Melflufen in combination with weekly dexamethasone in 
Clinical Trial O-12-M1 
System Organ Class 
(Preferred Term) 
Patients with Grade 3 or 4 
AEs 
n (%) 
Patients with Grade 4 
AEs n (%) 
Any melflufen treatment-related event 
37 (82) 
19 (42) 
Blood and lymphatic system disorders 
36 (80) 
19 (42) 
ThrombocytopeniaNeutropeniaAnemia 
26 (58) 
17 (38) 
Lymphopenia 
26 (58) 
11 (24) 
19 (42) 
0 (0) 
3 (7) 
1 (2) 
Continuous review of safety data in the Phase 2 part of the study lead the data safety 
monitoring committee (DSMC) to include an additional week to the cycle length (i.e. to 28 
days) to allow further recovery of platelet and neutrophil count and potentially allow the 
patients to stay on treatment longer and achieve more benefit. 
Please refer to the current IB for further safety data on melflufen. 
1.3.2 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 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. 


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1.3.3 Safety Summary 
The clinical trials results, to date, indicate that the safety profile for melflufen is similar to 
that for other alkylators, where thrombocytopenia, neutropenia and anemia are the most 
common treatment-related AEs.. The incidences of Grade 3 and 4 neutropenia and 
thrombocytopenia after 40 mg doses of melflufen are comparable to the incidences observed 
in studies with low dose melphalan regimens in combination with high dose steroids 
(Richardson et al. 2010). There have been no reports of syncope, seizures, ventricular 
arrhythmias, ventricular tachycardia, ventricular fibrillation, flutter, torsade de pointes, or 
sudden deaths in the clinical trials. The safety profile for melflufen is thus similar to that of 
other alkylators. 
Even though neutropenia and thrombocytopenia have been common in connection to 
melflufen treatment, few cases have been reported as serious adverse events (SAEs) as 
febrile neutropenia or bleeding (please see the current IB for details). 
Since both the disease of MM as well as treatment with alkylators may cause neutropenia 
and neutropenia may be connected with both pneumonia, sepsis or other infections, it is 
important to follow institutional or NCCN guidelines (NCCN 2017) for antimicrobial 
prophylaxis for multiple myeloma patients. Please refer to the current IB for further safety 
data on melflufen. 
1.4 
CLINICAL EFFICACY 
The clinical phase 1/2, O-12-M1 trial, was completed in November 2017 including data 
from 45 patients treated with 40 mg melflufen in combination with weekly dexamethasone 
and 13 patients treated with single agent 40 mg melflufen. ORR among the 45 patients 
treated with melflufen and dexamethasone was 31.1%, median DOR was 8.4 months based 
on 13 events in 14 patients (95% CI: 4.6-9.6), median PFS was 5.7 months based on 41 
events in 45 patients (95% CI: 3.7-9.2) and median OS was 20.7 months based on 23 events 
in 45 patients (95% CI: 11.8-∞). 
Please refer to the current IB for further clinical data on melflufen. 
1.4.1 Clinical Pharmacokinetics 
In humans, melflufen is metabolized to des-ethyl-melflufen, melphalan and the non- 
alkylating para-fluoro-phenylalanin ethyl ester. PK data for melflufen and melphalan are 
available from the completed clinical trial O-05-001 in patients with solid tumors and from 
six MM patients in the ongoing clinical trial O-12-M1. The elimination phase for melflufen 
could not be followed in clinical trial O-05-001 since the plasma concentrations were 
generally below the limit of quantitation during this phase. Subsequent improvements of 
the bioanalytical method and sampling schedule have allowed estimation of the melflufen 
elimination phase in clinical trial O-12-M1. Further, the metabolite des-ethyl-melflufen is 
quantified in clinical trial O-12-M1, while it was not measured in clinical trial O-05-001. 
In clinical trial O-05-001 (patients with solid tumors), melflufen plasma concentrations 
could be followed only up to end of infusion or very shortly thereafter. Melphalan 
concentrations were generally higher than those of melflufen both during and after the 
infusion. Melflufen and melphalan exposures increased slightly less than proportional to 
dose and the intra-patient variability in exposure between treatment cycles was low after 
administration of the same dose amount. Gender and body weight had no significant 
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In the clinical trial O-12-M1 in MM patients, PK data from 12 patients covering the dose 
range 15 mg to 55 mg were available as of 30 November 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 is eliminated with a half-life of approximately 15 minutes. 
The combined results from the two clinical trials demonstrate that the PK of melflufen is 
characterized by low plasma concentrations and a very rapid disappearance from plasma 
after end of the intravenous infusion. The reasons for the decrease in melflufen 
concentrations during the ongoing infusion, frequently observed in both studies, are not 
known. The PK of melphalan after administration of melflufen is characterized by a rapid 
formation, where plasma concentrations exceed those of melflufen within 15 minutes after 
start of melflufen infusion, but where peak plasma concentrations are lower and AUC 
similar compared with equimolar infusions of melphalan at a similar rate 
(Mougenot et al. 2004, Nath et al. 2010). Peak plasma concentrations of melphalan appear 
with a delay by up to 10 minutes after the end of melflufen infusion. The elimination phase 
of melphalan is similar after melflufen and melphalan infusions, according to published data 
for melphalan administration (Mougenot et al. 2004, Nath et al. 2010). 
Overall, the observations suggest a mechanism where melflufen is rapidly and widely 
distributed to cells and tissues (including any tumor cells present) outside of the plasma 
compartment. Melphalan is predominantly formed outside of the plasma compartment 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 current IB for details. 
1.5 
OVERVIEW OF POMALIDOMIDE 
Pomalidomide, an analogue of thalidomide, is an IMiD with antineoplastic activity. In in 
vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of 
hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of 
lenalidomide-resistant MM cell lines and synergized with dexamethasone in both 
lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. 
Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and 
inhibited production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes 
(Quach et al, 2009). 
Pomalidomide is indicated for patients with MM who have received at least two prior 
therapies including lenalidomide and bortezomib and have demonstrated disease 
progression on or within 60 days of completion of the last therapy. 
The approval of pomalidomide was based on a phase 3 multi-center, randomized, open-label 
trial (MM-003) that compared pomalidomide + low-dose dexamethasone to high-dose 
dexamethasone in adult patients with RRMM (FDA Pomalyst prescribing information 2015, 
San Miguel et al. 2013). The trial enrolled patients who had received at least two prior 
treatment regimens, including lenalidomide and bortezomib, and demonstrated disease 
progression on or within 60 days of the last therapy. A total of 455 patients were enrolled 
in the trial: 302 in the pomalidomide + low-dose dexamethasone arm and 153 in the high- 
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The trial demonstrated that treatment with pomalidomide in combination with low-dose 
dexamethasone was superior to high-dose dexamethasone in patients with primary 
refractory MM and RRMM. A statistically significant difference in favor of the 
experimental treatment was shown for the primary analysis of PFS based on IRAC assessed 
data (median 3.6 months versus 1.8 months, with a median follow-up of 4.2 months). The 
HR was 0.45 (95% CI: 0.35-0.59 p < 0.001) (FDA Pomalyst prescribing information 2015). 
The median PFS was subsequently reported to be 4.0 months versus. 1.9 months at a median 
of 10 months’ follow-up, based on investigator assessed data (San Miguel et al. 2013). The 
ORR 23.5% of the pomalidomide + low-dose dexamethasone arm was higher than the 3.9% 
in the high-dose dexamethasone arm. In addition, median OS was significantly longer with 
pomalidomide + low-dose dexamethasone than high-dose dexamethasone: HR 0.70 (95% 
CI: 0.54-0.92 p = 0.009) (FDA Pomalyst prescribing information 2015). 
Additional details regarding pomalidomide can be found in the US prescribing information 
or EU Summary of Product Characteristics (SmPC). 
 
2 
RATIONALE 
 
2.1 
RATIONALE FOR THE SELECTED PATIENT POPULATION 
The proposed pivotal trial will be conducted in MM patients who have received 2 to 4 prior 
lines of therapy, including lenalidomide and a PI, and who are refractory to both last line of 
therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to 
randomization (refractory defined as progression on or within 60 days of last dose, following 
at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle). In this 
population, there are few remaining treatment alternatives. This population is within the 
approved pomalidomide indication (at least 2 prior therapies including lenalidomide and a 
PI and have demonstrated disease progression on or within 60 days of completion of the last 
therapy). 
Important trial design features like pomalidomide plus dexamethasone treatment regimen 
(dose, schedule, treatment duration and dose reduction guidelines), patient visit frequency, 
tumor evaluations and other features have been developed to resemble those in the 
pomalidomide Phase 3 trial (MM-003). Further, the inclusion/exclusion criteria have been 
developed in order to create an as comparable patient population as possible. In common 
with the pomalidomide indication, all patients should have received at least 2 prior lines of 
therapy. A maximum number of 4 prior lines have been specified in order to limit the 
number of end-stage patients in the trial since these patients may have limited bone-marrow 
reserves and therefore, could benefit more from patient-tailored treatment regimens. As in 
the pomalidomide label, patients should be refractory to last line of therapy but in the 
melflufen pivotal trial lenalidomide refractoriness is required in order to reflect the 
widespread use of this drug. It is anticipated that these patients may have an improved 
clinical benefit of melflufen plus dexamethasone treatment in comparison to pomalidomide 
plus dexamethasone. 
Patients who have previously been exposed to pomalidomide will be excluded. 
2.2 
RATIONALE FOR DOSE SELECTION 
Patients will be randomized to either one of two arms. Patients in Arm A (experimental 
arm) will be treated with melflufen 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 


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8, 15 and 22 of each 28-day cycle. Patients in Arm B (control arm) will receive 
pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 
22 of each 28-day cycle. The starting dexamethasone dose is planned to be reduced to 20 
mg/day in all patients ≥ 75 years of age in line with the pomalidomide Phase 3 study 
(San Miguel et al. 2013). 
The dose and schedule of melflufen is based on data from the Phase 1/2 trial with melflufen 
in combination with weekly dexamethasone in RRMM patients. The Phase 1 portion of the 
trial established the MTD to be 40 mg of melflufen administered intravenously every 21 
days with 40 mg oral dexamethasone weekly. In the Phase 2 part of the trial, the DSMC 
decided to increase the cycle length to 28 days to improve tolerability by allowing additional 
time for hematologic recovery. This dose and schedule have been further evaluated in Phase 
2. It was found that this increase resulted in a higher proportion of cycle lengths according 
to the protocol default. Thus, the 28-day schedule will be implemented in this trial. 
Melflufen may be given until disease progression or unacceptable toxicity and dose and 
schedule should be adjusted based on tolerability. 
The dose and schedule of pomalidomide in combination with dexamethasone are based on 
the FDA Pomalyst prescribing information (2015), where the recommended starting dose of 
pomalidomide is 4 mg once daily orally on Days 1 to 21 of repeated 28-day cycles until 
disease progression. Dose and schedule may be adjusted based on tolerability. 
2.3 
RATIONALE FOR PATIENT REPORTED OUTCOMES 
A quality of life evaluation is added to the trial and will be used as an exploratory endpoint. 
Three scales will be used during this trial including EORTC QL-QC30 questionnaire, 
EORTC QLQMY20 questionnaire and EQ-5D questionnaire (Aaronson 1993). These 3 
questionnaires have been validated and used extensively in patients with MM and can be 
completed in a few minutes. The value and change from baseline in each scale of the 
EORTC QLQ-C30, each scale of the MY20, each dimension of the EQ-5D, and the visual 
analog scale (VAS) of the EQ-5D will be evaluated. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
3.1 
PRIMARY OBJECTIVES 
• To compare the PFS of melflufen plus dexamethasone (Arm A) versus 
pomalidomide plus dexamethasone (Arm B) as assessed by the Independent 
Review Committee (IRC) according to the International Myeloma Working 
Group Uniform Response Criteria (IMWG-URC) (Rajkumar et al. 2011, 
Appendix C). 
3.2 
SECONDARY OBJECTIVES 
3.2.1 Key Secondary Objectives* 
• To assess and compare the overall response rate (ORR), i.e., proportion of 
patients with ≥ PR (stringent complete response [sCR], complete response [CR], 
very good partial response [VGPR] and partial response [PR]) as best response 
in Arm A versus Arm B 
• To assess and compare duration of response (DOR) in patients with ≥ PR (sCR, 
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• To assess and compare overall survival (OS) in Arm A versus Arm B 
• To assess and compare the safety and tolerability in Arm A and Arm B 
3.2.2 Other Secondary Objectives* 
• To assess and compare clinical benefit rate (CBR) (i.e. proportion of patients 
with ≥ MR) as best response in Arm A versus Arm B 
• To assess and compare time to response (TTR) in patients with an PR or better 
in Arm A versus Arm B 
• To assess and compare time to progression (TTP) in Arm A versus Arm B 
• To assess and compare the duration of clinical benefit (i.e., ≥ MR) in Arm A 
versus Arm B 
• To assess and compare best response during the study in Arm A versus Arm B. 
• To assess and compare investigator assessment of primary and secondary 
endpoints in Arm A versus Arm B 
• To assess and compare the primary and secondary endpoints in various 
subgroups of Arm A and Arm B 
• To evaluate the melphalan pharmacokinetic (PK) parameters during treatment 
with melflufen, the impact of covariates on this relationship and the inter- 
occasion variability in melphalan exposure (Arm A) 
 
* All tumor response and progression-dependent objectives are as assessed by the 
Independent Review Committee (IRC) according to the IMWG-URC (Rajkumar et al. 
2011, Appendix C) unless otherwise specified. 
3.3 
EXPLORATIVE OBJECTIVES 
• To assess the relationship between melphalan exposure and effect on safety and 
efficacy variables, including PFS and ORR, in Arm A 
• To assess minimal residual disease (MRD) in patients that achieve a CR (Arm A 
and Arm B). 
• To assess functional status and well-being based on patient reported outcome 
(PRO) assessment 
 
4 
STUDY DESIGN 
 
4.1 
DESCRIPTION OF STUDY DESIGN 
This is a randomized, controlled, open-label, Phase 3 multicenter study which will enroll 
patients with RRMM following 2-4 lines of prior therapy (Appendix D), who are refractory 
to both last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months 
prior to randomization as demonstrated by disease progression on or within 60 days of 
completion of the last dose of lenalidomide. 
Patients will be randomized to either one of two arms. 
Arm A: 
Melflufen 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28- 
day cycle. 
Arm B: 


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Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 
22 of each 28-day cycle. 
Arm A and Arm B 
Patients ≥ 75 years of age will have a reduced dose of dexamethasone of 20 mg on Days 1, 
8, 15 and 22. 
Oral dexamethasone may be substituted with intravenous dexamethasone at the 
investigator’s discretion (USA only). In the event of a cycle delay, unrelated to 
dexamethasone toxicity, it is recommended to continue dexamethasone weekly. 
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 (See Section 7.8). 
A Schedule of Events for the study is outlined in Section 8.1. 
 
5 
PATIENT POPULATION 
 
5.1 
PATIENT SCREENING 
Written informed consent must be obtained before any protocol-specific screening tests or 
procedures are performed. Patients must meet all the entry criteria detailed in Section 5.3 
and Section 5.4. After informed consent is obtained, the screening assessments will be 
performed as detailed in Section 8 of the protocol. Table 8-1, Schedule of Event, lists all of 
the screening assessments including frequency and time lines of when assessments are to be 
performed. 
Assessments performed as part of the patient’s routine clinical evaluation and not 
specifically for this study need not be repeated after signed informed consent has been 
obtained provided the assessments fulfill the study requirements and are performed within 
the specified timeframe prior to enrollment. Laboratory results noted in the inclusion criteria 
must remain within the limits specified prior to first dose of study drug on Cycle 1 Day 1. 
5.1.1 Screening Failures 
Patients who sign an informed consent but fail to be randomized for any reason will be 
considered screen failures. Patients who screen fail may be rescreened as long as they were 
not previously randomized. 
5.2 
PATIENT ELIGIBILITY 
The Investigator must ensure that patients meet all the following inclusion and exclusion 
criteria. Confirmation of patient eligibility by the medical monitor is required prior to 
randomization. 
5.3 
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 


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2. A prior diagnosis of multiple myeloma with documented disease progression in need 
of treatment at time of screening. 
3. Measurable disease defined as any of the following: 
• Serum monoclonal protein ≥ 0.5 g/dL 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 
4. Received 2-4 prior lines of therapy (Appendix D), including lenalidomide and a 
proteasome inhibitor (PI), either sequential or in the same line, and is refractory 
(relapsed and refractory or refractory) to both the last line of therapy and to 
lenalidomide (≥ 10 mg) administered within 18 months prior to randomization, 
Refractory to lenalidomide includes patients who relapsed while on lenalidomide 
therapy or within 60 days of last dose following at least 2 cycles of lenalidomide 
with at least 14 doses of lenalidomide per cycle. 
5. Life expectancy of ≥ 6 months 
6. ECOG performance status ≤ 2. (Patients with lower performance status based solely 
on bone pain secondary to multiple myeloma may be eligible following consultation 
and approval of the medical monitor) (Appendix A) 
7. Females of child bearing potential (FCBP)* must have a medically supervised 
negative serum or urine pregnancy test with a sensitivity according to local Risk 
Evaluation and Mitigation Strategy™ (REMS) or pomalidomide pregnancy 
prevention plan (PPP) completed within 10 to 14 days prior to planned start of 
treatment. All FCBP must agree to either commit to continued abstinence from 
heterosexual intercourse or begin TWO acceptable methods of birth control, one 
highly effective method and one additional effective method AT THE SAME TIME, 
at least 28 days before she starts taking treatment and as appropriate based on the 
treatment assignment (See Section 7.7.1). FCBP must also agree to ongoing 
pregnancy testing. Men must agree to use a condom during sexual contact with a 
FCBP even if they have had a vasectomy from the time of starting study treatment 
through 3 months after the last dose of melflufen (Arm A) or 28 days after the last 
dose of pomalidomide (Arm B). All patients enrolled in Canada and the USA must 
be willing to comply with all requirements of the Canadian or USA pomalidomide 
REMS. All patients enrolled outside of Canada and the USA must be willing to 
comply with all requirements of the PPP (Appendix J). (Willingness, to comply with 
the REMS or PPP, must be documented prior to knowledge of randomization but is 
only required if randomized to Arm B). 
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. The following laboratory results must be met during screening (within 21 days) and 
also 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 prior to first drug administration) 
• Platelet 
count ≥ 75,000 
cells/mm3 
(75 x 109/L) 
(without 
required 
transfusions during the 10 days prior to first drug administration) 
• Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed 
with Gilberts syndrome, that have been reviewed and approved by the 
medical monitor. 
• Aspartate 
transaminase 
(AST/SGOT) 
and 
alanine 
transaminase 
(ALT/SGPT) ≤ 3.0 x ULN. 
• Renal function: Estimated creatinine clearance by Cockcroft-Gault 
formula ≥ 45 mL/min. (Appendix G). 
11. Must be able to take antithrombotic prophylaxis (See Section 7.7.1). 
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) 
(Willingness must be documented prior to randomization but insertion only required 
if randomized to Arm A). 
*(FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual 
cycles due to cancer therapy does not rule out childbearing potential) for at least 24 
consecutive months. 
5.4 
EXCLUSION CRITERIA 
Patients will be ineligible for this study if they meet any one of the following criteria: 
1. 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 
(i.e. platelet count fails to increase by > 10,000 cells/mm3 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. Prior exposure to pomalidomide 
5. Known intolerance to IMiDs. (≥ Grade 3 hypersensitivity reaction or at the 
investigators discretion) 
6. Known active infection requiring parenteral or oral anti-infective treatment within 
14 days of randomization 
7. 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 


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active surveillance 
8. Pregnant or breast-feeding females 
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse compliance or follow-up evaluation 
10. Known human immunodeficiency virus or active hepatitis C viral infection. 
11. Active hepatitis B viral infection (defined as HBsAg+) are excluded. 
• Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti- 
HBs+, Anti-HBc-). 
• Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the 
discretion of the investigator after consideration of risk of reactivation. 
12. Concurrent symptomatic amyloidosis or plasma cell leukemia 
13. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein (M-protein) and skin changes] 
14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple 
myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. The use 
of live vaccines within 30 days before randomization. IMiDs, PIs or corticosteroids 
within 2 weeks prior to randomization. Other investigational therapies and 
monoclonal antibodies within 4 weeks of randomization. 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 
randomization. 
15. Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia 
any grade and/or neuropathy grade 2 without pain are permitted) 
16. Prior peripheral stem cell transplant within 12 weeks of randomization 
17. Prior allogeneic stem cell transplantation with active graft-versus-host- disease. 
18. Prior major surgical procedure or radiation therapy within 4 weeks of randomization 
(this does not include limited course of radiation used for management of bone pain 
within 7 days of randomization). 
19. Known intolerance to steroid therapy 
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. The planned analysis will explore differences in 
treatment effect based on racial and gender groupings, but the sample size is not increased 
in order to provide additional power for such subset analyses. Investigators are encouraged 
to recruit a diverse population. 


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6 
PATIENT ENROLLMENT 
 
6.1 
ENROLLMENT PROCEDURE 
Site initiation visits must be completed at each site before patients can be consented at that 
site. Informed consent must be signed 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. 
Patients that do not meet all the eligibility criteria will be considered screen failures and will 
not be randomized. 
6.2 
PATIENT NUMBERING 
A unique patient number will be assigned at the time of enrollment (signing of consent) by 
Interactive Response Technology (IRT) system that will be used to identify the patient 
throughout the clinical study and must be used on all study documentation related to that 
patient. 
6.3 
RANDOMIZATION 
The recruitment will be stratified based on age (≥ 75 years versus < 75 years), number of 
previous lines (-2 previous lines versus 3 to 4 previous lines) and International Staging 
System (ISS) score (1 versus ≥ 2). 
Patient randomization will be managed by the IRT system. Details for interacting with this 
system can be found in the ISF. Treatment cannot begin prior to randomization and must 
begin ≤ 5 days after randomization. However, pretreatment tests/procedures must remain 
within the screening timelines specified in Table 8-1: Schedule of Events. Confirmation of 
patient eligibility by the medical monitor is required prior to randomization. 
6.4 
REPLACEMENT POLICY 
Randomized patients will not be replaced. 
 
7 
TREATMENT 
 
7.1 
STUDY TREATMENT 
Patients must begin treatment ≤ 5 days of randomization. However, pretreatment 
tests/procedures must remain within the screening timelines specified in Table 8-1 Schedule 
of Events. Treatment will be given in an outpatient treatment setting in cycles. Each cycle 
is 28 days. Patients will be randomized to one of 2 treatment arms: 
Arm A: 
• Melflufen 40 mg will be administered as a 30-minutes intravenous infusion on 
Day 1 of every 28 days via central catheter. 
• Dexamethasone tablets for 40 mg administered orally on Days 1, 8, 15 and 22 of 
each 28-day cycle for patient < 75 years of age. OR 
• Dexamethasone tablets for 20 mg administered orally on Days 1, 8, 15 and 22 of 
each 28-day cycle for patient ≥ 75 years of age. 


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All patients in Arm A must have central catheter prior to the initiation of the first dose of 
melflufen. (Port A Cath, PICC line or central venous catheter). 
Oral dexamethasone may be substituted with i.v. dexamethasone at the investigator’s 
discretion (USA only). 
Dose modifications and delays may be implemented based on patient tolerance as detailed 
in Section 7.8. In the event of a cycle delay, unrelated to dexamethasone toxicity, it is 
recommended to continue dexamethasone weekly. 
Arm B: 
• Pomalidomide capsules 4 mg will be administered orally on Days 1 to 21 in each 
28-day cycle. 
• Dexamethasone tablets for 40 mg administered orally on Days 1, 8, 15 and 22 of 
each 28-day cycle for patient < 75 years of age. OR 
• Dexamethasone tablets for 20 mg administered orally on Days 1, 8, 15 and 22 of 
each 28-day cycle for patient ≥ 75 years of age. 
Oral dexamethasone may be substituted with i.v. dexamethasone at the investigator’s 
discretion (USA only). 
All patients randomized to pomalidomide must agree to comply with all requirements of the 
pomalidomide REMS™ program or the pomalidomide PPP (See Appendix J), consistent 
with their geographic region of enrollment. 
Dose modifications and delays may be implemented based on patient tolerance as detailed 
in Section 7.8. In the event of a cycle delay, unrelated to dexamethasone toxicity, it is 
recommended to continue dexamethasone weekly. 
7.2 
INITIATION OF THERAPY 
Arm A and Arm B 
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 as follows: 
• ANC ≥ 1,000 cells/ mm3 (1.0 x 109/L) (Growth factors cannot be used within 
10 days of initiation of therapy); 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusion during the 
previous 10 days to initiation of therapy). 
• Hemoglobin ≥ 8.0 g/dl (RBC transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal, except patients diagnosed with 
Gilberts syndrome that have been reviewed and approved by the medical 
monitor. 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN 
• Renal 
function: 
Estimated 
creatinine 
clearance 
by 
Cockcroft-Gault 
formula ≥ 45 mL/min. (Appendix G). 


