Clinical trial NCT04649060
Conditions: Relapsed Multiple Myeloma Relapsed-Refractory Multiple Myeloma
Sponsor: Oncopeptides AB
Start date: 2020-12-21; Completion date: 2022-02-07
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI.

Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease.

Detailed description:

Arms: arm 1: Treatment was given in 28-day cycles in an outpatient treatment setting.

* Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle
* Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years)
* Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7 arm 2: Treatment was given in 28-day cycles in an outpatient treatment setting.

• Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Interventions: intervention 1: Melflufen intervention 2: Dexamethasone intervention 3: Daratumumab
Intervention descriptions: intervention 1: Powder for solution for i.v. infusion intervention 2: Oral tablets intervention 3: Solution for s.c. injection

Protocol documents:
Prot_000.pdf: 
Protocol OP-108  
Version 2.1, 25 November 2020 
 
Protocol Title: A Randomized, Controlled, Open-Label Phase 3 Study of 
Melflufen in combination with Daratumumab Compared with Daratumumab in 
Patients with Relapsed or Relapsed-Refractory Multiple Myeloma 
 
 
National Clinical Trial number: NCT04649060 


CONFIDENTIAL 
 
Protocol OP-108 Version 2.1 
25 November 2020 
 
 
Title Page 
 
Protocol Title: A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in 
combination with Daratumumab Compared with Daratumumab in Patients with Relapsed or 
Relapsed-Refractory Multiple Myeloma 
 
Protocol Number:   
 
OP-108 
Compound:  
 
 
Melflufen 
Brief Title:  
An Open-label, Phase 3 Study of Melflufen with 
Daratumumab compared to Daratumumab in patients with 
RRMM   
Study Phase:   
 
 
Phase 3 
Acronym: 
 
 
 
LIGHTHOUSE 
Sponsor Name: 
 
 
Oncopeptides AB 
Legal Registered Address: 
Västra Trädgårdsgatan 15 
SE-111 53 Stockholm, Sweden 
Regulatory Agency  
Identifying Number(s): 
 
IND:   
116362 
EudraCT:  
2019-002161-36 
 
Clinical Research Organization: 
PSI CRO AG 
 
 
 
 
 
Baarerstrasse 113a 
 
 
 
 
 
6300 Zug, Switzerland 
 
Approval Date: 
 
 
Version 1.0: January 29, 2020 
 
 
 
 
 
Version 2.0: Amendment 1, September 03, 2020  
 
 
 
 
 
Version 2.1: Amendment 2, November 25, 2020  
  
CONFIDENTIAL 
This document contains confidential information belonging to Oncopeptides AB. Except as may 
be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold 
such information in confidence and not to disclose it to others (except where required by 
applicable law) nor use it for unauthorized purposes. In the event of actual or suspected breach of 
this obligation, Oncopeptides AB should be promptly notified.  
 


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Protocol OP-108 Version 2.1 
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Signature Page – Sponsor and Lead Investigator 
 
 
Lead Investigator:  
 
 
 
_____________________________________________ 
_______________________ 
 
Date 
 
 
 
Complejo Hospitalario de Salamanca 
 
Paseo San Vicente, 88-182 
Salamanca 37007, Spain 
  
 
 
Sponsor: 
 
 
_______________________________________________         _______________________ 
 
Date 
 
 
 
Clinical Study Physician 
Oncopeptides AB 
Luntmakargatan 46 
111 37 Stockholm, Sweden 
Switchboard +46 8 615 20 40 
Phone: +46 70 300 90 82 
 
 
 
_______________________________________________         _______________________ 
 
Date 
Clinical Operations Director 
Oncopeptides AB 
Luntmakargatan 46 
111 37 Stockholm, Sweden 
 
 
 
 


CONFIDENTIAL 
Protocol OP-108 Version 2.1 
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Protocol Agreement Page - Principal Investigator 
 
Protocol Title:  A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in 
combination with Daratumumab Compared with Daratumumab in Patients with Relapsed or 
Relapsed-Refractory Multiple Myeloma 
Protocol Number: OP-108 
 
 
 
 
By signing this protocol acceptance page, I confirm I have read, understood, and agree to conduct 
the study in accordance with the current protocol.  
 
________________________________________________ 
 
Name of Study Center 
 
________________________________________________ 
 
Principal Investigator Name (Printed)  
 
 
 
________________________________________________ 
_______________________ 
Principal Investigator (Signature) 
Date 
 
 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), with applicable local regulations, and with the ethical principles laid 
down in the Declaration of Helsinki. 
Confidential information contained in the clinical study protocol will not be used for any purpose 
other than the evaluation and conduct of the clinical investigation, unless prior written approval 
has been obtained from the Sponsor Oncopeptides AB. 
 
 
 
 
 
 
 
 
 
 


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Protocol OP-108 Version 2.1 
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Protocol Amendment Summary of Changes 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 (non-substantial) 
25 November 2020 
Amendment 1 
03 September 2020 
Original Protocol 
29 January 2020 
Overall Rationale for Amendment 1, 03 September 2020: 
The overall rationale for Amendment 1 is an update of the study design to 1:1 randomization and 
increased sample size to 240 patients with 90% power at the request of Competent Authorities. 
Also, a crossover opportunity has been added to allow patients with documented disease 
progression in Arm B to receive melflufen, dexamethasone and daratumumab treatment. 
In addition, exclusion criteria related to infections have been updated with information about 
COVID-19.  
Information that the subcutaneous formulation of daratumumab used in the study has been 
approved by FDA in the US, EMA in Europe and MHRA in UK during 2020 has been added.  
 