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7.3 
MELFLUFEN 
7.3.1 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. 
Please refer to the Pharmacy Manual for further details on packaging and labeling. 
7.3.2 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). 
7.3.3 Preparation of Melflufen Solution for Infusion 
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 solution 
(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, as in the 250 ml bag. Careful 
attention and documentation of the preparation procedures and time frames are required 
since melflufen degrades in solutions*. 
 
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 the reconstituted melflufen solution. 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 
the reconstituted melflufen solution. The maximum allowed time from start of 
reconstitution to start of infusion is 45 minutes. 
 
• 250 ml bag of 0.9% saline 
o Pre-cooled: the 250 ml bag of 0.9% saline should be pre-cooled prior to adding 
the reconstituted melflufen solution. The maximum allowed time from start of 
reconstitution until the start of iv infusion is 3.5 hours if kept refrigerated. Once 
removed from the refrigerator, the infusion must start within 30 minutes. Use of 
ambient saline is not permitted. 
 
Refer to the Pharmacy Manual for detailed instruction for reconstitution and dilution of 
melflufen in preparation for infusion. A well-coordinated plan between the pharmacy and 
treatment room is recommended. (*See Pharmacy Manual for details). 


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7.3.4 Melflufen Administration (Arm A) 
Prophylactic treatment with anti-emetic drug(s) prior to melflufen solution 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 eCRF. 
The study treatment should be administered via an acceptable 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). 
Before infusion: 
• Document vital signs prior to start of infusion. 
• 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. 
Infusion: 
• The melflufen should be administered as a 30-minute intravenous infusion. 
• Record start and stop time for 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. 
7.4 
DEXAMETHASONE 
7.4.1 Dexamethasone Packaging and Labeling 
Oral dexamethasone will be supplied by Oncopeptides AB to sites located outside the USA 
and Canada. Oral dexamethasone may be substituted with i.v. dexamethasone at the 
investigator’s discretion (USA only). Only oral dexamethasone will be supplied to sites 
outside of USA and Canada. USA and Canada sites will use commercially available 
dexamethasone supplies. 
7.4.2 Dexamethasone Storage 
Dexamethasone is to be stored at controlled room temperature. Consult the package insert 
or Summary of Product Characteristics for dexamethasone for additional storage and usage 
instructions. 
7.4.3 Dexamethasone Administration (Arm A and Arm B) 
Dexamethasone should be administered orally. Oral dexamethasone may be substituted 
with i.v. dexamethasone at the investigator’s discretion (USA only). Patients should be 
instructed to document oral dexamethasone administration on a patient diary and return 
unused tablets and packaging for review of compliance at the end of each cycle. Sites are 
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patient compliance regarding dexamethasone dosing in the eCRF. Consult the package 
insert for additional instructions for dexamethasone administration. Dexamethasone is best 
taken prior to melflufen (Arm A) on days when both drugs are given on the same day (Day 
1 of each cycle). 
7.5 
POMALIDOMIDE 
7.5.1 Pomalidomide Supply USA and Canada Sites 
Commercial supplies of pomalidomide should be used for patients enrolling at sites in the 
USA and Canada. 
Pomalidomide should be provided in accordance with the Celgene Corporation’s 
pomalidomide REMS™ programs. Per the standard REMS™ programs requirements, all 
physicians who prescribe pomalidomide for research subjects enrolled into this trial, and all 
research subjects enrolled into this trial, must be registered in and must comply with all 
requirements of the USA or Canada pomalidomide REMS™ programs. 
Pomalidomide is available only from pharmacies that are certified in the pomalidomide 
REMS™ program. Only enough pomalidomide for one cycle of therapy will be supplied 
to the patient each cycle. This is in accordance with the pomalidomide REMS™ programs. 
7.5.2 Pomalidomide Supply for non-USA/Canada Sites 
Pomalidomide will be supplied by Oncopeptides to sites other than USA and Canada. Please 
refer to the Pharmacy Manual for complete details on drug supply and ordering procedures. 
Only enough pomalidomide for one cycle of therapy will be supplied to the patient at the 
time. Patients will be required to follow the pomalidomide PPP (See Appendix J). 
7.5.3 Special Handling Instructions 
Female caregivers of childbearing potential should not handle or administer pomalidomide 
unless they are wearing gloves. 
7.5.4 Pomalidomide Administration (Arm B only) 
Pomalidomide is available in capsules of 1 mg, 2 mg, 3 mg and 4 mg for oral administration. 
Pomalidomide 4 mg is planned to be taken orally from Day 1 to Day 21 of each 28-day cycle. 
Pomalidomide may be taken with water and should be swallowed whole. Patients are not 
permitted to break, chew or open the capsules. Pomalidomide can be taken with or without 
food preferably at the same time every day. 
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day. 
If it is missed for more than12 hours, it should not be taken, rather the patient should wait 
for the next scheduled time point. 
Patients who take more than the prescribed dose of pomalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
Patients should be instructed to document oral pomalidomide administration on a patient 
diary and return unused capsules and packaging for review of compliance at the end of each 
cycle. Sites are responsible to maintain the diary as source documentation and record 
administration and patient compliance regarding pomalidomide dosing in the eCRF. 


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7.6 
STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
7.6.1 Study Drug Compliance 
Compliance will be assured by administration of the study treatment (Arm A) under the 
supervision of the investigator or his/her designee and should be documented in the study 
drug administration and accountability records. In addition, a patient diary should be used 
to document administration of pomalidomide (Arm B) and oral dexamethasone (Arm A 
and Arm B). Patients should be instructed to return unused capsules, tablets, drug packaging 
and diary for review of compliance at the end of each cycle. 
7.6.2 Study Drug Accountability 
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Drug accountability will be 
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 
dexamethasone, melflufen, pomalidomide packaging and drug labels 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. 
7.7 
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. 
7.7.1 Required Concomitant Therapy 
• Anti-thrombotic therapy (Arm B) 
Pomalidomide increases the risk of thromboembolism. Anti-coagulation prophylaxis 
is required after an assessment of each patient’s underlying risk factors. Unless there 
is an excess risk of bleeding, all patients should receive prophylactic anti-thrombotic 
treatment, unless contraindicated. The use of aspirin is an acceptable anti-thrombotic 
therapy. If aspirin is contraindicated, patients should receive another form of anti- 
thrombotic therapy according to hospital guidelines or physician preference. 
• Contraceptive measures 
Arm A 
Males and females of child-bearing potential shall be required to use 2 effective 
contraceptive methods (or true abstinence) prior to randomization. If randomized to 
Arm A, at least one method of effective contraceptive (or true abstinence) must 
continue prior to initiation of melflufen, while on therapy and for 3 months for men or 
28 days for women, after the last dose of melflufen. The best method should be 
determined in consultation with the Investigator. 
True abstinence definition: When this is in line with the preferred and usual life-style 


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of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Declaration of abstinence must be for the duration of the trial as defined above. 
Females: 
Birth control methods that are considered as highly effective include: tubal ligation, 
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, 
unless due to hysterectomy. 
Males: 
Males must use a condom during any sexual contact with females of child-bearing 
potential even if they have had a successful vasectomy. Males should not donate 
sperm during the study and for three 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. 
Arm B 
Males and females of child bearing potential shall be required to use 2 effective 
contraceptive methods (or abstinence) according to the USA or Canada 
pomalidomide REMS™ programs if enrolled in USA or Canada or the pomalidomide 
PPP for all patients enrolled outside the USA or Canada. The best method should be in 
compliance with the REMS™ /PPP program and be determined in consultation with 
the Investigator. 
See Appendix J for details on the PPP for all patients enrolled outside the USA or 
Canada. 
7.7.2 Recommended Concomitant Therapy 
• Pneumocystis prophylaxis (Arm A and B) 
o All patients are recommended to receive pneumocystis prophylaxis 
concomitant treatment according to the National Comprehensive Cancer 
Network (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 
• Arm A: Prophylactic treatment with anti-emetic(s) prior to melflufen 
administration is recommended. Subsequent anti-emetic drugs against emesis 
should be administered at the discretion of the investigator. 
• Patients should receive full supportive care, including transfusions of blood and 
blood products (including platelets), antibiotics, anti-diarrheals, analgesics, etc. 
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• Bisphosphonate therapy i.v. or p.o. should be administered if indicated in 
accordance with institutional guidelines. 
• The prophylactic use of growth factors and platelet transfusions are not permitted 
to render the patient eligible for trial participation except as described within the 
entry criteria. 
• Thrombocytopenia and neutropenia are known consequences of MM but also the 
most common expected adverse event (AE)s associated with melflufen and 
pomalidomide treatment. 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 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 (refer to Section 7.8.2.2). (Excluding Cycle 1, Day 1 which 
adheres to the guidelines in Section 7.2 for use of growth factors and platelet 
transfusions prior to the first dose of therapy). 
• 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 
o Antiviral and antifungal prophylaxis should be considered. 
• Antiviral and antifungal prophylaxis should be considered. Additional 
considerations Arm B: Reactivation of hepatitis B has been reported rarely in 
patients receiving pomalidomide in combination with dexamethasone who have 
previously been infected with the hepatitis B virus (HBV). Caution should be 
exercised when pomalidomide in combination with dexamethasone is used in 
patients previously infected with HBV, including patients who are anti-HBc 
positive but HBsAg negative. Investigators should consider closely monitoring 
for signs and symptoms of active HBV infection throughout therapy. 
• Renal failure has been reported in patients receiving a single high dose of iv 
melphalan 140-250 mg/m2 followed by common doses of cyclosporine for the 
prevention of graft-versus-host-disease after organ transplant. It is recommended 
to monitor renal function in patients receiving cyclosporine and melflufen 
concomitantly. 
7.7.3 Contraindicated Concomitant Therapy 
• Concurrent therapy with any approved or investigative anticancer therapeutic 
drug with activity against MM, including alpha interferon, is not allowed. 


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• 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 and approval of the medical monitor. 
• The use of live vaccines is prohibited during the study and for 30 days after last 
dose of study drug. 
• Avoid co-administration of strong inhibitors of CYP1A2 in combination with 
pomalidomide. (e.g. ciprofloxacin, enoxacin, fluvoxamine) 
• Limitations on the use of growth factors and platelet transfusions prior to Cycle 
1 Day 1 are detailed in Section 7.2 and 7.7.2. 
• Because of the increased risk of venous thromboembolism in patients with MM 
taking pomalidomide and dexamethasone, combined oral contraceptive pills, 
although not contraindicated, are not recommended. 
• Although erythropoietic agents or other agents that may increase the risk of 
thromboembolic events are not contraindicated, they should be used with 
caution. 
7.8 
DOSE MODIFICATIONS 
Dose adjustments 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. 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. 
7.8.1 Dose Modification Guidelines for Melflufen (Arm A) 
Dose modifications of melflufen for drug related toxicity are permitted. Multiple dose 
reductions are permitted however, the lowest dose permitted is 20 mg. If a patient is unable 
to tolerate the lowest dose of melflufen due to drug related toxicity the patient must be 
withdrawn from treatment. Prior to each cycle of melflufen the criteria for initiation of 
therapy must be met. (See Section 7.8.1.4). 
7.8.1.1 Dose Reduction Steps for Melflufen 
Table 7-1 Dose Reduction Steps for Melflufen 
Starting Dose 
Dose reduction 
Step – 1 
Dose reduction 
Step - 2 
40 mg 
30 mg 
20 mg 




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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 8.2.6 and 8.2.7. 
7.8.1.3 Non-hematologic Toxicity (Arm A) 
The resolution of all non-hematologic drug related toxicity must be to ≤ Grade 1 or baseline 
(except alopecia any grade and fatigue ≤ Grade 2) on Day 1 of each cycle. 
The following guidelines should be followed: 
• If the criteria for initiation of a new cycle of therapy are not met on Day 29 (the next 
scheduled Day 1 of any given cycle), 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 
investigators discretion based on the time lines in Table 7-2 above. 
• If cycle prolongation of more than 28 days (beyond Day 57) is needed, study 
treatment is to be discontinued 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. 
• Grade 3 or 4 treatment related non-hematologic toxicity that occurs or persists on 
Day 29 (scheduled Day 1) of any cycle requires a one-step dose reduction when the 
criteria for a new cycle are met with the following exceptions: 
o The toxicity can be managed with appropriate therapy or the risk of recurrence 
may be reduced by the use of appropriate prophylactic therapy (e.g. anti-emetics 
and anti-diarrheals for nausea, vomiting and diarrhea) 
AND/OR 
o The toxicity was transient and/or does not warrant a dose reduction in the opinion 
of the investigator in consultation with the medical monitor (headache, abnormal 
laboratory value, fatigue). 
Alternate dose modification may be considered in discussion with the medical monitor or 
the sponsor. 
7.8.1.4 Initiation of a New Cycle of Treatment (Arm A) 
Patients should be assessed at the beginning of each cycle according to the tests and 
evaluations outlined on Day 1 of each cycle in Table 8-1: Schedule of Events. To begin a 
new cycle of treatment the following criteria must be met: 
** 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. 












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AE monitoring 
 
X 
Follow-up (PFS, OS) 
Xr, 
X 
(X) Only if indicated 
a) All patients must sign an (IRB/IEC/REB)-approved informed consent document within 28 days of enrollment and prior to any study related procedures. 
b) Medical History including demographics, prior and current medical illness and conditions, prior surgical procedures. Disease history includes date of initial 
diagnosis, ISS and cytogenetics at diagnosis (if previously evaluated). ISS and 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 progressive disease and relapsed or refractory status (Appendix E). 
The date of last dose of lenalidomide, best response and date of progression must be documented to confirm relapsed and refractory or refractory status to 
lenalidomide. 
c) A complete physical exam, including height (screening only) and weight, neurologic assessment and assessment for extramedullary myeloma (if present on PE) 
will be conducted at screening, Day 1 of each cycle and End of Treatment visit. A symptom directed physical examination will be conducted as needed during a 
cycle. A site visit is required for Cycle 1 and 2 for weekly symptom assessment. Plasmacytomas that can be followed by 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 (Arm A) and on Day 1 
of each cycle for Arm B 
e) All FCBP must have a medically supervised negative serum or urine pregnancy test with a sensitivity according to local REMS and PPP requirements within 10 
to 14 days prior to planned start and again within 24 hours of starting therapy (24 hours required if prior to knowledge of randomization or randomized to Arm B) 
and thereafter according to the randomized treatment arm. Arm A: repeat pregnancy test prior to each dose of each cycle and at End of Treatment visit. Arm B: 
within 24 hours of starting pomalidomide Cycle 1, Day 1. While on pomalidomide, repeat pregnancy test every week for the first 4 weeks and then every 28 days 
while on therapy and during interruptions in therapy and 4 weeks following discontinuation of pomalidomide. Women with irregular menstruation must have 
pregnancy testing every 14 days while on therapy and during interruptions and 14 and 28 days after discontinuation of pomalidomide. 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). All patients in Arm B must be counseled at the start of each cycle according to 
the commercial REMS™ program in the USA and Canada or according to the PPP in Appendix J for sites outside the USA and Canada. 
f) 
A12-lead ECG assessment will be performed on all patients at screening and End of Treatment visit and as clinically indicated. Q-Tc interval to be assessed by 
Fridericia formula (Appendix H). 
g) Hematology: CBC with differential, and platelet count. Patients are required to have all laboratory evaluations completed at the study center during Cycles 1 and 
2. Following Cycle 2, CBC evaluations may be done at the study center laboratory or other local laboratory as long as the results are reviewed by the study center 
within 24 hours and toxicity assessment is completed. If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive therapy (Growth 
factors, blood or platelet transfusions) in the two preceding cycles, then CBC assessments may be excluded Day 8 and Day 22.Patients should be still be contacted 
weekly by phone to follow up on AE/SAEs and Dexamethasone compliance.  Exceptions may be made only in consultation with the medical monitor (see also 


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footnote v) . All CBC values collected in addition to protocol specified time points must be recorded in the eCRF. See Section 9.1.5.1 for reporting requirements 
of scheduled and unscheduled results of thrombocytopenia and neutropenia. A screening CBC may need to be repeated just prior to randomization if the initial 
value was trending downward, not reached nadir from last dose of prior therapy or based on clinical presentation (this may be done at the Investigators discretion 
or upon request of the medical monitor. 
h) Coagulation: prothrombin time (PT), international normalized ratio (INR) at screening and as clinically indicated. 
i) 
Blood chemistry: sodium, chloride, potassium, magnesium, phosphate, uric acid, BUN (urea), glucose (fasting at baseline), ALT/AST (SGPT/SGOT), alkaline 
phosphatase, total protein, total bilirubin, albumin, serum creatinine, and estimated creatinine clearance by Cockroft-Gault Equations (Appendix G) calcium and 
lactate dehydrogenase (LDH). Patients are required to have all evaluations completed at the treatment center during Cycles 1 and 2. Following Cycle 2, 
Chemistry evaluations may be done at the study center laboratory or other local laboratory as long as the results are reviewed by the study center within 24 hours 
and toxicity assessment is completed. Exceptions may be made only in consultation with the medical monitor. 
j) 
Bone marrow aspirate (BMA) to be collected at screening for % plasma cells, morphology, and cytogenetics by Fluorescence In Situ Hybridization (FISH). 
Minimum FISH probes include 17p, 4;14 and 14;16. In addition, a BMA sample is to be collected at screening and stored for possible MRD. If a bone marrow 
aspirate and/or biopsy has been collected within 6 weeks, 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 and to assess MRD status. Stored BMA samples may be used for optional future testing if requested by Oncopeptides 
in consenting patients and where regionally acceptable. Refer to Laboratory manual. 
k) SPEP, UPEP, serum and urine IFE (if SPEP or UPEP are not detectable and to confirm CR) quantitative immunoglobulins per routine lab practice and serum free 
light chain (SFLC) assay (only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hrs and SPEP is < 0.5 g/dL] and to confirm a sCR), are to 
be conducted at screening, Cycle 1 Day 1 and on the planned day 1 of each cycle (i.e., Day 29 of the previous cycle) (quantitative immunoglobulins only need to 
be repeated for patients with IgA or IgD myeloma) even if treatment is delayed. Patients progressing while on treatment, require 2 consecutive M protein 
assessments at any time (including the same day for SPEP/FLC) prior to discontinuation of treatment. The second assessment must be a separate serum and urine 
sample. (If the second consecutive M protein sample can only be obtained after the start of subsequent therapy, it may be used as confirmation of PD). All 
assessment of SPEP, UPEP, IFE and FLC must be completed in the same laboratory for a given patient*(See footnote r). In the event treatment for a new cycle is 
delayed beyond Day 43 of the previous cycle, M protein disease status is required to be repeated on the day the new cycle starts, i.e. Day 1 of the new cycle (e.g. 
Day 50 or 57 of the previous cycle). If treatment is discontinued beyond Day 43, the assessment should be repeated on the day of that determination (or as soon 
as possible 30 days after the last dose of study drug) as part of end of treatment (EoT) visit. Refer to Laboratory manual. (Refer also to footnote v.) 
l) 
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 and the method should provide bidimensional measurements. (eg. Computerized tomography [CT]/ 
magnetic resonance imaging [MRI]/ positron emission tomography [PET]). All imaging assessments should be completed within 28 days prior to 
randomization and documented in the eCRF. 
m) Skeletal survey includes 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 


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with each evaluation). Required if previous survey > 6 weeks from randomization and at any time when clinically indicated. Limited X-rays may be performed 
as clinically indicated to confirm PD. 
n) PK samples will be collected only in patients randomized to Arm A. Three plasma samples for determination of melphalan concentrations will be drawn in 
connection to the first two melflufen treatment cycles, 10 – 15 minutes after the end of infusion, 1 hour after the end of infusion and after 2-4 hours after the end 
of infusion (as late as possible within the time frame). Refer to the Laboratory Manual for details on specimen collection and processing 
o) See Section 7 in the protocol for complete details on study drug administration, dose modifications and start of a new cycle of therapy and study drug compliance. 
p) Concomitant medications and procedures: - all blood products and medications within 21 days prior to first dose until the End of Treatment Visit. 
q) End of Treatment visit should be scheduled 30 days (accepted time window ±3 days) after last dose of melflufen or pomalidomide 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. 
r) 
Progression Free Survival Follow-Up (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. The 2 consecutive M 
protein assessments may be collected at any time (including the same day for SPEP/FLC). The second assessment must be a separate serum and urine sample. (If 
the second consecutive M protein sample can only be obtained after the start of subsequent therapy, it may be used as confirmation of PD). (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 hypercalcemia is the only evidence of PD. If the patient enters PFS-FU, the first PFS M protein assessment should be 
scheduled 4 weeks after the EoT visit. *Patients unwilling or unable to return to the site for PFS evaluations may have the lab done locally following approval by 
the medical monitor. If the patient is discontinued mid-cycle, prior to Day 28, the EoT visit should be scheduled 30 days (+/- 3days) after the last dose of study 
drug. 
s) 
Overall Survival Follow-up (OS-FU): Following confirmed disease progression or initiation of subsequent therapy, follow-up for overall survival status and 
second primary malignancies will take place every three months +/- 7 days for 24 months. In the event that Oncopeptides AB would like to determine the OS 
status of patients following 24 months, future inquiries about their health status may be conducted at any time beyond this time point. This information may be 
recorded 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. 
t) 
Patient reported outcome assessments include EORTC QLQ-C30, EQ-5D-3 and EORTC QLQ-MY20 (Appendix K): Only for patients enrolled in protocol 
version 4.0 or later. The patient should complete the questionnaires prior to any procedures on the day of the visit and prior to being told anything related to 


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health; the questionnaires should be administered even if the treatment is not given. If the patient wishes to have the questions read aloud and then answer orally 
and the study personnel write the answer on the questionnaires, this is acceptable. QoL questionnaires will be submitted to patients at Cycle1 Day 1, each 
subsequent cycle on day 1, at the time of EOT visit, at the time of progression and at the time of starting a new treatment (day 1 of new treatment). If PD/EOT and 
next treatment occur at the same time, only one assessment is required at that time, if the EOT is for a reason other than PD, continue QOL assessments each 
month until PD and at time new treatment begins. If the new treatment starts during OS follow-up an additional assessment must be completed at that time. See 
Section 8.2.5. A sample of all PRO assessments can be found in Appendix K. 
u)  +/- 3 day window permitted (except Cycle 1 Day 1) for holidays/administrative reasons. 
v) 
If, due to the COVID19 outbreak, the patient is unwilling or unable to return to the site for MM evaluations they may have the MM labs done locally 
following 
approval by the medical monitor. Alternate procedures may be implemented to accommodate individual patient circumstances related to COVID-19 
safety considerations in consultation with the medical monitor on a case by case basis. 


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8.2 
STUDY ASSESSMENTS 
All assessments should be done according to the timelines outlined in Table 8-1; Schedule of 
Events. 
8.2.1 Screening Disease Assessments 
• M-protein determination using the following procedures: 
• 
SPEP and serum protein IFE with quantitative immunoglobulins; 
• 
Quantitative immunoglobulin evaluation may be based on regional availability 
of the test 
• 
Immunofixation of serum is required at screening if M protein by SPEP is not 
detectable 
• 
UPEP and urine protein IFE (all using the same 24-hour urine collection); 
• 
Immunofixation of urine is required at screening if M protein by UPEP is not 
detectable 
• 
SFLC and SFLC ratio 
• 
FLC assessment is not required at screening in the presence of measurable SPEP 
and/or UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 mg/24 hours) 
• 
If the M protein is non-measurable in SPEP and UPEP at screening or Cycle 1, 
Day 1, the FLC is required 
• BMA to quantify percent myeloma cell involvement 
• Extramedullary plasmacytoma evaluation of known or suspected lesions (by PE or 
imaging procedures). Obtain bi-dimensional measurements. 
• 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 
• Lactate dehydrogenase (LDH) 
• Cytogenetics/ FISH 
• ISS staging score and revised R-ISS (Appendix I) 
8.2.2 Efficacy Assessments 
Efficacy Assessments 
• M-protein determination using the following procedures: 
• 
SPEP and serum protein IFE with quantitative immunoglobulins (For patients with 
IgA and IgD myeloma); 


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• 
Immunofixation of serum is required at any time when M protein by SPEP 
becomes non-detectable and confirm a CR. 
• 
UPEP and urine protein IFE (all using the same 24-hour urine collection); 
• 
Immunofixation of urine is required at any time when M protein by UPEP 
becomes not detectable and to confirm a CR. 
• 
SFLC and SFLC ratio 
• 
FLC assessment is not required in the presence of measurable SPEP and/or 
UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 mg/24 hours), 
• 
FLC is required to confirm sCR, regardless of type of measurable disease. 
It is up to the site to work with the laboratory that performs the response analyses to ensure that 
the laboratory completes the immunofixation and FLC evaluations when required, to enable 
response assessments according to IMWG criteria. 
• Extramedullary plasmacytoma evaluation with the same technique to be used with each 
evaluation. Obtain bi-dimensional measurements. 
• Bone marrow aspirate to quantify percent myeloma cell involvement 
• Skeletal X-rays and/or CT scans 
• Serum calcium (corrected calcium). 
Disease status (assessed by M-protein quantitation and IFE and FLC from serum and 24-hour 
urine collection for UPEP and IFE) should be assessed at screening and Cycle 1 Day 1 , and on 
planned Day 1 (i.e., Day 29 of the previous cycle) of each cycle even if treatment is delayed. In 
the event treatment for a new cycle is delayed beyond Day 43 of the previous cycle, M protein 
assessment is required to be repeated on the day the new cycle starts, i.e. Day 1 of the new cycle 
(i.e., Day 50 or 57 of the previous cycle). If treatment is discontinued beyond Day 43, the 
assessment should be repeated on the day of that determination (or as soon as possible 30 days 
after the last dose of study drug) as part of end of treatment (EoT) visit. If the patient enters 
PFS-FU, the first PFS M protein disease status assessment should be scheduled 4 weeks after 
the EoT visit. If the patient is discontinued mid-cycle, prior to Day 28, the EoT visit should be 
scheduled 30 days (+/- 3days) after the last dose of study drug. 
Starting with Cycle 2, M-protein response to treatment should be assessed every cycle. Disease 
status, including skeletal x-rays and/or CT scan of bones, and imaging procedures of known or 
suspected extramedullary plasmacytomas, should be performed at screening and if indicated 
according to the IMWG-URC. Bone marrow aspirate should be performed at screening and to 
confirm suspected CR and MRD status in patients who have negative immunofixation. 
Additional skeletal x-rays and/or imaging assessments may be performed if the patient has 
symptoms suggestive of progression of lesion(s) documented at screening or new lesions. If 
extramedullary plasmacytomas are present at screening and measurable on physical 
examination, they should be assessed at every cycle. Extramedullary plasmacytomas 
documented and measurable only by imaging assessments should be assessed by the same 
relevant modality to confirm response or progression according to the IMWG-URC (Rajkumar 
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8.2.3 Safety and Tolerability Assessments 
Safety Assessments: 
• Assessment and grading of AE 
• Physical examination with vital signs, neurologic assessment and assessment of 
performance status; 
• Routine safety laboratory tests (CBC with differential and platelets; clinical chemistry, 
coagulation tests and urinalysis) with calculation of creatinine clearance according to 
the Cockcroft-Gault equation) 
• Chest X-ray (postero-anterior/lateral) 
• Hepatitis B screen (HBsAg, Anti-HBs, Anti-HBc) 
• Pregnancy testing 
• Electrocardiogram 
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. 
8.2.4 Electrocardiogram Assessments 
At screening and End of Treatment visit a 12-lead ECG assessment will be performed on all 
patients and as clinically indicated thereafter. Q-Tc interval to be assessed by Fridericia formula 
(Appendix H). 
8.2.5 Patient Reported Outcome Assessments 
Three different PROs questionnaires will be used to evaluate functional status and well-being 
in the study; the EORTC QLQ-C30, EQ-5D-3L and EORTC QLQ-MY20 (Aaronson 1993). 
Paper versions of each form will be used. The questionnaires should be submitted to patients 
by site personnel familiar with these procedures and/or preferably a QoL dedicated person in 
the team. The patient should complete the questionnaires prior to any procedures on the day of 
the visit and prior to being told anything related to health; the questionnaires should be 
administered even if the treatment is not given. If the patient wishes to have the questions 
read aloud and then answer orally and the study personnel write the answer on the 
questionnaires, this is acceptable. QoL questionnaires will be submitted to patients at Cycle1 
Day 1, each subsequent cycle on day 1, at the time of EOT visit, at time of progression and at 
the time of starting a new treatment (day 1 of new treatment). If PD/EOT and next treatment 
occur at the same time, only one assessment is required, if the EOT is for a reason other than 
PD, continue QOL assessments each month until PD and at time new treatment begins. If the 
new treatment starts during OS follow-up an additional assessment must be completed at that 
time. A sample of all PRO assessments can be found in Appendix K. 
8.2.6 Pharmacokinetic Assessments 
Plasma samples for determination of melphalan concentrations will be drawn in connection to 
the first two melflufen treatment cycles, 10 – 15 minutes after the end of the infusion, 1 hour 
after the end of infusion and 2 – 4 hours after the end of infusion (as late as possible within the 


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time frame). Refer to the Laboratory Guidance document for details on collecting and 
processing specimens. 
8.2.7 End of Treatment 
The End of Treatment visit should be scheduled 30 days (accepted time window ±3 days) after 
last dose of melflufen or pomalidomide 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, completion of the PRO questionnaires 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 SAEs 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. At the end of the trial, any patient having signed the ICF will 
be allowed to proceed with treatment according to protocol. Patients ongoing on treatment that 
continue to have benefit from treatment will be able to continue therapy until there is disease 
progression or unacceptable toxicity. All patients on treatment will continue to be followed for 
safety. 
8.2.8 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. 
8.2.8.1 Progression Free Survival Follow-up 
Patients who discontinue therapy for reasons other than disease progression should continue to 
have monthly disease assessments done for PFS-FU until progression or initiation of subsequent 
therapy. If PD has not been confirmed prior to initiation of subsequent therapy the reason for 
the subsequent therapy should be documented. The date and regimen of the first subsequent 
therapy should be recorded in the eCRF if it occurs during PFS-FU. PRO assessment should be 
completed monthly until PD and Day 1 of subsequent therapy. 
8.2.8.2 Overall Survival Follow-up 
Following confirmed disease progression, patients will be followed for OS-FU, follow-up for 
overall survival status, second primary malignancies and first subsequent therapy will take place 
every three months +/- 7 days for 24 months. In the event that Oncopeptides AB would like to 
determine the OS status of patients following 24 months, future inquiries about their health 
status may be conducted at any time beyond this time point. This information may be recorded 
outside of the eCRF established for this study. OS-FU may be completed by phone contact. 
Death information from public sources, e.g. death registry, obituary listing, etc. can also be used 
when it is available and verifiable. The date and regimen of the first subsequent therapy should 
be recorded in the eCRF if it occurs during OS - FU. PRO assessment should be completed on 
Day 1 of subsequent therapy if it occurs during OS-FU. 


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8.2.9 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. 
8.2.10 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 Section 7.8). 
• 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. 
• 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 follow-up 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 
SAFETY MONITORING AND REPORTING 
 
9.1 
ADVERSE EVENTS 
9.1.1 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. 




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• Probably related: Clinical event with plausible time relationship to investigational agent 
administration, and that cannot be explained by concurrent disease or other drugs or 
chemicals 
The investigator must appraise all abnormal laboratory results for their clinical significance. 
Only if an abnormal laboratory result is considered clinically significant, should it be reported 
as a treatment emergent adverse event. (See Section 9.1.5.1). 
9.1.4 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 (eg. none, dose reduced, dose held, permanently discontinued). 
5. Whether medication or therapy was given (concomitant medication or procedure,). 
6. Outcome (eg; not resolved, resolved, resolved with sequalae, fatal, unknown). 
7. Whether it is a SAE as defined in Section 9.2.1. 
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 (ie, 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. 
9.1.5 Laboratory Test Abnormalities 
9.1.5.1 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 (eg, anemia requiring transfusions or hyperglycemia requiring 
treatment) or other abnormal assessments (eg, ECG, radiographs, vital signs) must be recorded 
as AEs (or serious adverse events) if they meet the definition of an AE (or serious adverse event) 
as described in Section 9.1 or 9.2. 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: 
• Induce clinical signs and symptoms 


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• Require concomitant therapy 
• Require change in study treatment 
• Investigator considers clinically significant for any reason 
Additional laboratory reporting guidelines. 
Extra attention should be given to reporting all Grade 3 and 4 thrombocytopenia and neutropenia 
events. They must be: 
• Collected and reported during the study period and the EoT visit. 
• Ongoing grade 3 and 4 thrombocytopenia and neutropenia at the time of the EoT visit 
are to be followed until resolution (≤ Grade 2), or stabilization, or initiation of a 
subsequent therapy. 
• All ANC and platelet counts collected during the protocol participation, i.e. both those 
collected at protocol specified time points and any additional time points (unscheduled 
assessments), must be reported in the eCRF and if applicable also in the SAE report. 
• All ANC and platelet counts associated with a SAE regardless of the nature of the event, 
must be reported in the details of the SAE report. 
• Supportive care such as platelet transfusions and G-CSF given for adverse events or 
prophylactic reasons must be reported in the eCRF and if applicable also in the SAE 
report. 
9.2 
SERIOUS ADVERSE EVENTS 
9.2.1 Definitions 
A SAE is defined as any AE, occurring at any dose that meets any one or more of the 
following criteria: 
• Is fatal or immediately life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
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). 
Note that hospitalizations for the following reasons should not be reported as serious adverse 
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• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
• Treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a 
serious adverse event 
• Disease progression: In instances of SAEs due to “disease progression” the event or 
condition that met the criteria for the SAE should be indicated as the event term or 
condition rather than disease progression to the extent possible (e.g. “respiratory failure” 
or “renal failure” due to progressive MM). 
9.2.2 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: 
• Safety.report@oncopeptides.com. 
 
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 serious adverse event. The investigator’s initial causality assessment must 
also be included if available. 
Each re-occurrence, change in grade, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated and 
whether the patient continued or withdrew from study participation. A SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one should be reported separately as a new event. 
Any SAE that occurs after the above defined regular SAE reporting period, should also be 
reported if the investigator suspects a causal relationship to the study treatment. All deaths 
occurring during the regular SAE reporting period must be reported, regardless of cause (See 
Section 9.2.2.1). 
SAEs should be followed until resolution, or stabilization with no anticipation of resolution 
regardless of 30-days reporting time line unless deemed by the investigator as not expecting to 


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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 Independent Ethics Committees 
(IECs/Institutional Review Boards (IRBs) 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. 
9.2.2.1 Reporting of Death 
• Death is an outcome of a serious adverse event and not a serious adverse event in itself. 
When death is an outcome, the event(s) resulting in death should be reported (eg, 
“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 (eg, “respiratory 
failure” due to progressive MM). 
• Deaths that occur later than 30 days after the last study drug administration should be 
reported as SAEs only if assessed as related to the study treatment. 
9.3 
PREGNANCY 
All instances of pregnancy or suspected pregnancy occurring in a patient or partner of a 
patient taking pomalidomide must be reported according to the regional REMS™/PPP 
program and the guidelines detailed below. 
Arm A and B 
The pregnancy should be followed-up to determine its outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications and possible relationship 
to the study treatment. 
A pregnancy reporting form must be filled out and sent via email. Fax number, (only to be used 
in case of email malfunction) is provided in the ISF. 
• Email: Safety.report@oncopeptides.comAny SAE experienced during pregnancy 
(such as congenital anomaly/birth defect/spontaneous abortions) must be reported via 
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. 
 
10 
DATA COLLECTION AND MANAGEMENT 
 
10.1 
DATA CONFIDENTIALITY 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization form informing 
the patient of the following: 


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• 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. 
10.2 
SITE MONITORING 
Before study initiation, at a site initiation visit 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 to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Oncopeptides AB (or CRO) monitoring standards require 
full source data verification for the presence of signed and dated informed consent, adherence 
to the inclusion/exclusion criteria and documentation of AE/SAEs. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. 
10.3 
DATA COLLECTION 
An 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. 


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The designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the electronic data 
capture (EDC) system until they have been trained. Automatic validation programs will check 
for data discrepancies in the eCRFs and allow modification or verification of the entered data 
by the investigator staff. 
The study Investigators are responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
10.4 
DATABASE MANAGEMENT AND QUALITY CONTROL 
Oncopeptides AB personnel (or designated CRO) will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the problem 
and requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
 
11 
STATISTICAL METHODS AND DATA ANALYSIS 
 
11.1 
STUDY ENDPOINTS 
11.1.1 Primary Endpoint 
PFS is defined as time (months) from date of randomization to the earlier of confirmed disease 
progression or death due to any cause. Progression dates will be assessed by the IRC using the 
IMWG-URC, (Rajkumar et al. 2011). The conventions for censoring of PFS are described in 
Table 11-1. 
11.1.2 Secondary Endpoints 
11.1.2.1 Key Secondary Endpoints 
Unless stated otherwise, response and progression status will be assessed by the IRC using the 
IMWG-URC, (Rajkumar et al. 2011, Appendix C). 
ORR: defined as a best confirmed response of sCR, CR, VGPR, or PR using local laboratory 
evaluation. 
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. 
OS: defined as time (months) from date of randomization to death due to any cause. Patients 
still alive at end of study, or lost to follow up, will be censored at last day known alive. 
The maximum grade (according to CTCAE v4.03) for each type of AE will be recorded for each 
patient, and frequency tables will be presented and reviewed to determine patterns. 
Additionally, the relationship of the AE(s) to the study treatment will be taken into 
consideration. Laboratory abnormalities will be presented and reviewed. 


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11.1.2.2 Other Secondary Endpoints 
Unless stated otherwise, response and progression status will be assessed by the IRC using the 
IMWG-URC, (Rajkumar et al. 2011 Appendix C). 
• CBR, i.e. ≥ MR: is the rate of response evaluable patients that achieve a confirmed MR 
or better. 
• TTR: is defined as the time from the date of randomization to the date of the first 
documented confirmed response in a patient that has responded with ≥ PR. 
• TTP: is defined as the time from the date of randomization to the date of the first 
documented confirmed PD. 
• Duration of clinical benefit (DOCB): defined as the time 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. DOCB is defined only for patients with a 
confirmed MR or better. 
• Best response during the study (sCR, CR, VGPR, PR, MR, stable disease [SD] or PD) 
using the IMWG-URC, (Rajkumar et al. 2011 Appendix C) 
• Primary and secondary endpoint as assessed by Investigator’s 
11.1.2.3 Exploratory Endpoints 
• PK parameters of melphalan (Arm A) 
• MRD for patients that achieve a CRValue and change from baseline in each scale of the 
EORTC QLQ-C30, each scale of the MY20, each dimension of the EQ-5D, and the VAS 
of the EQ-5D 
11.2 
SAMPLE SIZE CALCULATION 
The sample size calculation is based on comparing the melflufen + dexamethasone arm and the 
pomalidomide + dexamethasone arm in terms of PFS. The sample size estimation is based on 
the following assumptions: 
Power 
90 % 
Significance level 
0.05 % two-sided 
HR (melflufen+dex/pomalidomide+dex) 
0.70 
Distribution of survival times 
exponential 
Accrual time 
24 months 
Follow up time 
6 months after last patient randomized 
Total study time 
30 months 
Early censor rate 
approximately 15 % 
Time to full recruitment speed 
6 months 
Median PFS for control arm 
3.6 months (FDA Pomalyst Precribing Information 2015) 
The final analysis will take place when 339 patients have experienced a PFS event. Based on 
the assumptions, it is anticipated that a total of 450 patients will be randomized over 24 months 
in order to reach 339 events 6 months after the randomization of the last patient. 


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11.3 
STATISTICAL METHODS 
11.3.1 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. In general, 
summaries of all data will be provided for each group and the combined group (total group). 
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. 
11.3.2 Analysis Populations 
11.3.2.1 Enrolled Analysis Set 
The Enrolled analysis set is defined as all subjects who are assigned a subject ID. This analysis 
set includes randomized subjects and non-randomized subjects, identified as screen failures. 
The Enrolled analysis set will be the primary population for the summaries of disposition. 
Randomized subjects will be summarized according to the treatment assigned at randomization. 
11.3.2.2 Full Analysis Set 
The Full analysis set is defined as all subjects who are randomized. Subjects will be analyzed 
according to the treatment assigned at randomization. The primary analysis (PFS) will be 
performed using the Full analysis set. 
11.3.2.3 Safety Analysis Set: 
The Safety analysis set is defined as all subjects who received at least one or partial dose of 
melflufen, pomalidomide, or dexamethasone. The Safety analysis set will be the primary 
population for the summaries of all exposure and safety data. Subjects will be summarized 
according to the treatment actually received. 
11.3.2.4 Per Protocol Analysis Set 
The Per Protocol analysis set is defined as all subjects who received at least one dose of 
melflufen, pomalidomide, or dexamethasone and have a baseline assessment of disease status 
and at least one post-baseline assessment for disease response. Subjects who have major 
protocol deviations, related to critical eligibility criteria, the assessment of efficacy or the safety 
of the subject that could significantly impact the interpretation of study results, will be excluded 
from the Per Protocol analysis set. The supporting analysis of the primary and secondary 
efficacy endpoints will be evaluated using the Per Protocol analysis set. Subjects will be 
analyzed according to the treatment actually received. 
11.3.2.5 Patient Reported Outcomes Analysis Set 
HRQoL assessments were added at the time of protocol version 4.1. Only participants who 
enroll on or after protocol version 4.1, have completed at least 1 PRO questionnaire will be 
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The distribution of PFS will be summarized for each treatment arm using the Kaplan-Meier 
method. The median PFS will be estimated for each treatment arm from the 50th percentile of 
the corresponding Kaplan-Meier estimates. The 95% CI for median PFS will be constructed 
using the method of Brookmeyer (Brookmeyer and Croewey, 1982). Duration of follow-up for 
PFS will be summarized according to the Kaplan-Meier (K-M) estimate of potential follow-up 
also termed “reverse Kaplan-Meier” (Schemper and Smith, 1996). 
Non-inferiority of melflufen and dexamethasone versus pomalidomide and dexamethasone for 
the Full analysis set will be demonstrated if the upper limit of the 95 % confidence interval is 
below 1.2. This assessment is relevant for non-FDA submissions. 
Superiority of melflufen and dexamethasone versus pomalidomide and dexamethasone for the 
Full analysis set will be demonstrated if the upper limit of the 95 % confidence interval is below 
1.0. 
11.3.3.2 Subgroup Analyses for PFS 
The PFS data will be analyzed and presented by a number of prospectively identified subgroups 
based on the Full analysis set such as the following: 
• Age (< 65, ≥ 65 and < 75, and ≥ 75) 
• Number of prior lines of therapy 
• ISS Score 
• Subgroups of refractoriness to previous therapies 
• Race (American Indian or Alaskan native, Black or African American, Asian, 
Caucasian/White, Native Hawaiian or other Pacific Islander, other) 
The full list of prospectively identified subgroups are identified in the SAP. In addition, 
subgroups may be identified on a data driven basis, and such analyses will be considered as 
exploratory. 
11.3.3.3 Analysis of Secondary Endpoints 
All inferential analyses of the key secondary endpoints will be performed using two-sided tests 
at a significance level of 0.05. The key secondary endpoints will be tested in a closed testing 
procedure in a hierarchal fashion, starting with ORR, followed by DOR and OS, where the test 
of ORR is conditional on the test of the primary analysis of PFS being significant, the test of 
DOR is conditional on the test of ORR being significant, and the test of OS conditional on the 
test of DOR being significant. This closed testing procedure will control the family-wise type 
1 error rate. The analyses will primarily be based on the Full analysis set followed by the Per- 
protocol analysis set. 
The ORR will be estimated as the proportion of patients in each treatment group who achieve a 
confirmed response of sCR, CR, VGPR, or PR as their best response. The treatment groups will 
be compared using the Cochran Mantel Haenszel chi square test. The exact binomial 95% CI 
for ORR will be calculated for each treatment arm. 
The DOR will be calculated for subjects 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. The treatment arms will be compared with respect to DOR using a log-rank 


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test at a significance level of 0.05 with no adjustment for covariates. OS is defined as time 
(months) from the date of randomization to date of death due to any cause. Subjects who are 
alive will be censored at the last follow up visit. The treatment arms will be compared with 
respect to OS using a stratified Cox proportional hazards regression model based on the Full 
analysis set stratified by the stratification factors. 
K-M methods will be used to estimate the distribution of OS and the median and other quartiles 
with their 95% confidence intervals; a figure showing the estimated OS distribution will be 
provided. 
Best response (CR, VGPR, PR, MR, SD or PR) will be summarized without analysis. The 
approximate 95% CIs for CR, VGPR, and MR will be calculated for each treatment arm. 
CBR will be summarized without analysis. The approximate 95% CI for CBR will be calculated 
for each treatment arm. 
TTR will be summarized without analysis. 
TTP will be summarized without analysis. 
Duration of MR and SD will be summarized without analysis. 
The methods for the analysis of the PK data will be described in a separate population PK-PD 
plan. 
11.3.4 Analysis of Safety Endpoints 
All safety results will be presented for the safety analysis set. No formal statistical analysis will 
be performed for the safety endpoints. 
Study treatment administration, including duration of exposure, total dose, and dose 
modifications will be summarized for each group separately. 
Each reported AE term will be mapped to a preferred term (PT) and a system organ class (SOC) 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). The 
summaries of 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. 


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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. 
Actual value and change from baseline for all hematology, serum chemistry, and coagulation 
parameters will be summarized at each scheduled visit. Selected laboratory test results will be 
assigned toxicity grades using CTCAE 4.03. Shift tables assessing the toxicity grade at baseline 
versus worst toxicity recorded on study will be presented. A listing of all grade 3 or higher 
laboratory values will be provided. 
Actual value and change from baseline for weight and vital sign results, including blood 
pressure, pulse, and temperature, will be summarized at each scheduled visit. Any clinically 
significant values will be reported by the investigator as AEs. 
11.3.5 Analysis of Patient Reported Outcomes 
Three patient-reported outcome (PRO) scales will be assessed including EORTC QLQ-C30, 
EORTC MY20 and EQ 5D questionnaires (Aaronson et al, 1993). The observed value and 
change from baseline in each scale of the EORTC QLQ-C30, each scale of the MY20, each 
dimension of the EQ-5D, and the VAS of the EQ-5D will be summarized at each visit. The 
methods and results for additional analyses of the PRO data are described in the SAP and a 
separate supporting document. 
11.4 
HANDLING OF DROP-OUTS AND MISSING DATA 
The SAP describes how dropouts and missing data impact the calculation of the time to event 
variables. Missing data will not be estimated or carried forward for any of the other summaries 
or analyses. If only a partial date is available and is required for a calculation (e.g., time since 
diagnosis, time since most recent relapse, determination of whether a medication is 
concomitant, or an AE is treatment-emergent), the date will be imputed. Detail of the methods 
of imputation will be provided in the SAP. 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned. 
11.6 
NON-INFERIORITY ANALYSIS AND CHOICE OF NON-INFERIORITY 
MARGIN 
According to EU guidelines, the choice of non-inferiority margin is based on a combination of 
statistical reasoning and clinical judgment (Guideline of the choice of the non-inferiority margin 
EMEA/CPMP/EWP/2158/99). The proposed comparator has, in a previous Phase 3 trial, shown 
superiority over an active control (high-dose dexamethasone) with a PFS HR of 0.45 (2-sided 
95% confidence interval 0.35-0.59) (Pomalidomide Celgene EPAR 2013). The upper limit of 
the confidence interval (0.59) would then correspond to a HR of 1.69 (1/0.59). A non-inferiority 
trial comparing melflufen and dexamethasone versus pomalidomide and dexamethasone where 
the upper limit of the 95% confidence interval is less than 1.69 can then be interpreted as 
superiority over high-dose dexamethasone since the 95% confidence interval of the melflufen 
study will not overlap with the 95% confidence interval of the historical study data. Since high- 
dose dexamethasone is an active compound, the difference against a hypothetical placebo would 
be even larger. 


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Even though a non-inferiority margin of 1.69 might satisfy the statistical regulatory 
requirements, it would allow melflufen and dexamethasone to be substantially worse than the 
pomalidomide and dexamethasone comparator arm and this is clearly not clinically acceptable. 
In the current trial a non-inferiority margin of 1.2 will be used. With the planned sample size, 
this margin will ensure that the point estimate of the HR will be 1 or better (≤ 1). A non- 
inferiority margin of 1.2 will thus ensure a roughly similar or better efficacy of melflufen versus 
pomalidomide with the respect to the primary endpoint of PFS. 
11.7 
PHARMACOKINETIC ANALYSIS 
The pharmacokinetic (PK) evaluation will be performed only in patients randomized to 
melflufen + dexamethasone treatment (Arm A). 
Three plasma samples for determination of melphalan concentrations should be drawn at each 
of the first two melflufen treatment cycles. The first sample should be taken 10-15 minutes after 
end of infusion, the second sample 1 hour after end of infusion and the third sample 2 to 4 hours 
(as late as possible within the time frame) after end of infusion. 
The relationship between melphalan PK parameters and patient factors, will be assessed, as well 
as the inter-occasion variability in melphalan exposure when comparing data for treatment 
cycles 1 and 2. 
The melphalan concentration data will be pooled across patients and evaluated using a 
population approach with nonlinear mixed-effect modeling. Actual time points for drug 
administration and plasma sampling will be used. 
Covariates in the analysis will include, age, gender, ethnicity, renal function (as calculated by 
the Cockcroft-Gault formula), body weight, melflufen dose, and concomitant medications. 
Additional variables may be added. All covariates with the exception of ethnicity and 
concomitant medications will be analyzed as continuous variables. Concomitant medication 
will be entered as present/absent, dose data will not be used. 
The optimal structural population PK model will be determined with estimation of fixed and 
random effects. Data from previous pharmacokinetic studies in other populations will be 
included as appropriate for a more accurate determination of the structural PK model. Covariate 
relationships on the PK parameters of the structural model will be explored using graphical and 
statistical methods. 
Details on the modeling approach will be described in a separate population PK-PD plan which 
will be developed in parallel with the phase 3 program for melflufen. 
11.8 
EXPOSURE-RESPONSE ANALYSES 
The relationship between melphalan exposure as determined by the population PK analysis and 
by the administered melflufen doses, and safety and efficacy variables will be explored. The 
incidence 
of 
typical 
melphalan 
adverse 
drug 
reactions 
including 
neutropenia, 
thrombocytopenia, mucositis, nausea, vomiting, and diarrhea will be evaluated. Similarly, the 
relationship between melphalan exposure and disease response as described by the key efficacy 
variables will be explored. The methods will be detailed in a separate population PK-PD plan 
which will be developed in parallel with the phase 3 study. Data from other melflufen studies 
may be included in this analysis as appropriate. 


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12 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
 
12.1 
REGULATORY AND ETHICAL COMPLIANCE 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC 
and US Code of Federal Regulations Title 21), and with the ethical principles laid down in the 
Declaration of Helsinki. 
12.2 
DATA MONITORING COMMITTEE 
An independent data monitoring committee (DMC) will perform surveillance of efficacy/safety 
balance at regular intervals during the study, using unblinded treatment-aggregated data. All 
activities and processes surrounding the DMC will be outlined in the DMC Charter. 
• The Clinical Research Organizations (CROs) and the Sponsor will be unblinded to 
individual patient data during the study but will not have access to the unblinded, 
aggregate data listings used by the DMC for their review. 
• The CROs’ medical monitors and the Sponsor’s safety officer may have access to 
aggregate safety data and treatment assignment as needed to fulfill the obligation of 
safety oversight of the study. 
12.3 
INDEPENDENT REVIEW COMMITTEE 
An IRC will assess all tumor responses and PD assessments during the study. The IRC members 
will be blinded to all treatment data and perform their reviews in closed-meeting sessions. All 
activities and processes surrounding the IRC will be outlined in the IRC Charter. 
12.4 
RESPONSIBILITIES OF THE INVESTIGATOR AND IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB, IEC or REB before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Oncopeptides AB (or designated CRO) before study initiation. Prior to study start, the 
investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Oncopeptides AB 
(or designated CRO) monitors, auditors, Clinical Quality Assurance representatives, designated 
agents of Oncopeptides AB, IRBs/IECs/REBs and regulatory authorities as required. 
12.5 
INFORMED CONSENT PROCEDURES 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-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. 


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Oncopeptides AB (or designated CRO) will provide to investigators, in a separate document, a 
proposed informed consent form (ICF) that is considered appropriate for this study and complies 
with the ICH GCP guideline and regulatory requirements. Any changes to this ICF suggested 
by the investigator must be agreed to by Oncopeptides AB before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the Oncopeptides AB 
(or designated CRO) monitor after IRB/IEC/REB approval. 
12.6 
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 
unacceptable danger for the patient’s health caused by the study treatment. 
12.7 
PUBLICATION OF STUDY PROTOCOL AND RESULTS 
Oncopeptides AB assures that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. Any publication will 
be a joint publication between Oncopeptides AB and the investigators and authorship will be 
determined by mutual agreement. 
12.8 
STUDY DOCUMENTATION, RECORD KEEPING AND RETENTION OF 
DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in an Oncopeptides AB 
sponsored study, each site will permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 


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at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The study eCRF is the primary data collection instrument for the study. 
The 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. 
12.9 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Oncopeptides AB, their agents or Health Authorities. Signed 
informed consent forms and patient enrollment log must be kept strictly confidential to enable 
patient identification at the site. Refer to Section 10.1 for additional details regarding patient 
confidentiality. 
12.10 AUDITS AND INSPECTIONS 
Source data/documents must be available to inspections by Oncopeptides AB or designee or 
Health Authorities. 
12.11 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. 
 
13 
PROTOCOL ADHERENCE 
Investigators ascertain they will apply due diligence to avoid protocol deviations. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Oncopeptides 
AB or designated CRO should be notified of this action and the IRB/IEC at the study site should 
be informed according to local regulations. 


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13.1 
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 IRB/IEC/REB before it may be implemented. Only amendments that are required for 
patient safety may be implemented prior to IRB/IEC/REB approval. 


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14 
REFERENCES 
 
Aaronson NK, Ahmedzai S, Bergman B, et el. (1993) The European Organisation for Research 
and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical 
trials in oncology. Journal of the National Cancer Institute; 85: 365-376. 
 
Brookmeyer, R. and J. Crowley (1982). "A Confidence Interval for the Median Survival Time." 
Biometrics 38(1), 29-41 
Cavo, M., S. V. Rajkumar, A. Palumbo, et al. (2011). “International Myeloma Working Group 
consensus approach to the treatment of multiple myeloma patients who are candidates for 
autologous stem cell transplantation.” Blood 117(23): 6063-6073. 
Chauhan, D., A. Ray, K. Viktorsson, et al. (2013). “In vitro and in vivo antitumor activity of a 
novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells.” Clin Cancer 
Res 19(11): 3019-3031. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
FDA 
Pomalyst 
Precribing 
Information 
(2015). 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204026s005s006s008lbl.pdf 
Gullbo, J., E. Lindhagen, S. Bashir-Hassan, et al. “Antitumor efficacy and acute toxicity of the 
novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.” Invest New 
Drugs 2004, 22(4): 411-420. 
Gullbo, J., et al., Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour 
efficacy of the melphalan containing prodrug J1. J Drug Target, 2003c. 11(6): p. 355-63. 
Imnovid EPAR (2013). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- 
_Public_assessment_report/human/002682/WC500147721.pdf. 
Kumar, S., Paiva, B., Anderson, K. et al., et al. (2016). International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple myeloma. 
The Lancet Oncology, Volume 17, Issue 8, e328 - e346 
Kumar S., Rajkumar S.V., Dispenzieri A, et al., Improved survival in multiple myeloma and 
the impact of novel therapies Blood March 1, 2008 vol. 111 no. 5 2516-2520. 
Mougenot, P., F. Pinguet, M. Fabbro, et al. (2004). “Population pharmacokinetics of melphalan, 
infused over a 24-hour period, in patients with advanced malignancies.” Cancer Chemother 
Pharmacol 53(6): 503-512. 
Nath, C. E., P. J. Shaw, J. Trotman, et al. (2010). “Population pharmacokinetics of melphalan 
in patients with multiple myeloma undergoing high dose therapy.” Br J Clin Pharmacol 69(5): 
484-497. 
National Comprehensive Cancer Network (2016). “NCCN Clinical Practice Guidelines 
Multiple Myeloma Version 3.2016. .” National Comprehensive Cancer Network; 
https://www.nccn.org/professionals/physician_gls/pdf/myeloma_blocks.pdf 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649- 
55. 


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Paba-Prada, C., A. Palumbo, U. H. Mellqvist, et al. (2014). "Determination of the MTD and 
Preliminary Results in an Ongoing Open-Label Phase I/IIa Study of the Safety and Efficacy of 
Melflufen and Dexamethasone in Combination for Patients with Relapsed and Relapsed- 
Refractory Multiple Myeloma (RRMM)." Blood 2014 124:2123. 
Palumbo, A., Avet-Loiseau, H., Oliva, S., et al. (2015). Revised International Staging System 
for Multiple Myeloma: A Report from International Myeloma Working Group. Journal of 
Clinical Oncology 33:26, 2863-2869 
Quach H, Ritchie D, Stewart A.K., et al. (2009) Mechanism of action of immunomodulatory 
drugs (IMiDS) in multiple myeloma. Leukemia 24, 22–32. 
Rajkumar, S. V., J. L. Harousseau, B. Durie, et al. (2011). “Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus 
Panel 1.” Blood 117(18): 4691-4695. 
Rajkumar S.V. Richardson P, San Miguel, J. (2015). “Guidelines for determination of the 
number of prior lines of therapy in multiple myeloma.” Blood 126:921-922. 
Richardson, P. G., J. Laubach, C. Mitsiades, et al. (2010). "Tailoring treatment for multiple 
myeloma patients with relapsed and refractory disease." Oncology (Williston Park) 24(3 
San Miguel, J., K. Weisel, P. Moreau, et al. (2013). “Pomalidomide plus low-dose 
dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory 
multiple myeloma (MM-003): a randomised, open-label, phase 3 trial.” Lancet Oncol 14(11): 
1055-1066. 
Schemper, M. and Smith T.L. (1996) A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials 17:343–346 
SEER (2016). "Surveillance, Epidemiology, and End Results Program Cancer statistics Stat 
Fact Sheets: Myeloma." National Cancer Institute; 
http://www.seer.cancer.gov/statfacts/html/mulmy.html 
Wickström M, J.J., Ponthan F, The novel melphalan prodrug J1 inhibits neuroblastoma growth 
in vitro and in vivo. Mol Cancer Ther, 2007. 6: p. 2409-2417. 
Wickström M, The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a 
possible target directed release of melphalan. Biochem Pharmacol, 2010. 79: p. 1281-1290. 
Wickström, M., et al., The novel alkylating prodrug J1: diagnosis directed activity profile ex 
vivo and combination analyses in vitro. Invest New Drugs, 2008. 26(3): p. 195-204. 
 
Wisloff, F., Eika, S., Hippe E., et al. (1996). “Measurement of health-related quality of life in 
multiple myeloma. Nordic Myeloma Study Group.” Br J Haematol. 1996;92:604–613 
 
Wisloff F, Hjorth M. (1996). “Health-related quality of life assessed before and during 
chemotherapy predicts for survival in multiple myeloma” Br J Haematol. 1997;97:29–37 


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Dead 
5 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
4 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
3 
Ambulatory and capable of all self-care but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours. 
2 
Symptoms, but fully ambulatory, restricted in physically 
strenuous but ambulatory and able to carry out work of a light or 
sedentary nature (eg, light housework, office work). 
1 
Normal activity, fully active, able to carry on all pre-disease 
performance without restriction. 
0 
Description 
Grade 
15 
APPENDICES 
 
Appendix A. Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
 
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, et al. 2011) 
Stringent 
Complete 
Response 
(sCR) 
CR as defined below plus: 
• normal FLC ratio and 
• absence of clonal cells in bone marrow by immunohistochemistry 
or 2 – 4 color flow cytometry 
Complete 
Response 
(CR) 
• Negative immunofixation on the serum and urine and 
• disappearance of any soft tissue plasmacytomas and 
• 
< 5% plasma cells in bone marrow. 
• In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 
is required. 
Very Good 
Partial 
Response 
(VGPR) 
• Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis or 
•  > 90% reduction in serum M-protein plus urine M-protein 
level < 100 mg/24 h. 
• In patients with only FLC disease, > 90% decrease in the 
difference between involved and uninvolved FLC levels is 
required. 
Partial 
Response 
(PR) 
• 50% reduction of serum M-protein and reduction in 24 hours 
urinary M-protein by > 90% or to < 200 mg/24 h 
• If the serum and urine M-protein are unmeasurable, a > 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
• If serum and urine M-protein are not measurable, and serum free 
light assay is also not measureable, > 50% reduction in plasma 
cells is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was > 30% 
• In addition to the above listed criteria, if present at baseline, 
a > 50% reduction in the size of soft tissue plasmacytomas is also 
required 
Minimal 
response 
(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/24hrs. 
• In addition to above; if present at baseline, 25-49% reduction in the 
size of soft tissue plasmacytomas is also required 
• No increase in size or number of lytic bone lesions (development 
of compression fractures does not exclude response) 
Stable 
Disease (SD) 
• Not meeting criteria for CR, VGPR, PR, MR or progressive 
disease 


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Progressive 
disease 
(PD) 
Increase of > 25% from lowest response value in any one of the following: 
• 
Serum M-component (the absolute increase must be > 0.5 g/dL) and/or 
• 
Urine M-component (the absolute increase must be > 200 mg/24 h) 
and/or 
• 
Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL 
• 
Only in patients without measurable serum and urine M-protein and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute % must be ≥ 10%) 
• 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone lesions 
or soft tissue plasmacytomas 
• 
Development of hypercalcemia (corrected serum 
calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder 
 
All response categories (CR, sCR, VGPR, PR, MR and PD) require two consecutive 
assessments made at any time before the institution of any new therapy; 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 ≥ 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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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 Creatinine Clearance rate using Cockcroft-Gault Formula 
 
 
For males: 
Creatinine Clearance = (140-age[years] ×weight [kg]) OR (140–age[years] ×weight [kg]) 
72 × (serum creatinine[mg/dL]) 
0.81 × (serum creatinine[µmol/L]) 
 
For females: 
Creatinine Clearance = 0.85 (140-age[years] ×weight [kg]) OR 0.85 (140-age[years] ×weight [kg]) 
72 × (serum creatinine[mg/dL]) 
0.81 × (serum creatinine[µmol/L]) 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 




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Appendix J.  Pomalidomide Pregnancy Prevention Plan. 
 
Sites and patients randomized to Arm B in Canada or USA should be enrolled in and comply 
with the Celgene REMS™ program specific to the country of enrolment. 
Sites and patients randomized to Arm B outside Canada or USA are required to comply with 
the following pomalidomide Pregnancy Prevention Plan (PPP). Components of this plan are 
detailed below: 
1. Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods. 
This document provides the following information for reference by the health care 
professional: 
• Potential risks to the fetus associated with pomalidomide exposure 
• Definition of Female of Childbearing Potential (FCBP) 
• Pregnancy testing requirements for patients receiving Pomalidomide who are 
females of childbearing potential 
• Acceptable birth control methods for both females of childbearing potential and 
male patients receiving pomalidomide in the study 
• Requirements for counselling of all study patients receiving pomalidomide 
about pregnancy precautions and the potential risks of fetal exposure to 
pomalidomide 
2. Pomalidomide Education and Counseling Guidance Document 
• The Pomalidomide Education and Counselling Guidance Document must be 
completed and signed by either a trained counselor or the Investigator at the 
participating clinical center prior to each dispensing of pomalidomide study 
treatment. A copy of this document must be maintained in the patient records. 
3. Pomalidomide Information Sheet 
• The Pomalidomide Information Sheet must be given to each patient receiving 
pomalidomide study therapy. The patient must read this document prior to 
starting pomalidomide study treatment and each time they receive a new supply 
of study drug. 


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Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
Risks Associated with Pregnancy 
Pomalidomide is structurally related to thalidomide. Thalidomide is a known human 
teratogenic active substance that causes severe life-threatening birth defects. An embryofetal 
development study in animals indicates that pomalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy. The teratogenic effect 
of pomalidomide in humans cannot be ruled out. Therefore, a risk minimisation plan to prevent 
pregnancy must be observed. 
Definition of females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
Pregnancy testing requirements for FCBP 
Before starting pomalidomide 
FCBP must have two negative medically supervised pregnancy tests (sensitivity of at least 25 
mIU/mL) prior to starting pomalidomide including female patients who commit to complete 
abstinence, as outlined below. The first pregnancy test must be performed within 10 to 14 days 
prior to receiving the prescription for pomalidomide and the second pregnancy test must be 
performed within 24 hours prior to receiving the prescription for pomalidomide. The patient 
may not receive study drug until the Investigator has verified that the results of these pregnancy 
tests are negative. 
Pregnancy testing during the entire duration of pomalidomide treatment and for 28 days 
following discontinuation of pomalidomide 
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly 
for the first 4 weeks of study participation and then every 4 weeks while on 
pomalidomide treatment, and 4 weeks following pomalidomide discontinuation. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 4 
weeks and then every 2 weeks while on pomalidomide treatment, and 2 weeks and 4 
weeks following discontinuation of pomalidomide. 
• Pregnancy testing and counselling must be performed if a patient misses her period or 
if her pregnancy test or her menstrual bleeding is abnormal. Pomalidomide treatment 
must be discontinued during this evaluation. 
• At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control. 
Acceptable birth control methods 
Birth control for FCBP 


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FCBP taking pomalidomide must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual contact during the 
following time periods related to this study: for at least 28 days before starting pomalidomide 
treatment; throughout the entire duration of pomalidomide treatment; during dose interruptions; 
and for at least 28 days after discontinuation of pomalidomide. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. 
The following are examples of highly effective and additional effective methods of 
contraception: 
o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking pomalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently using combined oral contraception the patient should 
switch to one of the effective methods listed above. The risk of venous thromboembolism 
continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia. 
Birth control for males 
Males taking pomalidomide must practice complete abstinence or agree to use a condom during 
sexual contact with a pregnant female or a female of childbearing potential throughout the entire 
duration of pomalidomide treatment, during dose interruptions and for at least 4 weeks 
following discontinuation of pomalidomide, even if he has undergone a successful vasectomy. 
Counselling 
Counselling for FCBP 
For a female of childbearing potential, must be counselled about pregnancy precautions and the 
potential risks of fetal exposure prior to the start of pomalidomide and at a minimum of every 
4 weeks. The counsellor should verify that: 
• She understands the potential teratogenic risk to the unborn child 


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• She understands the need for effective contraception, without interruption 4 weeks 
before starting pomalidomide treatment, throughout the entire duration of 
pomalidomide treatment, dose interruption in therapy and 4 weeks after the end of 
pomalidomide treatment 
• She agrees and is capable of complying with effective contraceptive measures 
• She is informed and understands the potential consequences of pregnancy and the need 
to notify her study doctor immediately if there is a risk of pregnancy 
• She understands the need to commence the pomalidomide treatment as soon as 
pomalidomide is dispensed following a negative pregnancy test 
• She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined above. 
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of pomalidomide 
• She understands never to give pomalidomide to another person and to return any unused 
capsules to the Investigator each cycle and at the end of treatment. 
• She understands not to donate blood during therapy and for at least 4 weeks following 
discontinuation of pomalidomide. 
• She understands and agrees to abstain from breastfeeding while on pomalidomide, and 
for at least 4 weeks after discontinuation of pomalidomide. 
The investigator must verify that females of childbearing potential: 
• Comply with the conditions of the PPP, including confirmation that she has an adequate 
level of understanding 
• If pregnancy or a positive pregnancy test does occur in a study patient, pomalidomide 
must be immediately discontinued. 
Counselling for females NOT of childbearing potential 
All females NOT of childbearing potential must be counselled concerning the following risks 
and requirements prior to the start of pomalidomide study therapy: 
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of pomalidomide 
• She understands never to give pomalidomide to another person and to return any unused 
capsules to the Investigator each cycle and at the end of treatment. 
• She understands not to donate blood during therapy and for at least 4 weeks following 
discontinuation of pomalidomide. 
Counselling for male patients 
• Traces of pomalidomide have been found in semen. Male patients must be counselled 
concerning the risks and requirements prior to the start of pomalidomide therapy and at 
a minimum of every 4 weeks. 


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The counsellor must verify that the following: 
• He understands the potential teratogenic risk if engaged in sexual activity with a 
pregnant female or female of childbearing potential 
• He understands the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or female of childbearing potential. 
• He understands the requirement for complete abstinence or condom use during sexual 
contact with a pregnant female or female of childbearing potential and the potential risks 
of fetal exposure to pomalidomide 
• He understands that if pregnancy or a positive pregnancy test does occur in the partner 
of a male study patient during study participation, the investigator must be notified 
immediately. 
• He understands never to give pomalidomide to another person and to return any unused 
capsules to the Investigator each cycle and at the end of treatment. 
• He understands he should not donate blood, semen or sperm during therapy or for at 
least 4 weeks following discontinuation of pomalidomide. 
For ALL patients: 
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Pomalidomide Education and Counselling Guidance Document 
 
To be completed prior to each dispensing of study drug. 
Protocol Number:  OP-103 
Patient ID: 
 
(Check the appropriate box to indicate risk category) 
Female: □ 
If female, check one: 
 
□ FCBP sexually mature female who: 1) has not undergone a hysterectomy (the surgical 
removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 
2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at 
any time during the preceding 24 consecutive months) 
□ NOT FCBP 
 
Male: 
□ 
 
Do not dispense study drug if: 
• The patient is pregnant. 
• No pregnancy tests were conducted for a FCBP. 
• The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual contact) [at least 28 days prior to 
therapy, during therapy and during dose interruption]. 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 
 
2. I counseled FCBP regarding the following: 
• Potential risk of fetal exposure to pomalidomide: If pomalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. Females are advised to 
avoid pregnancy while taking pomalidomide. The teratogenic potential of pomalidomide in 
humans cannot be ruled out. FCBP must agree not to become pregnant while taking 
pomalidomide. 
• Using TWO reliable methods of birth control at the same time or complete abstinence from 
heterosexual contact [at least 28 days prior to therapy, during therapy, during dose 
interruption and 28 days after discontinuation of study drug]. 
• That even if she has amenorrhea she must comply with advice on contraception. 
Use of one highly effective method and one additional method of birth control AT THE SAME 
TIME. The following are examples of highly effective and additional effective methods of 
contraception: 


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- 
Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
- 
Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
• Pregnancy tests are required before and during treatment, even if the patient agrees not to 
have reproductive heterosexual contact. Two pregnancy tests will be performed prior to 
receiving study drug, one within 10 to 14 days and the second within 24 hours of the start 
of study drug. 
Frequency of pregnancy tests to be done: 
• Every week during the first 28 days of this study and a pregnancy test every 28 days during 
the patient’s participation in this study if menstrual cycles are regular or every 14 days if 
cycles are irregular. 
• If the patient missed a period or has unusual menstrual bleeding. 
• When the patient is discontinued from the study and at Day 28 after study drug 
discontinuation if menstrual cycles are regular. If menstrual cycles are irregular, pregnancy 
tests will be done at discontinuation from the study and at Days 14 and 28 after study drug 
discontinuation. 
• Stop taking study drug immediately in the event of becoming pregnant and to call their study 
doctor as soon as possible. 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping study drug. 
• Do not breastfeed a baby while participating in this study and for at least 28 days after study 
drug discontinuation. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug to the study doctor. 
3. Provide Pomalidomide Information Sheet to the patient. 
 
Female Not of Childbearing Potential 
(Natural menopause for at least 24consecutive months, a hysterectomy, or bilateral 
oophorectomy): 
1. I counseled the female NOT of child bearing potential regarding the following: 


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• Potential risks of fetal exposure to pomalidomide (Refer to item #2 in FCBP) 
• NEVER share pomalidomide with anyone else. 
• Do not donate blood while taking pomalidomide and for 28 days after stopping 
pomalidomide 
• Do not break, chew, or open pomalidomide capsules 
• Return unused pomalidomide capsules to the study doctor. 
2. Provide Pomalidomide Information Sheet to the patient. 
Male: 
1. I counseled the Male patient regarding the following: 
• Potential risks of fetal exposure to pomalidomide (Refer to item #2 in FCBP). 
• To engage in complete abstinence or use a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or a female of 
childbearing potential, while taking pomalidomide, during dose interruptions and for 
28 days after stopping pomalidomide. 
• Males should notify their study doctor when their female partner becomes pregnant and 
female partners of males taking pomalidomide should be advised to call their healthcare 
provider immediately if they get pregnant. 
• NEVER share pomalidomide with anyone else. 
• Do not donate blood, semen or sperm while taking study drug and for 28 days after 
stopping pomalidomide. 
• Do not break, chew, or open pomalidomide capsules. 
• Return unused pomalidomide capsules to the study doctor. 
2. Provide Pomalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print):  
 
(circle applicable) 
 
Investigator/Counselor Signature 
 
 
(circle applicable) 
 
Date 
 
 /  
 
/  
 
 
**Maintain a copy of the Education and Counseling Guidance Document in the patient records.** 


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Pomalidomide Information Sheet 
Please read this Pomalidomide Information Sheet before you start taking pomalidomide and 
each time you get a new supply. This Pomalidomide Information Sheet does not take the place 
of an informed consent to participate in clinical research or talking to your study doctor or 
healthcare provider about your medical condition or your treatment. 
What is the most important information I should know about pomalidomide? 
For all patients; male and female: 
Pomalidomide may cause birth defects (deformed babies) or death of an unborn baby. 
Pomalidomide is similar to the medicine thalidomide. It is known that thalidomide causes life- 
threatening birth defects. Pomalidomide has not been tested in pregnant women but may also 
cause birth defects. Findings from a monkey study indicate that pomalidomide caused birth 
defects in the offspring of female monkeys who received the drug during pregnancy. 
Restrictions in sharing pomalidomide and donating blood: 
• Do not share pomalidomide drug with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
• Do not break, chew, or open pomalidomide capsules. 
• You will get no more than a 28-day supply of pomalidomide at one time. 
• Return unused pomalidomide capsules to your study doctor. 
• Do not donate blood while you take pomalidomide and for 28 days after stopping 
pomalidomide 
For females who are able to become pregnant: 
You may be able to get pregnant if you have not undergone a hysterectomy (the surgical 
removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or have 
not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has had menses at any time during 
the preceding 24 consecutive months) 
• Do not take pomalidomide if you are pregnant or plan to become pregnant 
• You must practice complete abstinence or use two reliable, separate forms of effective birth 
control at the same time: 
- 
for 28 days before starting pomalidomide 
- 
while taking pomalidomide 
- 
during dose interruptions of pomalidomide 
- 
for 28 days after stopping pomalidomide 
• You must have pregnancy testing done at the following times: 
- 
within 10 to 14 days and again 24 hours prior to the first dose of pomalidomide 
- 
weekly for the first 28 days 


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- 
every 28 days after the first month or every 14 days if you have irregular menstrual 
periods 
- 
if you miss your period or have unusual menstrual bleeding 
- 
28 days after the last dose of pomalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular) 
• Stop taking pomalidomide if you become pregnant during treatment 
- 
If you suspect you are pregnant at any time during the study, you must stop study 
drug immediately and immediately inform your study doctor. Your study doctor will 
report all cases of pregnancy to Oncopeptides, the sponsor of this study and to 
Celgene, the manufactures of pomalidomide 
• Do not breastfeed while taking pomalidomide 
• The study doctor will be able to advise you where you can obtain additional advice on 
contraception 
For all males 
Pomalidomide is detected in trace quantities in human semen. The risk to the fetus in females of 
child bearing potential whose male partner is receiving pomalidomide is unknown at this time. 
• Male patients (including those who have had a vasectomy) must practice complete 
abstinence or must use a condom during sexual contact with a pregnant female or a female 
that can become pregnant: 
- 
While you are taking pomalidomide 
- 
During dose interruptions of pomalidomide 
- 
For 28 days after you stop taking pomalidomide 
• Male patients should not donate sperm or semen while taking pomalidomide and for 28 days 
after stopping pomalidomide. 
• If you suspect that your partner is pregnant any time during the study, you must immediately 
inform your study doctor. The study doctor will report all cases of pregnancy to 
Oncopeptides and Celgene. Your partner should call their healthcare provider immediately 
if they get pregnant. 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information 


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Appendix K Quality of Life Instruments 
EQ-5D-3L 


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EORTC QLQ-C30 
 


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SAP_003.pdf: 
Melflufen
Oncopeptides AB
Protocol OP-103 Statistical Analysis Plan
25 October 2021
CONFIDENTIAL
1
Statistical Analysis Plan
Protocol OP-103
A Randomized, Controlled, Open-Label, Phase 3 Study of
Melflufen/Dexamethasone Compared with Pomalidomide/Dexamethasone for
Patients with Relapsed Refractory Multiple Myeloma who are Refractory to
Lenalidomide
Investigational Agent: Melphalan flufenamide (referred to as melflufen)
Sponsor:
Oncopeptides AB
Västra Trädgårdsgatan 15
SE-111 53 Stockholm, Sweden
Version:
1.0, 09 December 2020
2.0, 17 March 2021
3.0, 29 April 2021
4.0, 25 October 2021
Confidential Information
The information in this document contains trade secrets and commercial information that are privileged or confidential and
may not be disclosed unless such disclosure is required by applicable laws and regulations. In any event, persons to whom
the information is disclosed must be informed that the information is privileged or confidential and may not be further
disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you which is
indicated as privileged or confidential.














Melflufen
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Protocol OP-103 Statistical Analysis Plan
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TABLE OF CONTENTS
DOCUMENT HISTORY..................................................................................3
LIST OF ABBREVIATIONS ...........................................................................5
TABLE OF CONTENTS.................................................................................8
1
INTRODUCTION ...................................................................................14
2
OVERVIEW OF STUDY DESIGN...........................................................14
3
STUDY OBJECTIVES AND ENDPOINTS..............................................15
3.1
Primary Objective..................................................................15
3.1.1
Primary Endpoint ..................................................................15
3.2
Key Secondary Objectives.....................................................15
3.2.1
Key Secondary Efficacy Endpoints ........................................16
3.2.2
Safety and Tolerability Endpoints...........................................16
3.3
Other Secondary Objectives..................................................16
3.3.1
Other Secondary Endpoints...................................................17
3.4
Exploratory Objectives ..........................................................17
3.4.1
Exploratory Endpoints...........................................................18
4
DETERMINATION OF SAMPLE SIZE ...................................................18
5
NON-INFERIORITY CHOICE OF MARGIN............................................19
6
ANALYSIS POPULATIONS ..................................................................19
6.1
Enrolled Analysis Set ............................................................19
6.2
Full Analysis Set (FAS) .........................................................20
6.3
Safety Analysis Set ...............................................................20
6.4
Per Protocol Analysis Set......................................................20
6.5
Patient Reported Outcomes Analysis Set...............................20
6.6
Pharmacokinetic (PK) Analysis Set........................................20
7
DATA MANAGEMENT..........................................................................21
7.1
Data Cutoff ...........................................................................21
7.2
Data Validation .....................................................................21
7.3
Data Standards.....................................................................21


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8
ANALYTIC DEFINITIONS .....................................................................21
8.1
General.................................................................................21
8.1.1
Study Day 1..........................................................................21
8.1.2
Study Day.............................................................................22
8.1.3
Baseline................................................................................22
8.1.4
Unscheduled Visits................................................................22
8.1.5
HRQoL Visits ........................................................................23
8.1.6
Duration................................................................................23
8.2
Medical Coding .....................................................................24
8.2.1
MedDRA...............................................................................24
8.2.2
WHO Drug Dictionary............................................................24
8.3
Patient Characteristics ..........................................................24
8.3.1
Age.......................................................................................24
8.3.1
Body Surface Area................................................................24
8.3.2
Geographic Region ...............................................................24
8.4
Disease Characteristics.........................................................25
8.4.1
Time Since Initial Diagnosis...................................................25
8.4.2
Time Since Most Recent Relapse..........................................25
8.4.3
Prior and Concomitant Medications .......................................25
8.4.4
Therapeutic Drug Classes.....................................................25
8.4.5
Prior Regimens .....................................................................26
8.4.6
Refractory Status ..................................................................26
8.4.7
Transplants...........................................................................27
8.4.8
Cytogenetic Risk Groups.......................................................27
8.4.9
International Staging System (ISS)........................................27
8.4.10
Monoclonal Protein Spike (M-protein) ....................................28
8.4.11
Plasma Cell Involvement.......................................................29
8.4.12
Presence of Bone Lesions and Extramedullary Disease (EMD)29
8.5
Protocol Deviations ...............................................................29


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8.6
Myeloma and Safety Laboratory Assessments (Hematology,
Coagulation, and Serum Chemistry)..........................................................30
8.6.1
Unit Conversion ....................................................................30
8.6.2
Derived Laboratory Parameters and Subgroups.....................32
8.6.3
Toxicity Grades.....................................................................33
8.7
Myeloma Response Parameters............................................34
8.7.1
Progression Free Survival (PFS) ...........................................34
8.7.2
Response Rates ...................................................................35
8.7.3
Overall Survival.....................................................................36
8.7.4
Duration of Response (DOR).................................................36
8.7.5
Time to Response (TTR) .......................................................36
8.7.6
Time to Progression (TTP) ....................................................36
8.7.7
Duration of Clinical Benefit (DOCB) .......................................37
8.7.8
Long Term Follow-up for PFS and OS...................................37
8.8
Patient Reported Outcomes / Health related quality of life
(HRQoL)
37
8.8.1
EQ-5D-3L .............................................................................37
8.8.2
EORTC QLQ-C30 and QLQ-MY20 ........................................38
8.9
PK Parameters for Melphalan................................................38
8.10
Exposure ..............................................................................39
8.10.1
Overall Study Drug Exposure ................................................39
8.10.2
Melflufen Exposure ...............................................................39
8.10.2.1 Kaplan-Meier Analysis of Melflufen Dose Modifications.............40
8.10.3
Pomalidomide Exposure........................................................40
8.10.4
Dexamethasone Exposure ....................................................41
8.10.5
Action Taken with Study Drug................................................41
8.11
Safety Evaluation ..................................................................42
8.11.1
Adverse Events.....................................................................42
8.11.2
Dose Modifications due to Adverse Event ..............................43
8.11.3
Adverse Events of Special Interest ........................................43


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8.11.4
Deaths..................................................................................44
8.12
Subsequent Therapies ..........................................................45
8.12.1
Grouping Therapies into SDGs..............................................45
8.12.2
Missing Dates .......................................................................45
8.12.3
Multiple Therapies.................................................................45
9
STATISTICAL METHODS .....................................................................45
9.1
General Considerations.........................................................45
9.2
Disposition of Patients...........................................................46
9.3
Protocol Deviations ...............................................................48
9.4
Demographic, Baseline Characteristics, and Prior Therapy ....49
9.4.1
Demographic and Baseline Characteristics............................49
9.4.2
Medical History .....................................................................49
9.4.3
Disease Characteristics.........................................................49
9.4.4
Prior Myeloma Therapy .........................................................50
9.4.5
Prior and Concomitant Medications .......................................52
9.5
Efficacy Analyses..................................................................52
9.5.1
Primary Efficacy Analysis: Progression Free Survival.............52
9.5.1.1
Sensitivity Analyses for PFS.....................................................53
9.5.1.1.1
Unstratified Analysis..............................................................................53
9.5.1.1.2
PFS Adjusted for Version of Protocol......................................................53
9.5.1.1.3
Initiation of Non-Protocol Anti-Cancer Therapy Treated as PFS Event.......53
9.5.1.1.4
Death or Progression Immediately After More than 1 Consecutively Missed
Disease Assessment Visit Treated as a PFS Event .....................................................54
9.5.1.1.5
Initiation of Non-Protocol Anti-Cancer Therapy Treated as neither a PFS
Event nor a Censoring Event...................................................................................54
9.5.1.1.6
Analysis based on Scheduled Assessment Dates instead of Actual
Assessment Dates..................................................................................................54
9.5.1.1.7
Per Protocol Analysis.............................................................................54
9.5.1.1.8
COVID-19..............................................................................................54


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9.5.2
Key Secondary Efficacy Analysis: Overall Response Rate (ORR)
55
9.5.3
Key Secondary Efficacy Analysis: Overall Survival (OS).........56
9.5.4
Other Secondary Efficacy Analyses.......................................57
9.5.4.1
Duration of Response (DOR)....................................................57
9.5.4.2
Clinical Benefit Rate (CBR) ......................................................57
9.5.4.3
Time to Response (TTR) ..........................................................57
9.5.4.4
Time to Progression (TTP) .......................................................57
9.5.4.5
Duration of Clinical Benefit .......................................................57
9.5.4.6
Best Confirmed Response........................................................58
9.5.5
Exploratory Efficacy Analyses................................................58
9.5.5.1
MRD in Patients that Achieve CR or Better ...............................58
9.5.5.2
Changes in M-protein...............................................................58
9.5.5.3
HRQoL ....................................................................................58
9.5.6
Analyses by Subgroups.........................................................58
9.5.7
Assessments by Investigator .................................................60
9.6
PK Parameters for Melphalan................................................60
9.7
Safety Analysis .....................................................................60
9.7.1
Exposure ..............................................................................60
9.7.1.1
Overall Study Drug Exposure ...................................................61
9.7.1.2
Melflufen Exposure ..................................................................61
9.7.1.3
Pomalidomide Exposure...........................................................61
9.7.1.4
Dexamethasone Exposure .......................................................62
9.7.2
Adverse Events.....................................................................62
9.7.3
Adverse Events of Special Interest ........................................63
9.7.4
Deaths..................................................................................63
9.7.5
Hematology, Serum Chemistry, and Coagulation ...................63
9.7.6
Vital Signs and Weight ..........................................................64
9.7.7
ECOG Performance Status ...................................................64


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9.7.8
Physical Examination ............................................................64
9.7.9
12-Lead Electrocardiograms..................................................65
9.7.10
Analyses by Subgroups.........................................................65
10 STATISTICAL/ANALYTICAL ISSUES...................................................65
10.1
Handling of Dropouts or Missing Data....................................65
10.1.1
Efficacy Assessments ...........................................................65
10.1.2
Safety Assessments..............................................................66
10.1.2.1 Adverse Events........................................................................66
10.1.2.2 Laboratory Assessments..........................................................66
10.1.3
Dates and Times...................................................................67
10.1.4
Dates for Prior Autologous Transplant Subgroup....................68
10.2
Multiplicity/Multiple Comparisons...........................................68
10.3
Interim Analysis and Data Monitoring.....................................69
10.3.1
Interim Analysis.....................................................................69
10.3.2
Data Monitoring Committee...................................................69
10.3.3
Independent Review Committee (IRC)...................................69
10.4
Changes to Protocol Planned Analyses .................................69
11 REFERENCES ......................................................................................71


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1
INTRODUCTION
This statistical analysis plan (SAP) was prepared in accordance with version 5 of
Protocol OP-103, datedMarch 24, 2020, and was generated prior to locking the
study database. This document outlines the main safety and efficacy analyses to
be performed for the clinical study report (CSR).
Any changes that are made to the planned analyses after the SAP is finalized,
along with an explanation as to when and why they occurred, will be noted in the
CSR.  Any changes made to the planned analyses that are in the protocol are
summarized in Section 10.4 of this document.
2
OVERVIEW OF STUDY DESIGN
This is a randomized, controlled, open-label, Phase 3 multicenter study which will
enroll patients with relapsed refractory multiple myeloma (RRMM) following 2-4
lines of prior therapy, who are refractory to both last line of therapy and to
lenalidomide (≥ 10 mg) administered within 18 months prior to randomization as
demonstrated by disease progression on or within 60 days of completion of the
last dose of lenalidomide.
Patients will be randomized to either one of two treatment arms. Randomization
will be stratified by:

Age (≥ 75 years of age versus < 75 years of age)

Number of lines of prior therapy (2 versus 3-4 prior lines)

International staging system (ISS) Score (1 versus ≥ 2)
Arm A:
Melflufen 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of
each 28-day cycle.
Arm B:
Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1,
8, 15 and 22 of each 28-day cycle.
For Both Arms:
Patients ≥ 75 years of age will have a reduced dose of dexamethasone of 20 mg
on Days 1, 8, 15 and 22.


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Oral dexamethasone may be substituted with intravenous dexamethasone at the
investigator’s discretion (USA only). In the event of a cycle delay, unrelated to
dexamethasone toxicity, it is recommended to continue dexamethasone weekly.
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 section 7.8.
A schedule of events for the study is outlined in the protocol section 8.1.
An Independent Review Committee (IRC) will assess all tumor responses and
PD assessments during the study. The IRC members will be blinded to all
treatment data and perform their reviews in closed-meeting sessions. All
activities and processes surrounding the IRC will be outlined in the IRC Charter.
The Sponsor may be unblinded to individual subject data during the study but will
not have access to the unblinded summaries and listings used by the Data
Monitoring Committee (DMC) for their review.
All activities and processes surrounding data access will be outlined in a Data
Access Plan.
3
STUDY OBJECTIVES AND ENDPOINTS
3.1
Primary Objective
To compare the PFS of melflufen plus dexamethasone (Arm A) versus
pomalidomide plus dexamethasone (Arm B) as assessed by the IRC according
to the International Myeloma Working Group Uniform Response Criteria (IMWG-
URC). [Rajkumar 2011]
3.1.1 Primary Endpoint
PFS is defined as time (months) from date of randomization to the earlier of
confirmed disease progression or death due to any cause. Progression dates will
be assessed by the IRC using the IMWG-URC. The conventions for censoring of
PFS are described in Table 3.
3.2
Key Secondary Objectives

To assess and compare the overall response rate (ORR), i.e., proportion
of patients with ≥PR (stringent complete response [sCR], complete


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response [CR], very good partial response [VGPR] and partial response
[PR]) as best response in Arm A versus Arm B

To assess and compare overall survival (OS) in Arm A versus Arm B

To assess and compare the safety and tolerability in Arm A and Arm B
All tumor response and progression-dependent objectives are as assessed by
the Independent Review Committee (IRC) according to the IMWG-URC.
3.2.1 Key Secondary Efficacy Endpoints
Unless stated otherwise, response and progression status will be assessed by the
IRC using the IMWG-URC.
ORR: defined as a best confirmed response of sCR, CR, VGPR, or PR using local
laboratory evaluation.
OS: defined as time (months) from date of randomization 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.
3.2.2 Safety and Tolerability Endpoints

Frequency and grade of treatment emergent adverse events (TEAEs)

Frequency and grade of TEAEs of special interest

Frequency of TEAEs leading to dose modifications

Frequency of melflufen dose modifications based on study drug exposure

Treatment duration of melflufen and pomalidomide

Time to dose modification for melflufen and pomalidomide
3.3
Other Secondary Objectives

To assess and compare duration of response (DOR) in patients with ≥PR
(sCR, CR, VGPR, PR) as best response in Arm A versus Arm B

To assess and compare clinical benefit rate (CBR) (i.e. proportion of
patients with ≥MR) as best response in Arm A versus Arm B

To assess and compare time to response (TTR) in patients with an PR or
better in Arm A versus Arm B

To assess and compare time to progression (TTP) in Arm A versus Arm B


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
To assess and compare the duration of clinical benefit (i.e., ≥MR) in Arm
A versus Arm B

To assess and compare best response during the study in Arm A versus
Arm B.

To assess and compare investigator assessment of primary and
secondary endpoints in Arm A versus Arm B
All tumor response and progression-dependent objectives are as assessed by
the Independent Review Committee (IRC) according to the IMWG-URC.
3.3.1 Other Secondary Endpoints
Unless stated otherwise, response and progression status will be assessed by
the IRC using the IMWG-URC.

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.

CBR, i.e. ≥MR: is the rate of response evaluable patients that achieve a
confirmed MR or better.

TTR: is defined as the time from the date of randomization to the date of the
first documented confirmed response in a patient that has responded
with ≥PR.

TTP: is defined as the time from the date of randomization to the date of the
first documented confirmed PD.

Duration of clinical benefit (DOCB): defined as the time 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.  DOCB is
defined only for patients with a confirmed MR or better.

Best response during the study (sCR, CR, VGPR, PR, MR, stable disease
[SD] or PD) using the IMWG-URC

Primary and secondary endpoint as assessed by Investigators
3.4
Exploratory Objectives

To assess and compare the primary and secondary endpoints in various
subgroups of Arm A and Arm B


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
To evaluate the melphalan pharmacokinetic (PK) parameters during
treatment with melflufen, the impact of covariates on this relationship and
the inter-occasion variability in melphalan exposure (Arm A)

To assess the relationship between melphalan exposure and effect on
safety and efficacy variables, including PFS and ORR, in Arm A

To assess minimal residual disease (MRD) in patients that achieve a CR
(Arm A and Arm B).

To assess functional status and well-being based on patient reported
outcome (PRO) assessment
3.4.1 Exploratory Endpoints

PK parameters of melphalan (Arm A)

Proportion of patients with MRD (yes/no) for patients that achieve a CR

Value and change from baseline in EORTC QLQ-C30 summary score, each
scale of the EORTC QLQ-C30, each scale of the MY20, EQ-5D utility score,
each dimension of the EQ-5D, and the VAS of the EQ-5D

Maximum post-baseline health related quality of life (HRQoL) scores
(EORTC Global Health Status, EORTC summary score, EQ-5D-3L health
utility score, EQ VAS)

Relationship between concurrent IMWG response and time to maximum
HRQoL score
Additional exploratory analyses of endpoints related to pharmacokinetics and
HRQoL will be described separately.
4
DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on comparing the melflufen +
dexamethasone (MEL+DEX) arm and the pomalidomide + dexamethasone
(POM+DEX) arm in terms of PFS. The sample size estimation is based on the
following assumptions:

Power
= 90 %

Significance level
= 0.05 two-sided

Hazard ratio
= 0.70 (MEL+DEX / POM+DEX)

Distribution of survival
= Exponential

Accrual time
= 24 months


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
Follow up time
= 6 months after last patient randomized

Total study time
= 30 months

Early censor rate
= approximately 15 %

Time to full recruitment speed
= 6 months

Median PFS for POM+DEX
= 3.6 months (FDA Pomalyst Prescribing
Information 2015)
Based on these assumptions the final analysis should take place when 339
patients have experienced a PFS event.
5
NON-INFERIORITY CHOICE OF MARGIN
According to EU guidelines, the choice of non-inferiority margin is based on a
combination of statistical reasoning and clinical judgment (Guideline of the choice
of the non-inferiority margin EMEA/CPMP/EWP/2158/99). The proposed
comparator has, in a previous Phase 3 trial, shown superiority over an active
control (high-dose dexamethasone) with a PFS HR of 0.45 (2-sided 95%
confidence interval 0.35-0.59) (Pomalidomide Celgene EPAR 2013). The upper
limit of the confidence interval (0.59) would then correspond to a HR of 1.69
(1/0.59). A non-inferiority trial comparing melflufen and dexamethasone versus
pomalidomide and dexamethasone where the upper limit of the 95% confidence
interval is less than 1.69 can then be interpreted as superiority over high-dose
dexamethasone since the 95% confidence interval of the melflufen study will not
overlap with the 95% confidence interval of the historical study data. Since high
dose dexamethasone is an active compound, the difference against a
hypothetical placebo would be even larger.
Even though a non-inferiority margin of 1.69 might satisfy the statistical
regulatory requirements, it would allow melflufen and dexamethasone to be
substantially worse than the pomalidomide and dexamethasone comparator arm
and this is clearly not clinically acceptable. In the current trial a non-inferiority
margin of 1.2 will be used. With the planned sample size, this margin will ensure
that the point estimate of the HR will be 1 or better (≤ 1). A non-inferiority margin
of 1.2 will thus ensure a roughly similar or better efficacy of melflufen versus
pomalidomide with the respect to the primary endpoint of PFS.
6
ANALYSIS POPULATIONS
6.1
Enrolled Analysis Set
The Enrolled analysis set is defined as all subjects who are assigned a unique
patient number by Interactive Response Technology system at the time of


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enrollment (signing of consent). This analysis set includes randomized subjects
and non-randomized subjects, identified as screen failures. The Enrolled analysis
set will be the primary population for the summaries of disposition.  Randomized
subjects will be summarized according to the treatment assigned at
randomization.
6.2
Full Analysis Set (FAS)
The Full analysis set (FAS) is defined as all subjects who are randomized.
Subjects will be analyzed according to the treatment assigned at randomization.
The primary analysis (PFS) will be performed using the FAS.
6.3
Safety Analysis Set
The Safety analysis set is defined as all subjects who received at least one dose
of melflufen, pomalidomide, or dexamethasone.  The Safety analysis set will be
the primary population for the summaries of all exposure and safety data.
Subjects will be summarized according to the treatment actually received.
6.4
Per Protocol Analysis Set
The Per Protocol analysis set is defined as all subjects who received at least one
dose of melflufen, pomalidomide, or dexamethasone, and have a baseline
assessment of disease status and at least one post-baseline assessment for
disease response. Subjects who have major protocol deviations, related to
critical eligibility criteria, the assessment of efficacy or the safety of the subject
that could significantly impact the interpretation of study results, will be excluded
from the Per Protocol analysis set. The supporting analysis of the primary and
secondary efficacy endpoints will be evaluated using the Per Protocol analysis
set.  Subjects will be analyzed according to the treatment actually received.
6.5
Patient Reported Outcomes Analysis Set
HRQoL assessments were added at the time of protocol version 4.1.  Only
participants who enroll on or after protocol version 4.1 and have completed the
same PRO questionnaire at baseline and post-baseline and will be included in
the PRO analysis set. Subjects will be analyzed according to the treatment
actually received.
6.6
Pharmacokinetic (PK) Analysis Set
The PK analysis set is defined as all subjects in FAS who received at least 1
dose of melflufen and have 3 samples with measurable concentrations in at least
one treatment cycle.


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Analyses will be performed according to the treatment actually received.
7
DATA MANAGEMENT
7.1
Data Cutoff
The cutoff will be set and described in the Data Management Plan.
Data pertaining to any assessments performed as part of a visit per the data
cutoff date for a patient, and any AE or CM starting or ending before or on that
data cutoff date for a patient, will be included in the database for the CSR.
7.2
Data Validation
Data will be validated according to the Data Management Plan (DMP). Prior to
the data cutoff, the study data will be reviewed for any data inconsistencies and
major protocol deviations. Any data inconsistencies remaining after the data
cutoff will be documented according to the DMP and Clinical Data Interchange
Standards Consortium (CDISC) requirements. Any changes made regarding
analysis sets or analytic definitions after the data cutoff will be documented and
referred to in the CSR.
7.3
Data Standards
Study datasets will be developed according to CDISC Study Data Tabulation
Model (SDTM) Implementation Guide Version 3.2. All datasets used for the
analyses and presentations of summary results will be developed according to
CDISC analysis data model (ADaM) Implementation Guide Version 1.1. The
source data for all ADaM datasets will be SDTM datasets.
8
ANALYTIC DEFINITIONS
Definitions of terms used for the calculation of derived variables and general
terms used for the analyses are provided in this section.
8.1
General
8.1.1 Study Day 1
Study Day 1 corresponds to the date of the first dose of any study drug.


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8.1.2 Study Day
Unless otherwise specified, the timing of all study-related events, assessments,
and interventions will be calculated relative to Study Day 1. For events,
assessments, and interventions after Study Day 1, study day represents the
elapsed number of days from Study Day 1, inclusive:
Study Day n = (Date of assessment – Date of Study Day 1) + 1 day
Study Day −1 will be the day before Study Day 1, and in general for assessments
prior to Study Day 1, study day is defined as:
Study Day n = (Date of assessment – Date of Study Day 1)
For listings (such as for adverse events) that include the derivation of “days since
last dose,” this is defined as event date – date of last dose. Events that occur on
the same day as the last dose of study drug will therefore be described as
occurring zero days from the last dose of study drug.
8.1.3 Baseline
Unless otherwise specified, the baseline value is defined as the most recent
assessment prior to administration of the first dose of study drug, melflufen,
pomalidomide, or dexamethasone. For randomized not treated patients, the
baseline value is defined as the most recent assessment prior to randomization.
8.1.4 Unscheduled Visits
All results not taken at a scheduled timepoint are unscheduled. Unscheduled
assessments are labelled as ‘Unscheduled’ in the listings and will include the
study day from first dose of all dates.
Because unscheduled assessments are not associated with any scheduled
timepoint, they are excluded from all summaries by timepoint.  Unscheduled
assessments will be considered when deriving myeloma response parameters as
described in Section 8.7.
The study protocol accepts a time window of ± 3 days for scheduled visits and
assessments (visit window). In the event multiple protocol-specified assessments
are reported within the same visit window the value reported for the scheduled
visit should be used in summaries by timepoint (i.e. clinical safety labs and vital
signs), and if this value is missing or unknown the earliest reported value of
unscheduled assessments within the visit window should be used. Derivations
using multiple assessments should be based on assessments from the same
visit.


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


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
Minutes – Durations expressed in minutes between one timepoint (time1)
and another later timepoint (time2) are calculated using the following
formula: duration in minutes = (time2-time1)/60.
8.2
Medical Coding
8.2.1 MedDRA
Events recorded as medical history or adverse events will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0. Preferred
term (PT) and system organ class (SOC) will be summarized.
8.2.2 WHO Drug Dictionary
All prior systemic cancer therapies as recorded on the Multiple Myeloma History -
Prior Systemic Cancer Drug Therapy CRF page and prior and concomitant
medications as recorded on the Concomitant Medications CRF will be coded
using WHO Drug Dictionary (WHO DD) Enhanced version September 2020.
Medications are coded to Anatomical/Therapeutic/Chemical (ATC) drug class
level 4 and preferred drug names.  If ATC drug class level 4 code is unavailable,
level 3 is used; if level 3 coding is unavailable, level 2 is used.
8.3
Patient Characteristics
8.3.1 Age
Age is calculated as the integer duration from the date of birth to the date of
informed consent, if age is not recorded in the electronic case report form
(eCRF). Age will be categorized as <65, 65 - <75, and ≥75 (years) and separately
per the randomization strata <75 and ≥75 (years).
8.3.1 Body Surface Area
Body surface area (BSA) will be calculated based on patients’ height in
centimeters (Ht) and weight in kilograms (Wt) at study entry using the Mosteller
formula, i.e. {Ht*Wt/3600}0.5. BSA will categorized into subgroups with BSA
below or above median BSA for FAS.
8.3.2 Geographic Region
Geographic location of study site will be categorized as United States of America,
Europe and Rest of World. Rest of World includes Russia, Israel, Korea and
Taiwan.


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8.4
Disease Characteristics
8.4.1 Time Since Initial Diagnosis
Time since initial diagnosis in years at study entry will be defined as duration
from diagnosis to first dose of study. Partial dates will be imputed according to
Section 10.1.
8.4.2 Time Since Most Recent Relapse
Time since most recent relapse in months at study entry will be defined as
duration from date of most recent documented progressive disease to
randomization.  Partial dates will be imputed according to Section 10.1.
8.4.3 Prior and Concomitant Medications
Concomitant medications are defined as medications with start date or end date
on or after the date of first dose and start date before the date of the last dose +
30 days or are ongoing at the time of first dose.  Prior medications are defined as
medications with a stop date before the date of first dose of study drug.
For the purpose of determining if a medication should be noted as a concomitant
medication, the imputation rules stated in Section 10.1 will be used.  Imputed
dates will not be presented in the listings.
Patients may have more than one medication per ATC level and preferred name.
At each level of patient summarization, a patient is counted once if he/she
reported one or more medications at that level.
Transfusions will be defined as WHO DD preferred names of “Platelets” or “Red
blood cells”.  Growth factor agents will be defined as WHO DD Standardized
Drug Groupings (SDG) “Colony stimulating factors”.
8.4.4 Therapeutic Drug Classes
Proteasome inhibitor (PI) is defined as WHO DD SDG “Antineoplastic
proteasome inhibitors”.
Immunomodulatory drug (IMiD) is defined as SDG “Antineoplastic thalidomide
analogues”.
Anti-CD38 monoclonal antibodies (mAb) is defined as SDG “Antineoplastic CD38
antigen inhibitors”.
Other mAb is defined as SDG “Monoclonal antibodies – antineoplastics”
excluding SDG “Antineoplastic CD38 antigen inhibitors”.


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Alkylators is defined as SDG “Antineoplastic alkylating drugs”.
Other antineoplastic drugs for the treatment of multiple myeloma will be referred
to as “Other”.
Any experimental or investigational drugs that are not covered by WHO DD will
be reviewed manually and classified as one of the above therapeutic drug
classes if applicable. Classifications will be documented as part of database lock
procedures and further described in the CSR.
8.4.5 Prior Regimens
A prior regimen is defined as one or more cycles of a planned treatment
program. This may consist of one or more planned cycles of single-agent therapy
or combination therapy, as well as a sequence of treatments administered in a
planned manner. For example, a planned treatment approach of induction
therapy followed by autologous stem cell transplantation, followed by
maintenance is considered one regimen. A new regimen starts when a planned
course of therapy is modified to include other treatment agents (alone or in
combination) as a result of disease progression, relapse, or toxicity. A new
regimen also starts when a planned period of observation off therapy is
interrupted by a need for additional treatment for the disease. [Rajkumar 2011]
Number of prior regimens per patient will be the ‘Total Lines of Therapy’ as
reported by investigator on the Multiple Myeloma History – Prior Systemic
Cancer Therapy Summary CRF.
8.4.6 Refractory Status
A patient is defined as refractory to a drug within a prior regimen if the patient
fulfills any of the following criteria [Rajkumar 2011]:
1. Reason for termination was PD
2. Best response was PD or SD
3. Relapse or progression occurred within 60 days from last administration
Double-class refractory is defined as refractory to at least one PI and at least one
IMiD.
Triple-class refractory is defined as refractory to at least one PI, at least one
IMiD, and at least one Anti-CD38 mAb.


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8.4.7 Transplants
A front-line transplant is defined as the transplant indicated for the first line of
therapy. This can be single or tandem transplant. Planned tandem autologous or
autologous-allogeneic are considered as one transplant.
A salvage transplant is defined as any transplant given following failure of front-
line therapy. Planned tandem autologous or autologous-allogeneic are
considered as one transplant.
Time from autologous transplant to relapse is the duration in years from date of
transplant (or date of first transplant if given in tandem) to date of relapse. Time
from autologous transplant to relapse will be categorized as <1 year, 1 - <1.5
years, 1.5 – 2 years, >2 years.
8.4.8 Cytogenetic Risk Groups
Genetic subtypes from cytogenetics analysis by fluorescence in situ hybridization
(FISH) will be categorized into risk groups as follows [Sonneveld 2016]:

High-risk group: consists of patients who have the genetic subtype t(4;
14), t(14:16), deletion 17p, gain 1q (+1q), t(14,20) , and gain (1q21).1

Standard-risk group: consists of patients who have a genetic subtype
recorded but none of the genetic subtypes categorized as high-risk

Unknown: consists of patients for whom the procedure was not done or
unevaluable.
8.4.9 International Staging System (ISS)
ISS Stage and Revised ISS (R-ISS) Stage will be used as reported in CRF
[Palumbo, 2015], see Table 1.
1 The addition of subtypes gain 1q (+1q), t(14,20) were added to the IMWG definition of high risk
cytogenetics [Sonneveld 2016] as an update to initial IMWG guideline [Rajkumar 2011]. As this
definition was changed during the study and the protocol did not require testing of the additional
high-risk cytogenetic abnormalities, these additional subtypes may be underrepresented.2 IMWG
defined measurable serum M-protein as ≥ 1.0 g/dL [Rajkumar 2011].


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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 by florescent in situ hybridization (iFISH)
High-Risk
Presence of del(17p) and/or translocation of t(4:14) and/or translocation of
t(14:16)
Standard-Risk
No high-risk CA
Lactase Dehydrogenase (LDH)
Normal
Serum LDH < upper limit of normal (ULN)
High
Serum LDH > ULN
A new model for risk stratification of MM R-ISS
Stage I
ISS stage I and standard-risk CA by iFISH and normal LDH
Stage II
Not R-ISS stage I or III
Stage III
ISS stage III and either high-risk CA by iFISH or LDH
ISS as reported in CRF will be referred to as ‘ISS’ {I, II, III, Unknown, Not Done}.
R-ISS as reported on the CRF will be referred to as ‘R-ISS’ {R-I, R-II, R-III,
Unknown, Not Done}.
8.4.10 Monoclonal Protein Spike (M-protein)
M-protein is assessed from serum and urine protein electrophoresis test
(SPEP/UPEP), and/or serum free light chain (sFLC).
Measurable M-protein at screening and baseline are defined as follows:

Measurable SPEP is defined as M-protein ≥ 0.5 g/dL.2

Measurable UPEP is defined as M-protein ≥ 200 mg/24 hr.

Measurable sFLC is defined as involved FLC ≥ 10 mg/dL with abnormal
Kappa/Lambda ratio (defined as values outside 0.26-1.65).
2 IMWG defined measurable serum M-protein as ≥ 1.0 g/dL [Rajkumar 2011].


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If the sFLC kappa/lambda ratio is >1.65, kappa is the involved sFLC, and lambda
is the uninvolved sFLC. If the kappa/lambda ratio is <0.26, lambda is the involved
sFLC, and kappa is the uninvolved sFLC. Difference in sFLCs (dFLC) is defined
as (Involved sFLC – Uninvolved sFLC) and is used for response assessment
according to IMWG [Rajkumar 2011].
Maximum percent decrease of M-protein or dFLC as summarized in waterfall
plots is defined as maximum decrease from baseline to lowest level (nadir) per
patient divided by baseline level, expressed as percent. Maximum percent
decreases of less than -100% will be set to -100%.
When estimating maximum percent decrease; If both SPEP and UPEP are
measurable at baseline, SPEP will be used. If only SPEP is measurable, SPEP
will be used. If only UPEP is measurable UPEP will be used. If neither SPEP and
UPEP are measurable, FLC will be used.
8.4.11 Plasma Cell Involvement
Bone marrow plasma cell involvement (%) as assessed by aspiration and biopsy
will use the higher value in cases of discrepancy and referred to as maximum
plasma cell involvement. Maximum plasma cell involvement will be categorized
as (<30%, 30 - <60%, ≥60%).
8.4.12 Presence of Bone Lesions and Extramedullary Disease (EMD)
Presence of bone lesions and/or EMD at baseline will be defined the Multiple
Myeloma Status at Study Entry CRF, or Multiple Myeloma Status at Diagnosis
CRF if not available at study entry, and if not available from investigator
assessments of imaging at study entry, recorded on the Bone Lesion
Assessment-Screening and Extramedullary Plasmacytoma Evaluation-Screening
CRFs.
8.5
Protocol Deviations
Major protocol deviations related to the eligibility, efficacy, or safety of the subject
that could significantly impact the interpretation of study results will be identified
prior to database lock and may include, but are not limited to:

Subjects who missed one or more assessments that have a significant
effect on the evaluation of efficacy or safety

Subjects who did not satisfy critical inclusion and exclusion criteria

Subjects who received the wrong treatment or incorrect dose








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For hypocalcemia and hypercalcemia (as defined from laboratory ranges), serum
calcium values and normal ranges will be corrected using the formula:
Corrected calcium = Serum calcium mg/dL + 0.8 × (4 - serum albumin g/dL)
β2 microglobulin (mg/L) will be categorized as < 3.5, 3.5 – 5.5 and > 5.5.
Platelet count (10^9/L) will be categorized as <75, 75 – 100, >100 – 150, and
>150.
ANC (10^9/L) will be categorized as <1.0, 1.0 – 1.5, and >1.5.
Hemoglobin (g/L) will be categorized as <80, 80 – 100, >100.
Lactase dehydrogenase (LDH) will be categorized as <1.5xULN and ≥1.5xULN,
where ULN=upper limit of normal range based on reference ranges provided
from each site.
Albumin (g/dL) will be categorized as <3.5, and ≥3.5.
Creatinine clearance (ml/min) will be categorized as <45, ≥45 - <60, ≥60 - <90, ≥
90.
8.6.3 Toxicity Grades
The following laboratory test results will be assigned toxicity grades using NCI
CTCAE version 4.03:

Hematology
o
Hemoglobin (increase, decrease)
o
Platelets (decrease)
o
WBC (increase, decrease)
o
ANC (decrease)
o
Lymphocyte Count (increase, decrease)

Serum Chemistry
o
Alanine transaminase (ALT) (increase)
o
Aspartate transaminase (AST) (increase)
o
Alkaline Phosphatase (increase)
o
Total Bilirubin (increase)
o
Creatinine (increase)
o
Corrected Calcium (increase, decrease)


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o
Glucose (increase, decrease)
o
Albumin (decrease)
o
Uric Acid/Urate (increase)
o
Magnesium (increase, decrease)
o
Phosphorus/Phosphate (decrease)
o
Potassium (increase, decrease)
8.7
Myeloma Response Parameters
The primary analysis of tumor response and progression-dependent endpoints
will be based the Independent Review Committee (IRC). All tumor response and
progression-depended endpoints will be assessed using the International
Myeloma Working Group Uniform Response Criteria (IMWG-URC) [Rajkumar
2011].
8.7.1 Progression Free Survival (PFS)
PFS is defined as the duration in months from randomization until first evidence
of confirmed disease progression. Disease progression is defined according to
IMWG-URC as PD or death due to any cause, whichever occurs first. PFS will be
right-censored according to the conventions described in Table 3.




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complete response (CR), very good partial response (VGPR), or partial response
(PR).
The clinical benefit rate (CBR) will be defined as the proportion of patients with
the best overall confirmed response of minimal response (MR) or better.
Stable disease (SD) will be defined as the proportion of patients with the best
overall confirmed response of SD.
Disease stabilization will be defined as the proportion of patients with the best
overall confirmed response of SD or better.
‘Best overall confirmed response’ is the best response achieved on study based
on two consecutive assessments according to IMWG-URC.
Responses of not evaluable (NE) will be determined if no measurable disease at
baseline or no post-baseline response assessment.  No post-baseline response
will be presented separately for patients still on study at the time of the data cut
or if patient has withdrawn from study.
8.7.3 Overall Survival
OS is defined as the time in months from randomization to date of death due to
any cause. Patients who are alive will be censored at the last follow up visit or
data cut-off date for patients still on-study.
8.7.4 Duration of Response (DOR)
DOR will be estimated for patients who achieve a PR or better. DOR is defined
as the duration in months from first documentation of a confirmed response to
first evidence of confirmed disease progression or death due to any cause.
Disease progression, and dates of progression and censoring, will be determined
as described for the analysis of PFS (Section 8.7.1).
8.7.5 Time to Response (TTR)
TTR will be estimated for patients with confirmed responses of PR or better. TTR
is defined as the duration in months from randomization to the first occurrence of
a response of PR or better.
8.7.6 Time to Progression (TTP)
TTP will be estimated for patients with confirmed PD. TTP is defined as the
duration in months from randomization to first evidence of disease progression.
Disease progression, and dates of progression and censoring, will be determined
as described for the analysis of PFS (Section 8.7.1), with the exception that


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patients who die will be censored as of the last response assessment prior to
death.
8.7.7 Duration of Clinical Benefit (DOCB)
Duration of clinical benefit will be estimated for patients whose best confirmed
response is MR or better. Duration is defined as the time in months from first
post-baseline documentation of a confirmed MR or better to disease progression
or death due to any cause.
8.7.8 Long Term Follow-up for PFS and OS
According to the study protocol, patients who discontinue therapy for reasons
other than disease progression should continue to have monthly disease
assessments done until confirmed progression or initiation of subsequent
therapy.
Following confirmed disease progression or initiation of subsequent therapy,
follow-up for overall survival status, second primary malignancies and
subsequent therapy will take place every three months +/- 7 days for 24 months.
8.8
Patient Reported Outcomes / Health related quality of life (HRQoL)
Health related quality of life (HRQoL) assessments were added at the time of
protocol version 4.1.  HRQoL analyses will use the PRO analysis set.
Domains of focus will include summary score, global health status, physical
functioning, emotional functioning, fatigue and pain (EORTC QLQ-C30), disease
symptoms and side effects of treatment (EORTC QLQ-MY20) and EQ-5D health
utility and VAS analyses.
8.8.1 EQ-5D-3L
The EQ-5D-3L questionnaire converts 5 dimensions (Mobility, Self-Care, Usual
Activities, Pain/Discomfort, and Anxiety/Depression) of patient-reported, current-
day health status into a “health utility” score.  For the EQ-5D questionnaire, each
dimension is scored on a Likert-type scale with 3 available levels of response
and scores ranging from 1 to 3, “no problems,” “some problems,” and “extreme
problems,” respectively. For EQ-5D health utility values will be mapped in
accordance with the EQ-5D manual using United Kingdom as value set. The EQ
VAS scores are anchored on 100 = best imaginable health and 0 = worst
imaginable health.
The maximum EQ-5D-3L health utility score and EQ VAS will be calculated as
the highest scores from post-baseline to end of treatment. The time to maximum


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score will be calculated as the time (months) from randomization to the first
occurrence of a maximum score.
8.8.2 EORTC QLQ-C30 and QLQ-MY20
The scoring for the EORTC instruments will be done according to the procedures
described by their respective EORTC Scoring Manual.
EORTC QLQ-C30 and QLQ-MY20 raw scores will be transformed into a range
from 0 to 100. For EORTC QLQ-C30 Global Health Status and functional
domains (Physical Functioning, Role Functioning, Emotional Functioning,
Cognitive Functioning, Social Functioning), a higher score indicates better
function, and for symptom domains (Fatigue, Nausea & vomiting, Pain, Dyspnea,
Insomnia, Appetite loss, Constipation, Diarrhea, Financial Difficulty), a lower
score indicates fewer symptoms. For EORTC QLQ-MY20, higher scores
represent better functioning for future perspective and body image, and higher
scores representing worse impact for disease symptoms and side effects of
treatment.
The EORTC QLQ-C30 Summary Score is calculated from the mean of 13 of the
15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact
scale are not included). Prior to calculating the mean, the symptom scales need
to be reversed to obtain a uniform direction of all scales. The summary score
should only be calculated if all of the required 13 scale scores are available
(using scale scores based on the completed items, provided that at least 50% of
the items in that scale have been completed.
The maximum EORTC QLQ-C30 summary score will be calculated as the
highest score from post-baseline to end of treatment.
The time to maximum EORTC QLQ-C30 summary score will be calculated as the
time (months) from randomization to the first occurrence of a maximum score.
The maximum EORTC QLQ-MY20 summary score will be calculated as the
highest score from post-baseline to end of treatment.
The time to maximum EORTC QLQ-MY20 summary score will be calculated as
the time (months) from randomization to the first occurrence of a maximum
score.
8.9
PK Parameters for Melphalan
PK parameters for melphalan will be derived using non-compartmental analysis
in Phoenix WinNonLin® and transferred to Precision.
The following PK parameters will be calculated.

Cmax: Maximum observed concentration.


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
AUClast: Area under the concentration versus time curve from start of
infusion to the last data point with measurable concentration.

AUCinf: Area under the concentration versus time curve from start of
infusion to infinity.

t½: Elimination half-life.
8.10 Exposure
The study drugs for this study are melflufen, pomalidomide, and dexamethasone.
8.10.1 Overall Study Drug Exposure
Duration of treatment with study drug in weeks is defined as the longer of (date of
last dose + 28 days – date of first dose + 1 for melflufen), (date of last dose + 1
day – date of first dose + 1 for pomalidomide) or (date of last dose + 7 days –
date of first dose + 1 for dexamethasone) divided by 7.
8.10.2 Melflufen Exposure
Duration of melflufen treatment in weeks is defined as ((date of last dose + 28
days) – date of first dose + 1) divided by 7.
Melflufen treatment cycle is defined as cycle during which at least one dose of
melflufen was administered. A treatment cycle starts on the date of melflufen
administration.
Cumulative dose of melflufen in mg is the sum of all melflufen doses
administered.
Average dose of melflufen in mg/week is defined as the cumulative dose divided
by the duration of melflufen treatment.
The dose intensity of melflufen is defined as the ratio of the average dose of
melflufen to the prescribed dose, where prescribed dose is 40 mg per 4 weeks =
10 mg/week and expressed as a percent.
A dose delay is defined as a consecutive dose of melflufen administered on day
32 or later following a preceding dose of melflufen. Dose delays will be
categorized as delays in weeks as 1 (day 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.
If a subject missed the cycle with a dose delay due to COVID-19, these dose
delays will be summarized separately.


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A dose reduction is defined as a consecutive dose of melflufen lower than a
preceding dose of melflufen.
8.10.2.1
Kaplan-Meier Analysis of Melflufen Dose Modifications
Time to dose modification is defined from the treatment start date to the start
date of the first dose modification (Date of first dose modification – date of the
first dose of melflufen + 1), where a dose modification is either a subsequent
dose reduced from preceding dose or a subsequent dose administered after day
32 from preceding dose whichever occurs first. Those patients who do not
experience an event will be censored at the date of last melflufen dose plus 28
days, end of study date, data cutoff date, or death date, whichever is earlier.
Time to dose delay is defined from the treatment start date to the start date of the
first dose delay (Date of first dose delay– date of the first dose of melflufen + 1),
where a dose delay is a subsequent dose administered after day 32 from
preceding dose. Those patients who do not experience an event will be censored
at the earliest of the date of last melflufen dose plus 28 days, end of study date,
data cutoff date, or death date.
Time to dose reduction is defined from the treatment start date to the start date of
the first dose reduction (Date of first dose reduction– date of the first dose of
melflufen + 1), where a dose reduction is a subsequent dose reduced from
preceding dose. Those patients who do not experience an event will be censored
at the earliest of the date of last melflufen dose plus 28 days, end of study date,
data cutoff date, or death date.
8.10.3 Pomalidomide Exposure
Duration of pomalidomide treatment in weeks is defined as ((date of last dose +1
day) – date of first dose + 1) divided by 7.
Pomalidomide treatment cycle is defined as cycle during which at least one dose
of pomalidomide was administered. A treatment cycle starts on the date of
pomalidomide administration.
Cumulative dose of pomalidomide in mg is the sum of all pomalidomide doses
administered.
Average dose of pomalidomide in mg/week is defined as the cumulative dose
divided by the duration of pomalidomide treatment.
The dose intensity of pomalidomide is defined as the ratio of the average dose of
pomalidomide to the prescribed dose, where prescribed dose is 4 mg per day for
21 days = 84 mg/month = 21 mg/week and expressed as a percent.
The planned dosing are days 1 through 21. A dose delay is defined as the next
cycle of pomalidomide administered on day 32 or later of current cycle.


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If a subject missed the cycle with a dose delay due to COVID-19, these dose
delays will be summarized separately.
A dose reduction is defined as a consecutive dose of pomalidomide lower than a
preceding dose of pomalidomide.
8.10.4 Dexamethasone Exposure
Duration of dexamethasone treatment in weeks is defined as ((date of last dose
+7 days) – date of first dose + 1) divided by 7.
Cumulative dose of dexamethasone in mg is the sum of all dexamethasone
doses administered.
The dose intensity of dexamethasone is defined as the ratio of (cumulative dose
divided by the duration of dexamethasone treatment) to the prescribed dose,
where prescribed dose is 160 mg per 4 weeks = 40 mg/week for patients with
age <75 years, or 80 mg per 4 weeks = 20 mg/weeks for patients with age ≥75
years, and expressed as a percent.
A dose delay is defined as a dose of dexamethasone administered on day 4 or
later following the planned dosing days 1, 8, 15 and 22 respectively, and before
the day of a planned subsequent dose. A missed dose of dexamethasone is a
planned dose that is not given before the day of a planned subsequent dose (e.g.
if planned dose on day 8 is not given before day 15).
A dose reduction is defined as a consecutive dose of dexamethasone lower than
a preceding dose of dexamethasone.
8.10.5 Action Taken with Study Drug
The protocol and eCRF use the terms dose held and dose delay.  A dose held is
the same as a dose delay. The term dose delay is used herein and will be used
for the CSR.
Dose delays or dose reductions in summaries of scheduled study drug
administration will be analyzed using the derived continuous variables described
in Sections 8.10.2, 8.10.3, and 8.10.4, and not as reported in the CRF. The ‘Dose
adjustment’ as reported in CRF {NO ACTION TAKEN, DOSE HELD, DOSE
REDUCED, and DRUG PREMANENTLY DISCONTINUED} and dose adjustment
according to CDISC Controlled terminology (CT) {DOSE NOT CHANGED, DOSE
REDUCED, DRUG INTERRUPTED, and DRUG WITHDRAWN} will be included
in listings. CRF entry ‘DOSE HELD’ correspond to CT ‘DRUG INTERRUPTED’,
and CRF entry ‘DRUG PERMANENTLY DISCONTINUED’ correspond to CT
‘DRUG WITHDRAWN’.


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8.11 Safety Evaluation
8.11.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a study patient
administered an investigational product and that does not necessarily have a
causal relationship with this treatment. An AE can therefore be any unfavorable
and unintended sign (including laboratory finding), symptom, or disease
temporally associated with the use of a medicinal product, whether or not
considered drug-related. In addition to new events, any increase in the severity
or frequency of a pre-existing condition that occurs after the patient begins study
therapy is considered an AE. This includes any side effect, injury, toxicity, or
sensitivity reaction.
Further details for the definition of AE is provided in study protocol section 9.1.1.
A serious adverse event (SAE) is defined as any AE, occurring at any dose that
meets any one or more of the following criteria:

Is fatal or immediately life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the
patient or may require medical or surgical intervention to prevent one of
the outcomes listed above

Requires inpatient hospitalization or prolongation of existing
hospitalization
Further details for the definition of SAE is provided in study protocol section
9.2.1.
A treatment-emergent adverse event (TEAE) is an AE with an onset or
increase in severity level after the initial dose of study drug and no later than day
30 after the last dose of study drug or initiation of new multiple myeloma therapy,
whichever is sooner.
A treatment-related adverse event is an AE that is recorded by the investigator
as possibly or probably related to either or both of melflufen/pomalidomide and
dexamethasone. A melflufen related AE is an AE that is noted as possibly or


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probably related to melflufen/pomalidomide independently of relationship with
dexamethasone, and a dexamethasone related AE is an AE that is noted as
possibly or probably related to dexamethasone independently of relationship with
melflufen/pomalidomide.
Patients may have more than one adverse event per SOC and preferred term. At
each level of patient summarization, a patient is counted once if he/she reported
one or more adverse events at that level. For such cases, the maximum NCI
CTCAE (version 4.03) toxicity grade and strongest causal relationship to study
drug will be used in the incidence calculations.
8.11.2 Dose Modifications due to Adverse Event
Dose delays or dose reductions in summaries of ‘Action taken with study drug’
due to AE will be analyzed as reported in the CRF {NO ACTION TAKEN, DOSE
HELD, DOSE REDUCED, DRUG INTERRUPTED, and DRUG PREMANENTLY
DISCONTINUED}. Listings will include Action taken as reported on CRF and
Action taken as mapped according to CDISC Controlled terminology (CT) {DOSE
NOT CHANGED, DOSE REDUCED, DRUG INTERRUPTED, and DRUG
WITHDRAWN}.
8.11.3 Adverse Events of Special Interest
AEs of special interest (AESIs) are TEAEs defined as follows:

Neutropenia: Preferred terms of 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

Thrombocytopenia: Broad search including in the Standardized MedDRA
Query (SMQ) {“Haematopoietic thrombocytopenia”}

Anemia: Broad search including in the SMQ {“Haematopoietic
erythropenia”}

Febrile neutropenia: PT {“Febrile neutropenia”}3

Infections: SOC {“Infections and infestations”}

Infective pneumonia: SMQ {“Infective pneumonia”}, including and
excluding broad terms.
3 PT “Febrile neutropenia” is listed as an individual PT and is also included in the SMQ
“Haematopoietic leukopenia”. Hence, that PT will be counted in the 2 separate AESIs.


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
Hemorrhage: All terms included in the SMQs {“Haemorrhage terms,
excluding laboratory terms”} and narrow terms included in the SMQ
{“Haemorrhage laboratory terms”}

Thrombocytopenia concomitant to hemorrhage: Hemorrhage with an
onset date within ± 7 days of the onset and/or resolution date of a grade 3
or 4 thrombocytopenia.

Neutropenia concomitant to infection: Infection with an onset date within ±
7 days of the onset and/or resolution date of a grade 3 or 4 neutropenia.

Thromboembolism: SMQ {“Embolic and thrombotic events”}

Central Nervous System Bleeding (CNS Bleeding): SMQ {“Haemorrhagic
central nervous system vascular conditions”}

Second Primary Malignancy (SPM): {SMQ “Malignant or unspecified
tumours including SMQ Malignant tumours”}, as well as {SMQ “Tumours
of unspecified malignancy”}, and high level term (HLT) {“Myelodysplastic
syndromes”}, but will exclude high level group term (HLGT) {Plasma cell
neoplasms”}.

Myelodysplastic Syndrome (MDS): HLT Myelodysplastic syndromes,
which includes PTs {5q minus syndrome, Chronic myelomonocytic
leukaemia, Myelodysplastic syndrome, Myelodysplastic syndrome
transformation, Myelodysplastic syndrome unclassifiable, Refractory
anaemia with an excess of blasts, Refractory anaemia with ringed
sideroblasts, Refractory cytopenia with multilineage dysplasia, Refractory
cytopenia with unilineage dysplasia, or Sideroblastic anemia}

Peripheral Neuropathy: Narrow terms included in the SMQ {“Peripheral
neuropathy”}

Tachyarrhythmias: Narrow terms included in the SMQ {“Tachyarrhythmias
(incl supraventricular and ventricular tachyarrhythmias)”}
8.11.4 Deaths
Deaths will be categorized as occurring within 30 days of the last dose of study
drug or more than 30 days after the last dose respectively. Deaths related study
drug occurring more than 30 days after the last dose will also be categorized.
Early deaths will be defined as occurring within 60 days of first dose of study
drug.


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8.12 Subsequent Therapies
8.12.1 Grouping Therapies into SDGs
Subsequent therapies are not codded according to WHO DD.  Therefore, the
following algorithm will be used to group each therapy’s reported term to the
respective SDG:

First, test for a direct match between reported term and SDG terms
(preferred term),

Next, test for trade name match to SDG term (e.g. Revlimid to
lenalidomide),

Next, split reported terms out that have been recorded as combination
therapies and repeat steps 1 and 2,

Finally, identify misspellings (e.g., lenalidomid as lenalidomide) and repeat
steps 1 and 2.
8.12.2 Missing Dates
If a subject’s subsequent therapy initiation start date is missing, end of study
treatment date will be used.
8.12.3 Multiple Therapies
For analysis purposes (e.g. censoring for overall survival), the date of a subject’s
first subsequent therapy will be used when multiple subsequent therapies have
been initiated.
9
STATISTICAL METHODS
9.1
General Considerations
All statistical summaries and analyses will be performed in SAS® version 9.4 or
higher (SAS Institute Inc., Cary, NC, USA).
Statistical analyses will be reported using summary tables, figures, and data
listings. In general, summaries of all data will be presented by treatment arm:
Melflufen + Dexamethasone and Pomalidomide + Dexamethasone. Summaries
will also be provided for the total group (combined treatment arms) for all
summaries, except efficacy.


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Inferential statistical analyses will be performed as described below.  Unless
otherwise stated, the null hypothesis for all inferential analyses is that there is no
difference between the treatment arms. The alternative hypothesis is that there is
a difference. All tests will be two-sided, at an alpha level of 0.05. See Section
10.2 for a description of multiplicity adjustments.
For continuous variables, the number of patients with non-missing data (n),
mean, standard deviation (SD), median, minimum, and maximum will be
presented.
For discrete data, the frequency and percent distribution will be presented.
Unless otherwise indicated, percentages will be calculated based upon the
number of patients in the applicable analysis set in each study group as the
denominator.  Graphical methods will be used, as appropriate, to illustrate study
endpoints.
Confidence intervals, when presented, will be constructed at the 95% level and
will be provided for each treatment group and differences between treatment
groups. For binomial variables, exact distribution methods will be employed.
The distribution of time-to-event endpoints will be summarized by the K-M
method. Quartiles including median will be estimated by K-M method along with
their 95% confidence intervals based on a log(-log(survival)) distribution.
Assuming raw or derived variables are recorded to “x” decimal places; range will
be presented to x decimal places; mean, median, and quartiles to x+1; and SD
and confidence intervaIs to x+2 decimal places. Presented decimal places should
however not be greater than 4.
Percentages will be presented to 1 decimal place, with the exception of 0, which
will be presented without percent, and 100, which will be presented without
decimal places. Categorization of a variable based on percentages will be done
before rounding.
Tables that summarize categorical data will present data as “0”, if the number of
events is zero. Denominators for percentages will be based on the number of
patients with non-missing data in the population used in each column. A
“missing” category will be included for any parameter for which information is
missing, without a percentage.
Individual patient data recorded on the electronic case report forms (eCRFs) and
any derived data will be presented by study group and by patient in data listings.
9.2
Disposition of Patients
The population of primary interest for the summary of disposition is the Enrolled
analysis set. The following patient disposition information will be summarized:


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
Number of screened patients (Total group only)

Number of patients not randomized (Total group only)

Reason for not being randomized (Total group only)

Number of randomized subjects (FAS)

Number of randomized and treated subjects

Number of treated subjects (Safety analysis set)

Number (%) of subjects evaluable for response with no major protocol
deviations (Per Protocol analysis set)

Number (%) of treated patients who discontinued treatment

Primary reason for treatment discontinuation

Number (%) of treated patients in long-term PFS follow-up

Number (%) of treated patients in long-term OS follow-up

Number (%) of treated patients who discontinued the study

Primary reason for study discontinuation

Number (%) of subjects evaluable for HRQoL analyses (PRO analysis set)

Number (%) of subjects evaluable for PK/PD analyses (PK analysis set)
Treatment discontinuations due to AE specific to COVID-19 or other pandemic-
related reasons will be presented separately.
Time on study in months will be calculated as (last known date of contact minus
date of randomization plus one)/30.4375. Time on treatment in months will be
calculated as (last treatment date minus first treatment date plus one)/30.4375.
KM estimates of the distribution of the time-to-study discontinuation and time-to-
treatment discontinuation will be tabulated and graphed by treatment arm. The
tabulation will include the KM estimate of the medians, 25th and 75th percentiles,
and corresponding 95% CIs, if estimable. The tabular and graphical summaries
will include the at-risk counts for every visit.
In addition, the number and percentage of subjects who complete scheduled
visits will be presented for the FAS. In addition, visit compliance will be presented
by calendar year and month to evaluate the effect of COVID-19 pandemic on visit
completion.
The number and percentage of subjects randomized by geographical region and
site will also be presented by treatment arm for the FAS. The same summary will
be presented by calendar year and month.


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A summary table will be produced of the randomization stratification factors from
the interactive response technology (IRT) and the combined stratum groups:

Age (≥ 75 years of age versus < 75 years of age)

Number of lines of prior therapy (2 versus 3-4 prior lines)

ISS Score (1 versus ≥ 2)

Stratum Group 1: Age ≥ 75 years of age, 2 lines of prior therapy, ISS
Score = 1

Stratum Group 2: Age ≥ 75 years of age, 3-4 lines of prior therapy, ISS
Score = 1

Stratum Group 3: Age ≥ 75 years of age, 2 lines of prior therapy, ISS
Score ≥ 2

Stratum Group 4: Age ≥ 75 years of age, 3-4 lines of prior therapy, ISS
Score ≥ 2

Stratum Group 5: Age < 75 years of age, 2 lines of prior therapy, ISS
Score = 1

Stratum Group 6: Age < 75 years of age, 3-4 lines of prior therapy, ISS
Score = 1

Stratum Group 7: Age < 75 years of age, 2 lines of prior therapy, ISS
Score ≥ 2

Stratum Group 8: Age < 75 years of age, 3-4 lines of prior therapy, ISS
Score ≥ 2
In addition, in case the site accidentally stratified a patient using the wrong
stratification value, the derived stratification value reported in the eCRF data
versus the one the site entered in the IRT during randomization process will be
presented.
For analysis purposes, subject disposition, as outlined above, will be presented
for each prior autologous stem cell transplant subgroup (<2.5 years, 2.5-5 years,
<5 years, >5 years, and no transplant).
9.3
Protocol Deviations
All protocol deviations will be collected by the clinical research associates. Major
protocol deviations leading to exclusion from the Per Protocol analysis set, will be
summarized by deviation type for the FAS.
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.


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9.4
Demographic, Baseline Characteristics, and Prior Therapy
9.4.1 Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized for
the Full, Safety, and Per Protocol analysis sets.

Age (years) and age categories

Sex

Race

Ethnicity

Baseline ECOG performance status

Baseline fertility status

Baseline weight (kg)

Baseline BSA (m2)
For analysis purposes, subject demographics, as outlined above, will be
presented for each prior autologous stem cell transplant subgroup (<2.5 years,
2.5-5 years, <5 years, >5 years, and no transplant).
9.4.2 Medical History
The number (%) of patients who experienced a prior disease or disorder will be
summarized by SOC, PT, and treatment arm using the FAS. Summaries will be
ordered by descending order of total incidence of SOC and PT within each SOC.
Any medical history of COVID-19 will be presented as separate PTs specific to
COVID-19 or coronavirus.
9.4.3 Disease Characteristics
The following disease characteristics at diagnosis will be summarized for the Full,
Safety, and Per Protocol analysis sets based on data recorded on the Multiple
Myeloma History at Diagnosis CRF:

Stage of disease (ISS and R-ISS)

Heavy chain and light chain status, heavy chain and light chain
combinations (e.g., IgG-lambda, IgG-kappa)

Presence of bone lesions

Presence of extramedullary disease


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
Cytogenetic risk groups (as determined by FISH)
o
Each cytogenetic abnormality by FISH
The following disease characteristics at baseline/study entry will be summarized
for the FAS:

Stage of disease (ISS, R-ISS)

Time from diagnosis to randomization in years

Time from most recent relapse to randomization in months

Type of measurable disease

SPEP, UPEP, Kappa/Lambda values

Heavy chain and light chain status, heavy chain and light chain
combinations

Maximum plasma cell involvement (%)

Presence of bone lesions

Presence of extramedullary disease

Cytogenetic risk groups (as determined by FISH)
o
Each cytogenetic abnormality by FISH

Laboratory Assessments
o
β2 microglobulin as values and categories
o
Platelet count as values and categories
o
ANC as values and categories
o
Hemoglobin as values and categories
o
LDH as values and categories
o
Albumin as values and categories
o
Creatinine
o
Creatinine clearance (mL/min) as values and categories
o
Corrected calcium
9.4.4 Prior Myeloma Therapy
The following information related to prior myeloma therapy will be summarized
for the Full, Safety, and Per Protocol analysis sets:

Number of regimens of prior treatment for multiple myeloma


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
Best response to last (most recent) line of prior therapy

Best response to second to last line of prior therapy

Number (%) of subjects who are refractory to lenalidomide 25 mg vs.
lenalidomide < 25 mg (10 mg or 15 mg) during last (most recent) line of
prior therapy or administered within 18 months prior to randomization.

Refractory (refractory versus relapsed-refractory) status to lenalidomide
during last (most recent) line of prior therapy or administered within 18
months prior to randomization.

Number (%) of patients with at least one prior regimen including a
therapeutic drug class, i.e. IMiD, PI, Alkylators, anti-CD38 mAb, Other
mAb, and Other.

Number (%) of patients who are refractory to a prior regimen including a
therapeutic drug class.

Number (%) of patients who received an IMiD and PI (double-class)

Number (%) of patients who received an IMiD, PI, and anti-CD38 mAb
(triple-class)

Number (%) of patients who are double-class refractory (IMiD and PI)

Number (%) of patients who are triple-class refractory (IMiD, PI, and anti-
CD38 mAb)

Number (%) of patients who are refractory to most recent prior regimen

Number (%) of patients per last prior therapeutic class.

Number (%) of patients refractory to any agent per last prior therapeutic
class.

Number (%) of patients who are refractory to IMiD, PI, Alkylators, anti-
CD38 mAb, Other mAb, or Other per the most recent prior regimen by
therapeutic classes.

Number (%) of patients with at least one prior autologous transplant, and
number (%) of patients with at least two prior autologous transplants

Number of prior autologous transplants

Number (%) of patients with ≥ 2 autologous transplants

Number (%) of patients with an allogenic transplant, regardless of whether
it was a tandem transplant

Time (years) from front line transplant to relapse


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
Number (%) of patients with prior radiotherapy
9.4.5 Prior and Concomitant Medications
Concomitant medications will be summarized by ATC level 2, ATC level 4, and
preferred name as counts and percentages using the FAS. 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 summarized in the
same manner.
A separate summary table will summarize the number and percentage patients
with transfusions and taking growth factor agents.
9.5
Efficacy Analyses
The primary population for all efficacy analyses will be the FAS. Additional select
analyses will use the Per Protocol analysis set as indicated below. All tumor
response and progression-depended endpoints will be assessed using the
International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
[Rajkumar 2011].
9.5.1 Primary Efficacy Analysis: Progression Free Survival
The primary analysis of PFS will be performed using a log rank test stratified by
the randomization stratification factors to compare treatment group survival
distributions based on the FAS. K-M estimates of the survival distributions of the
time-to-event based on log(-log(survival)) distribution will be tabulated and
graphed by treatment arm. The tabulation will include the K-M estimate of the
medians, 25th and 75th quartiles, and corresponding 95% CIs, if they can be
estimated. The tabular and graphical summaries will include the at-risk counts.
The number and percent of subjects censored, reason for censoring, and with
events will be presented. The median PFS will be estimated for each treatment
arm 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 Crawley,1982].
Potential follow-up for PFS will be summarized by treatment arm for the FAS
using the reverse K-M method where the censoring variable is inverted
[Schemper and Smith, 1996]. The median potential follow-up time will be
summarized.
The hazard ratio and 95% CI will be determined based on a semi parametric Cox
proportional hazards regression model stratified by randomization strata to
estimate the magnitude of the effect. Ties will be handled using the Efron
methodology.


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In addition to a significant p-value for the treatment comparison based on the log
rank test, the superiority of Melflufen + Dexamethasone versus Pomalidomide +
Dexamethasone will be demonstrated if the upper limit of the 95% confidence
interval for the hazard ratio is < 1.0.
Non-inferiority of Melflufen + Dexamethasone versus Pomalidomide +
Dexamethasone will be demonstrated if the upper limit of the 95% confidence
interval for the hazard ratio is < 1.2. This assessment is relevant for non-FDA
submissions.
“Swim lane” plots based on PFS will be provided for the FAS analysis set. The
plots will be stacked by day of first documentation of the different response levels
(SD, MR, PR, VGPR, CR, sCR) on study.
9.5.1.1 Sensitivity Analyses for PFS
The following sensitivity analyses will be performed for PFS.
9.5.1.1.1 Unstratified Analysis
In addition to the stratified primary analysis of PFS, the unstratified log rank test
and Cox proportional hazards regression model will be used to obtain the
unstratified p-values and estimate of the hazard ratio. This analysis will be based
on the FAS.
9.5.1.1.2 PFS Adjusted for Version of Protocol
The analysis of PFS will be performed as specified above in Section 9.5.1 adding
a fixed effect for protocol version (enrolled prior to version 3.0 versus after
implementation of version 3.0) and will be based on the FAS.
9.5.1.1.3 Initiation of Non-Protocol Anti-Cancer Therapy Treated as PFS
Event
In this sensitivity analysis, initiation of non-protocol anti-cancer therapy will be
treated as a PFS event whereby PFS is broadly defined as duration from
randomization to documented disease progression, initiation of non-protocol anti-
cancer therapy, or death, whichever occurs earlier. The data censoring rules are
the same as those for the primary analysis of PFS except that the use of non-
protocol anti-cancer therapy will be treated as an event rather than a mechanism
for censoring. The analysis method will be the same as that for the primary PFS
analysis. This analysis will be based on the FAS.


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9.5.1.1.4 Death or Progression Immediately After More than 1 Consecutively
Missed Disease Assessment Visit Treated as a PFS Event
In this sensitivity analysis, death or progression immediately after more than 1
consecutively missed disease assessment visit will be treated as a PFS event.
The data censoring rules are the same as those for the primary analysis of PFS
except that the death or progression immediately after more than 1 consecutively
missed disease assessment visit will be treated as an event rather than a
mechanism for censoring. The analysis method will be the same as that for the
primary PFS analysis. This analysis will be based on the FAS.
9.5.1.1.5 Initiation of Non-Protocol Anti-Cancer Therapy Treated as neither
a PFS Event nor a Censoring Event
In this sensitivity analysis, the use of non-protocol anti-cancer therapy will be
treated as neither a PFS event nor a censoring event. The data censoring rules
are the same as those for the primary analysis of PFS except that the initiation of
non-protocol anticancer therapy will be excluded as a mechanism for censoring.
The analysis method will be the same as that for the primary PFS analysis. This
analysis will be based on the FAS.
9.5.1.1.6 Analysis based on Scheduled Assessment Dates instead of Actual
Assessment Dates
In this sensitivity analysis, the impact on the analysis of PFS due to potential
systematic difference in disease assessments between treatment arms will be
assessed. The estimated scheduled dates based on the protocol specified
disease assessment window will be used instead of the actual assessment
dates. If the actual assessment date does not correspond to a scheduled
assessment date, the next scheduled assessment date will be used. Other than
that, the censoring rules and the analysis method will be the same as those for
the primary PFS analysis. This analysis will be based on the FAS.
9.5.1.1.7 Per Protocol Analysis
PFS will be analyzed in the same way as the primary analysis but will be based
on the Per Protocol analysis set.
9.5.1.1.8 COVID-19
In order to evaluate the effect of the COVID-19 pandemic the following sensitivity
analyses will be performed based on FAS.
Patients will be categorized based on whether randomization occurred on or after
versus before October 1, 2019. October 1, 2019 was chosen to allow 6 months
pre-pandemic follow-up in the subgroup of patients enrolled before October 1,
2019.


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Regional restrictions due COVID-19 pandemic may have caused delays in
response assessments regardless of whether a subject contracted COVID-19.
The following sensitivity analyses due to COVID-19 pandemic will be performed
to assess the impact of delays in response assessments:

For the censoring rule “Death or PD after more than 1 consecutively
missed response assessment”,
o
2 consecutively missed assessments will be used instead of 1
o
3 consecutively missed assessments will be used instead of 1

For the censoring rule “Unconfirmed PD as the final response
assessment”, if the subject discontinued due to COVID-19 pandemic, the
subject will be censored at the date of discontinuation instead of counted
as progressed.
To assess the impact of subjects who contracted or potentially contracted
COVID-19, the following sensitivity analyses will be performed:

Subjects who have a fatal AE due to COVID-19, will be censored at the
AE start date instead of counted as progressed.

Subjects who have a COVID-19 AE prior to progression will be
censored at the start date of the AE.
To assess the impact of Pomalidomide + Dexamethasone subjects who had the
drug delivered to their home instead of dispensing at the clinical site, the
following sensitivity analyses will be performed:

Pomalidomide + Dexamethasone subjects who had the drug delivered
to their home, will be censored at the date of delivery if not progressed
by that date.
9.5.2 Key Secondary Efficacy Analysis: Overall Response Rate (ORR)
The key secondary efficacy analysis will compare Melflufen + Dexamethasone
and Pomalidomide + Dexamethasone on the ORR, using a Cochran Mantel
Haenszel (CMH) test stratified by the randomization stratification factors. The
number and percentage, with two-sided 95% exact binomial confidence interval
(Clopper-Pearson method [Fleiss, 1981]), of subjects in each category will be
presented by arm. The proportional treatment difference with associated two-
sided 95% CI will be presented.
ORR will be summarized for the Full and Per Protocol analysis sets.
See Section 10.2 for a description of multiplicity adjustments.


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The following sensitivity analyses based on FAS will be conducted to assess the
impact of COVID-19 pandemic:

Pomalidomide + Dexamethasone subjects who had the drug delivered
to their home, only response assessment up to the date of delivery will
be included.

Subjects who have an AE due to COVID-19, only response
assessments up to the start date of the COVID-19 AE will be included.
Patients will also be categorized based on whether randomization occurred on or
after versus before October 1, 2019.  October 1, 2019 was chosen to allow 6
months pre-pandemic follow-up in the subgroup of patients enrolled before
October 1, 2019.
In addition to the stratified analysis, the unstratified CMH will also be presented
based on the FAS.
9.5.3 Key Secondary Efficacy Analysis: Overall Survival (OS)
OS will be estimated and summarized using the same method as for PFS
(Section 9.5.1), including median potential follow-up time.
OS will be summarized for the Full and Per Protocol analysis sets.
See Section 10.2 for a description of multiplicity adjustments.
To assess the impact of subjects who contracted or potentially contracted
COVID-19, the following sensitivity analyses will be performed:

Subjects who have a fatal AE due to COVID-19, will be censored at the
AE start date.

Subjects who have an AE due to COVID-19 prior to death will be
censored at the start date of the AE.
To assess the impact of Pomalidomide + Dexamethasone subjects who had the
drug delivered to their home instead of dispensing at the clinical site, the
following sensitivity analyses will be performed:

Pomalidomide + Dexamethasone subjects who had the drug delivered
to their home, will be censored at the date of delivery.
Patients will also be categorized based on whether randomization occurred on or
after versus before October 1, 2019.  October 1, 2019 was chosen to allow 6
months pre-pandemic follow-up in the subgroup of patients enrolled before
October 1, 2019.


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9.5.4 Other Secondary Efficacy Analyses
The analysis of subgroups is specified as an other secondary endpoint, see
Section 9.5.6 for complete details on prospectively defined subgroups.
The analyses based on investigator is specified as an other secondary endpoint,
see Section 9.5.7 for complete details on prospectively defined analyses based
on investigator assessments.
9.5.4.1
Duration of Response (DOR)
DOR will be summarized by treatment group for patients who achieve a PR or
better. DOR will be summarized for the Full and Per Protocol analysis sets.
For exploratory and descriptive purposes only, the distributions of DOR will be
analyzed using the same methods as for PFS (Section 9.5.1).
The same COVID-19 pandemic-related sensitivity analyses described for PFS
(Section 9.5.1.1.8) will also be performed for DOR.
9.5.4.2 Clinical Benefit Rate (CBR)
CBR will be estimated and summarized using the same methods as for ORR
(Section 9.5.2). CBR will be summarized for the Full and Per Protocol analysis
sets.
9.5.4.3 Time to Response (TTR)
TTR will be summarized by treatment group without hypothesis testing. TTR will
be summarized for the Full and Per Protocol analysis sets.
9.5.4.4 Time to Progression (TTP)
The distribution of TTP will be estimated and summarized using the same
methods as for PFS (Section 9.5.1).
TTP will be summarized for the Full and the Per Protocol analysis sets.
9.5.4.5 Duration of Clinical Benefit
Duration of clinical benefit will be summarized by treatment group for patients
whose best confirmed response is MR or better. Duration of clinical benefit will
be summarized for the Full and the Per Protocol analysis sets.
For exploratory and descriptive purposes only, the distributions of DOCB will be
analyzed using the same methods as for PFS (Section 9.5.1).


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9.5.4.6 Best Confirmed Response
Best confirmed response will be estimated and summarized using the same
methods as for ORR (Section 9.5.2). Best confirmed response will be
summarized for the Full and Per Protocol analysis sets.
9.5.5 Exploratory Efficacy Analyses
9.5.5.1 MRD in Patients that Achieve CR or Better
The number and percentage of patients with MRD or not in patients who achieve
CR or better will be presented. MRD will be defined based on external vendor
assessment.
9.5.5.2 Changes in M-protein
“Waterfall” plots will display the maximum percent decrease in the M-protein
being used to determine response for all patients. Bars will be stacked per best
responses.
9.5.5.3 HRQoL
Results and change from baseline at each scheduled visit for the EQ-5D-3L
health utility score, each of the 5 dimensions, and the EQ VAS will be
summarized with descriptive statistics. In addition, the maximum post-baseline
scores will be summarized.
Results and change from baseline at each scheduled visit for the EORTC QLQ-
C30 summary score, global health status, functional domains, and symptom
scales and EORTC QLQ-MY20 5 domains will be summarized with descriptive
statistics. In addition, the maximum post-baseline scores will be summarized.
The time to maximum HRQoL score will be summarized with descriptive statistics
by concurrent IMWG response categories. Concurrent is defined as occurring
within 7 days of the PRO assessment.  If there are multiple response
assessments within 7 days, then choose the assessment closest to the date of
PRO assessment.  If there are 2 response assessments on the same date then
worst response is selected.
9.5.6 Analyses by Subgroups
Exploratory analyses of subgroups are planned to evaluate the robustness of
results.
PFS, ORR, DOR, OS, CBR, duration of clinical benefit, best confirmed response,
TTR, and TTP will also be summarized for the following bulleted subgroups.


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In addition, forest plots presenting the hazard ratio and 95% confidence interval
for efficacy endpoints PFS, DOR, OS, TTR, TTP, and DOCB will be provided for
the following subgroups.  The summaries will be based on the Full analysis set.

Age
o
<65, ≥65 years
o
<75, ≥75 years

Sex (male, female)

BSA (below or above median BSA for FAS)

Race (White, All Other Races)

Geographic region (United States of America, Europe, Rest of World)

Number of prior regimens (2, 3-4)

ISS at baseline (I, II or III)

R-ISS at baseline (R-I, R-II or R-III)

Refractory to lenalidomide in last line versus refractory in earlier line

Refractory status:
o
Refractory to an alkylator (yes, no)
o
Refractory to an anti CD38 mAb (yes, no)
o
Refractory to a PI and IMiD but not to an anti CD38 mAb (yes, no)

Presence of Extramedullary Disease at Baseline (yes, no)

Prior autologous stem cell transplant (yes, no)

Maximum plasma cell involvement (%) at baseline, as assessed with bone
marrow assessment (<30, 30 - <60, ≥60)

Baseline creatinine clearance (ml/min) (<45, 45 - < 60, 60 - < 90, ≥90)

Baseline LDH (<1.5×ULN, ≥1.5×ULN)

Baseline albumin (g/L) (<35, ≥35)

Cytogenetic risk groups as determined by FISH (standard risk, high risk,
unknown)

Version of protocol (enrollment prior to version 3.0 versus after
implementation of version 3.0)


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In addition to the above subgroup analyses, PFS, OS, and ORR will be
summarized by time from prior autologous stem cell transplant to randomization
at the following levels:

<2.5 years

2.5 – 5 years

<5 years

>5 years

No transplant
9.5.7 Assessments by Investigator
Summaries of PFS, ORR, DOR, CBR, duration of clinical benefit, best confirmed
response, TTR, and TTP will be repeated for the assessments performed by the
investigator. These summaries will be provided for both the Full and the Per
Protocol analysis sets.
Summaries of PFS, ORR, DOR, CBR, and duration of clinical benefit by
subgroups of disease characteristics (Section 9.5.5.1) will be repeated for the
assessments performed by the investigator and provided for the FAS only.
A summary table of concordance between Investigator and IRC will be
presented.
9.6
PK Parameters for Melphalan
Analyses of PK parameters will be based on the PK analysis set.
PK parameters of melphalan per treatment cycle will be summarized as
continuous variables using descriptive statistics, including geometric mean and
CV.
Additional exploratory analyses, including covariates and the inter-occasion
variability, will be described in a separate plan.
9.7
Safety Analysis
All analyses of safety will be based on the Safety analysis set.
9.7.1 Exposure
All analyses of exposure will be based on the Safety analysis set.


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9.7.1.1 Overall Study Drug Exposure
Duration of treatment will be summarized as a continuous variable using
descriptive statistics.
Treatment cycles and patients dosed by cycle will be summarized as counts
and percentages, and as a continuous variable using descriptive statistics.
9.7.1.2 Melflufen Exposure
Duration of treatment, treatment cycles, cumulative dose, infusion time,
average dose, and dose intensity will be summarized as continuous variables
using descriptive statistics.
Number of patients dosed, treatment cycles (overall and per dose), patients
with dose modifications, cycles with dose modifications, cycles with dose
reduction after dose delay of 3 weeks or longer, reason for dose reduction,
patients with dose delay by cycle and categories of delay, and patients with
dose reductions by cycle, will be summarized as counts and percentages.
The number patients with dose delays due to COVID-19 pandemic will also be
summarized.
K-M estimates of the survival distributions of the time to dose modifications will
be tabulated and graphed by treatment arm. The tabulation will include the K-M
estimate of the medians, 25th and 75th quartiles, and corresponding 95% CIs,
if they can be estimated. The tabular and graphical summaries will include the
at-risk counts. The number and percent of subjects censored, reason for
censoring, and with events will be presented.
9.7.1.3 Pomalidomide Exposure
Duration of treatment, treatment cycles, cumulative dose, average dose, and
dose intensity will be summarized as continuous variables using descriptive
statistics.
Number of patients dosed, treatment cycles (overall and per dose), patients
with dose modifications, cycles with dose modifications, reason for dose
reduction, patients with dose delay by cycle and categories of delay, and
patients with dose reductions by cycle, will be summarized as counts and
percentages.
Where applicable, the number patients who had their study drug delivered,
instead of dispensed at the site, due to COVID-19 pandemic will also be
summarized.


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9.7.1.4 Dexamethasone Exposure
Duration of treatment, number of doses, cumulative dose, and dose intensity
will be summarized as continuous variables using descriptive statistics.
Dose modifications and reasons for permanent discontinuation will be
summarized as counts and percentages.
9.7.2 Adverse Events
Number and percentage of patients with TEAEs will be summarized overall by
treatment arm by categories of maximum severity, relationship with study drug
(either, melflufen/pomalidomide, and dexamethasone), seriousness and dose
modifications of study drug (either, melflufen/pomalidomide, and
dexamethasone).
Number and percentage of TEAEs will be summarized by treatment arm by SOC
and PT by categories of severity, relationship with study drug, seriousness and
dose modifications of study drug. A separate summary of non-hematological
TEAEs will be summarized by treatment arm by SOC and PT by maximum
severity.  Non-hematological AEs are defined as all AEs excluding the SOC
"Blood and Lymphatic System disorders" and the HLGT “Haematology
investigations (incl blood groups)” from the SOC “Investigations” (keeping the
rest of the “Investigations” SOC). All summaries of TEAEs will include event
counts.
Number and percentage of patients with TEAEs will be summarized for melflufen
arm by MedDRA SOC and PT at frequencies of Very common (≥10%); Common
(≥1 to <10%); Uncommon (≥0.01 to <1%); Rare (≥0.001 to <0.01%); Very rare
(<0.001%).
Summaries that are displayed by SOC and PT will be ordered by descending
order of incidence per SOC and PT within each SOC for the total group.
Any AEs related to COVID-19 will be presented as separate PTs specific to
COVID-19 or coronavirus.
Number and percentage of patients with TEAEs, SAEs, fatal TEAEs, and AEs
leading to study drug discontinuation, by SOC and PT will also be summarized
by subgroups listed in Section 9.7.10.
Separate listings of serious AEs, AEs leading to dose modification of
melflufen/pomalidomide, AEs leading to discontinuation of
melflufen/pomalidomide, AEs leading to dose modification of dexamethasone, or
AEs leading to discontinuation of dexamethasone will be provided.  AEs that are
not treatment-emergent will be provided in listings.


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9.7.3 Adverse Events of Special Interest
All AESIs defined in Section 8.11.3 will be summarized as counts and
percentages, overall and per severity grade by treatment arm. SMQ Infective
pneumonia will be summarized using all terms and narrow terms only,
separately.
AESIs neutropenia concomitant to infection and thrombocytopenia concomitant
to hemorrhage will be summarized as counts and percentages by treatment arm.
For the AESIs of neutropenia, febrile neutropenia, thrombocytopenia, anemia,
infections, infective pneumonia and hemorrhage, and thromboembolism, the
maximum toxicity grade during each cycle and at the End of Treatment visit will
be summarized respectively by treatment arm. These tables will be presented for
three subsets of cycles during which the AESI’s starts: 1) excluding last cycle per
patient; 2) including the last cycle per patient; and 3) only the last cycle per
patient.
9.7.4 Deaths
Number of deaths and the cause of death, as collected on the Patient Death
CRF, will be summarized by treatment arm and total as counts and percentages,
overall, and as categorized. All deaths which occur on study are recorded on the
Patient Death CRF, i.e. on treatment and off treatment.  The total number of
deaths will not be equivalent to the number of fatal TEAEs.
A listing of all deaths will be provided.
9.7.5 Hematology, Serum Chemistry, and Coagulation
Results and change from baseline at each scheduled visit for all hematology,
serum chemistry, and coagulation parameters will be summarized by treatment
arm with descriptive statistics. Corresponding line series plots of average values
will also be provided by treatment arm.
Toxicity grade of applicable parameters will be summarized by treatment arm as
counts and percentages in shift tables of baseline versus worst toxicity grade
through the End of Treatment visit. Number of patients with grade 3 or higher
toxicity will be summarized as counts and percentages by cycle.  A separate
listing of all laboratory results corresponding to grade 3 or 4 will be provided.
For hemoglobin, leukocytes (WBC), lymphocytes, ANC and platelet count, the
maximum toxicity grade recorded during each cycle and at the End of Treatment
visit will be summarized separately.


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For ANC and platelet count, results and change from the Day 1 pre-infusion
value at Days 8, 15, and 22 during each cycle will be summarized as descriptive
statistics by treatment arm.
Time, in days, to first occurrence of grade 3 or 4 neutropenia (ANC), time to first
grade 4 neutropenia (ANC), time to first occurrence of grade 3 or 4
thrombocytopenia (platelet count), and time to first grade 4 thrombocytopenia
(platelet count) will be summarized descriptively by treatment group.  Time, in
days, to resolution of first grade 3 or 4 neutropenia (ANC), time to resolution of
first grade 4 neutropenia (ANC), time to resolution of first grade 3 or 4
thrombocytopenia (platelet count), and time to resolution of first grade 4
thrombocytopenia (platelet count) will be summarized descriptively by treatment
group.  Resolution is defined as less than grade 3 for grade 3 or 4 analyses and
less than grade 4 for grade 4 analyses. Duration of grade 3 or 4 neutropenia
(ANC), duration of grade 4 neutropenia (ANC), duration of grade 3 or 4
thrombocytopenia (platelet count), and duration of grade 4 thrombocytopenia
(platelet count) by cycle will also be summarized descriptively. Duration in days
will be calculated from first lab date in the cycle with grade 3 or 4 to the next
result in the same cycle less than grade 3 (or less than grade 4 for grade 4 only
analyses) plus 1. Per protocol a patient should not initiate a new cycle if ANC or
platelet count has a CTCAE grade 3 or 4.
In the cases where a new cycle was
initiated despite having a grade 3 or 4 ANC or platelet count, the observations
will be excluded.
9.7.6 Vital Signs and Weight
Results and change from baseline for weight, blood pressure, pulse, respiratory
rate and temperature will be summarized by treatment arm by visit. Results and
change from pre-infusion to post-infusion for blood pressure, pulse, respiratory
rate and temperature will be summarized by treatment arm and cycle. The
nominal pre and post infusion timepoints on the CRF will be used as vital signs
assessment time is not collected.
9.7.7 ECOG Performance Status
ECOG performance status will be summarized by treatment arm as counts and
percentages using shift tables of baseline versus worst performance status
during study. The number of patients with improvement of ≥1 unit and ≥2 units
respectively at the last available visit and at the End of Treatment visit will be
summarized as counts and percentages.
9.7.8 Physical Examination
Physical examination results will be listed without summary.


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9.7.9 12-Lead Electrocardiograms
QTc-Fridericia (QTcF) interval results and changes from baseline will be
summarized by treatment arm with descriptive statistics at baseline and End of
Treatment visit. QTcF is calculated in the database as QTcF = QT / (RR)1/3
assuming units of milliseconds.
9.7.10 Analyses by Subgroups
Analysis of TEAEs, AESIs, SAEs, fatal TEAEs, TEAEs leading to discontinuation,
and TEAEs leading to dose modifications will be provided by the following
subgroups:

Age
o
<65, ≥65 years
o
<75, ≥75 years

Sex (male, female)

BSA (below or above median BSA for FAS)

Race (White, All Other Races)

Geographic region (United States of America, Europe, Rest of World)

Prior Autologous Transplant (Yes, No)

Time from Prior Autologous Stem Cell Transplant to Randomization
o
<2.5 years
o
2.5 – 5 years
o
<5 years
o
>5 years
o
No transplant
10 STATISTICAL/ANALYTICAL ISSUES
10.1 Handling of Dropouts or Missing Data
10.1.1 Efficacy Assessments
The handling of dropouts and missing disease status assessments for the
efficacy variables is described in their definitions. Table 3 describes how
dropouts and missing data impact the calculation of the time to event variables.
Missing data will not be estimated or carried forward for any of the other
summaries.


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10.1.2 Safety Assessments
10.1.2.1
Adverse Events
Adverse events with missing relationship are considered related for purposes of
summaries. Imputed relationship will not be included in the listings.
Adverse events with missing severity are considered severe (grade 3) for
purposes of summaries.  Imputed severity will not be included in the listings.
Adverse events with missing action taken with study drug are excluded from
analyses.
10.1.2.2
Laboratory Assessments
The following imputations will be made for missing reported units:

Beta-2 Microglobulin, FLCs
o
Values less than 10: mg/L
o
Values greater than or equal to 1000: µg/L

Creatinine clearance: mL/min

ALT, AST, Alkaline Phosphatase: U/L

Albumin
o
Values less than 10: g/dL
o
Values greater than or equal to 10: g/L

INR: RATIO

Prothrombin Time (PT): seconds (sec)

Hematocrit
o
Values greater than 1: %
o
Values less than or equal to 1: RATIO

Hemoglobin
o
Values less than 30: g/dL
o
Values greater than or equal to 30: g/L

RBC: 10^12/L.

Platelets:
o
Values less than 1000: 10^9/L.


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o
Values greater than or equal to 1000: /µL

WBC
o
Values less than 20: 10^9/L.
o
Values greater than or equal to 20: /µL

WBC differential counts
o
Values less than 10: 10^9/L.
o
Values greater than or equal to 100: /µL
Prothrombin times reported as %, which will not be imputed, will be omitted from
summaries.
10.1.3 Dates and Times
If only a partial date is available and is required for a calculation (e.g., time since
diagnosis, time since most recent relapse, determination of whether a medication
is concomitant or an AE is treatment-emergent), the following standards will be
applied:

Start dates (e.g., AE onset date or start date of medication, date of
diagnosis, date of relapse)
For missing start day only - Day will be imputed as the first day of the
month (i.e., 1) with the following exception: if the partial date falls in the
same month and year as the date being used in the calculation (e.g.,
first dose date, informed consent date), then the partial date will be
imputed to equal the date being used for the calculation.
For missing start day and month - Day and month will be imputed as the
first day of the year (i.e., 1 January) with the following exception: if the
partial date falls in the same year as the date being used in the
calculation (e.g., first dose date, informed consent date), then the partial
date will be imputed to equal the date being used for the calculation.

Stop dates (e.g., AE resolution date or stop date of medication)
For missing stop day only - Day will be imputed as the last day of the
month (i.e., 28, 29, 30, or 31)
For missing stop day and month - Day and month will be imputed as
the last day of the year (i.e., 31 December)


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If a patient is known to be dead, but the death date is unknown, the death date
will be imputed as the survival status contact date where the patient was known
to have died.
Any partial dates will be displayed in data listings without imputation of missing
days and/or months (e.g., MAR2011, 2009).
If time is not available but is required for a calculation (e.g., timing of AE vs study
drug administration) the most conservative approach should be used, i.e.
assuming that the time of AE was after study drug administration or that the time
of concomitant medication was after AE.
10.1.4 Dates for Prior Autologous Transplant Subgroup
If only a partial date is available and is required for a calculation (e.g., time since
prior autologous transplant to randomization), the following standards will be
applied:

Start dates
For missing start day only - Day will be imputed as the 15th day of the
month.
For missing start day and month - Day and month will be imputed as the
first day of the July (i.e., 1 July).
10.2 Multiplicity/Multiple Comparisons
For the primary and the key secondary efficacy analyses, the overall 2-sided
level of significance will be alpha = 0.05. The hypothesis testing of key secondary
endpoints will be conducted using a gatekeeping procedure based on a closed
fixed-sequence test, provided the primary efficacy endpoint comparison is
statistically significant at an alpha level 0.05. If this comparison is not statistically
significant, then the comparison of key secondary efficacy endpoints will be
considered nominal, descriptive and exploratory. This procedure controls the
study-wise type I error and is described below.
1. First Melflufen + Dexamethasone and Pomalidomide + Dexamethasone
will be compared with respect to the primary efficacy endpoint. If the
comparison achieves statistical significance at the 2-sided 0.05 level in
favor of Melflufen + Dexamethasone, then
2. Melflufen + Dexamethasone and Pomalidomide + Dexamethasone will be
compared with respect to ORR. If the comparison achieves statistical


Melflufen
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69
significance at the 2 sided 0.05 level in favor of Melflufen +
Dexamethasone, then
3. Melflufen + Dexamethasone and Pomalidomide + Dexamethasone will be
compared with respect to OS.
If at any step defined above, the comparison is not statistically significant at the
2-sided 0.05 level, then the remaining comparisons in the stated hierarchy will be
considered nominal, descriptive and exploratory. The study-wise type I error will
be maintained with the above closed procedure.
10.3 Interim Analysis and Data Monitoring
10.3.1 Interim Analysis
No interim analyses are planned.
10.3.2 Data Monitoring Committee
An independent DMC will perform surveillance of efficacy/safety balance at
regular intervals during the study, using summaries and listings that will be
unblinded to the assigned treatment arm. All activities and processes
surrounding the DMC will be outlined in the DMC Charter.
10.3.3 Independent Review Committee (IRC)
An Independent Review Committee (IRC) will assess all tumor responses and
progression as detailed in the IRC Charter. The IRC members will be blinded to
all treatment data and perform their reviews in closed-meeting sessions. All
activities and processes surrounding the IRC will be outlined in the IRC Charter.
10.4 Changes to Protocol Planned Analyses
Per FDA feedback received 27APR2021, the following updates were made:

Primary endpoint analysis based on stratified log-rank test

DOR moved from key secondary objective/endpoint to other secondary
objective/endpoint, removing it from multiplicity adjustment.

Efficacy subgroup analyses and DOCB analyses clarified to be exploratory
The PK Analysis Set was added for evaluation of melphalan PK endpoints.
Exploratory analyses to evaluate the effect of the COVID-19 pandemic were
added.
The protocol specifies that TTP will be summarized without analysis, however,
TTP will be analyzed using K-M methods.


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Duration of MR and SD will not be summarized separately.
Unstratified CMH analyses were added for consistency with time-to-event
unstratified analyses.


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11 REFERENCES
Brookmeyer, R. and J. Crowley (1982). A Confidence Interval for the Median
Survival Time.
Biometrics 38(1), 29-41Cockcroft DW, Gault MH. Prediction of creatinine
clearance from serum creatinine. Nephron 1976;16(1):31-41.
FDA Guidance for Industry on Clinical Trial Endpoints for the Approval of
Cancer Drugs and Biologics.
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics
FDA Guidance for Industry on Clinical Trial Endpoints for the Approval of
Non-Small Cell Lung Cancer Drugs and Biologics.
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-trial-endpoints-approval-non-small-cell-lung-cancer-
drugs-and-biologics
FDA review of selinexor. XPOVIO (Selinexor) MULTI-DISCIPLINE REVIEW
– FDA.
https://www.accessdata.fda.gov/drugsatfda docs/nda/2019/212306Orig1s00
0MultidisciplineR.pdf
Fleiss, J.L. Statistical Methods for Rates and Proportions, Second Edition,
1981, New York: John Wiley & Sons, Inc.
ICH E9 Statistical Principles for Clinical Trials.
https://www.ema.europa.eu/en/ich-e9-statistical-principles-clinical-trials
Imnovid (Pomalidomide Celgene) EPAR (2013).
https://www.ema.europa.eu/en/documents/assessment-report/pomalidomide-
celgene-epar-public-assessment-report en.pdf
Rajkumar SV, Harousseau JL, Durie BGM, Anderson KC, Dimopoulos M,
Kyle R et al.  Consensus recommendations for the uniform reporting of
clinical trials: report of the International Myeloma Workshop Consensus
Panel 1. Blood 2011; 117: 4691-4695.
Palumbo A, et al. Revised International Staging System for Multiple
Myeloma: A Report from International Myeloma Working Group. Journal of
Oncology 2015. 33:26, 2863-2869.
pomalidomideALYST label. pomalidomideALYST (pomalidomide) capsules -
FDA. NDA204026, NDC 59572-503-21.
https://www.accessdata.fda.gov/drugsatfda docs/label/2017/204026s019lbl.
pdf


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Oncopeptides AB
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25 October 2021
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72
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure
time. Controlled Clinical Trials 1996; 17:343–346.
Sonneveld P, et al. Treatment of multiple myeloma with high-risk
cytogenetics: a consensus of the International Myeloma Working Group.
Blood. 2016 Jun 16; 127(24): 2955–2962.
The National Cancer Institute. Common Terminology Criteria for Adverse
Events (NCI CTCAE 4.03) June 14, 2010
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03/CTCAE 4.03 2010-06-
14 QuickReference 8.5x11.pdf






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