Overall Rationale for Amendment 2, 25 November 2020: 
Non-substantial amendment due to update of assigned safety CRO from PSI to TFS. SAE 
reporting email address updated to safety.report@oncopeptides.com.  


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Protocol OP-108 Version 2.1 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
2 Introduction 
Adding that melphalan 
flufenamide is referred to as 
melflufen. 
The international nonproprietary name 
of melflufen is melphalan flufenamide. 
1.1 Synopsis 
2.1 Study Rationale 
Adding that the subcutaneous 
formulation of daratumumab to be 
used in the study was approved by 
FDA in US, by EMA in Europe 
and MHRA in UK in 2020.  
Approval of subcutaneous (s.c.) 
daratumumab obtained by FDA, EMA 
and MHRA since protocol version 1.0 
was finalised. 
1.1 Synopsis 
1.2 Schema 
2.1 Study Rationale 
2.3 Benefit/Risk 
Assessment  
3 Objectives and 
Endpoints 
4.1 Overall Design 
4.2 Scientific 
Rationale for Study 
Design 
6.1 Study Treatment 
Administered 
8.1.3Procedures 
after active study 
treatment  
Appendix 3:  
Optional crossover 
for patients in Arm 
B to treatment with 
melflufen, 
dexamethasone and 
daratumumab 
Patients that received 
daratumumab monotherapy and 
have confirmed disease 
progression may receive the 
melflufen, daratumumab and 
dexamethasone combination as an 
optional crossover within the 
study.  
 
Updates are made throughout the 
protocol in applicable sections. All 
assessments for the optional 
crossover are specifically 
described in Appendix 3:  Optional 
crossover for patients in Arm B to 
treatment with melflufen, 
dexamethasone and daratumumab. 
Revised study design 
1.1 Synopsis 
3 Objectives and 
Endpoints 
Clarification of Key secondary 
objectives. 
 
Objectives based on PROs are 
moved from secondary to 
exploratory objectives with 
clarification that endpoints based 
on PROs are including summary 
score of EORTC QLQ-C30 and 
utility index of EQ-5D. 
 
Clarification 
 


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1.1 Synopsis 
5.1 Inclusion 
Criteria 
5.2 Exclusion 
Criteria 
Exclusion criteria 2: If treated with 
daratumumab or another anti-
CD38 antibody:  Refractory to 
treatment or failure to achieve at 
least PR as best response 
 
Replaced with  
 
Inclusion criteria 5:  
Prior treatment with daratumumab 
or another anti-CD38 antibody is 
allowed if the patient has: 
• Achieved at least PR and is not 
refractory to previous anti-CD38 
antibody treatment 
• At least 6 months since last 
dose of anti-CD38 antibody prior 
to Cycle 1/Day 1 (C1/D1) 
• Not discontinued anti-CD38 
antibody treatment due to related 
Grade ≥ 3 toxicity 
Clarifying patient eligibility for patients 
previously treated with daratumumab or 
another anti-CD38 antibody. 
 
 
 
 
 
 
 
 
  
1.1 Synopsis 
5.1 Inclusion 
Criteria 
5.2 Exclusion 
Criteria 
8.4.7 Laboratory 
Test Abnormalities 
Exclusion criteria 8 updated.  
Known active infection that is 
uncontrolled (including 
symptomatic or asymptomatic 
COVID-19) or has required 
intravenous systemic therapy 
within 14 days of randomization. 
Patients that has required oral anti-
infective treatment within 14 days 
of randomization should be 
discussed with the Medical 
Monitor. 
 
Added information in Laboratory 
Test Abnormalities:  
A positive COVID-19 (SARS-
CoV-2) test should always be 
considered clinically significant. 
Adding clarification that known 
infection due to COVID-19 is an 
exclusion criterion. 
1.1 Synopsis 
6.1.1 Study 
Regimens and 
Administration 
 
2:1 randomization changed to 1:1 
randomization and number of 
patients randomized updated from 
170 to 240.   
 
Revised study design from 2:1 to 1:1 
randomization and 90% power. 
 


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1.1 Synopsis 
 
Study Treatment Arm A; Table 
updated with footnote to 
correspond to protocol.  
b) Premedication should be 
administered to prevent infusion 
related reactions (see protocol). 
Clarification in synopsis. 
1.2 Schema 
Study Schema updated. 
Revised study design. 
1.3 Schedule of 
Activities (SoA) 
8.1.3.2 Procedures 8 
weeks after last dose 
of daratumumab 
8.1.3.3.1 Progression 
Free Survival 
Follow-Up 
 
Pregnancy test added for Woman 
of Child Bearing Potential at 8 and 
12 weeks after last daratumumab 
dose.  The 8 and 12- weeks urine 
test can be taken at home. 
Updated to have monthly pregnancy 
testing during the same time period as 
contraception is required. 
1.3 Schedule of 
Activities (SoA) 
8.1 Study procedures 
Table 10-2 
Blood 
and Bone Marrow 
Volumes 
8.10.2 DNA/RNA 
Sequencing 
 
Blood sample for DNA/RNA 
sequencing should be collected 
before dosing at cycle 1, at time of 
response (CR or VGPR), and at the 
time of disease progression.  
 
Clarification of when samples shall 
be taken in case of response and 
disease progression and removed 
as assessment on Day 8, 15 and 22. 
  
Clarification  
1.3 Schedule of 
Activities (SoA) 
Table 10-2 
Blood 
and Bone Marrow 
Volumes 
 
Blood sample for myeloma related 
bone disease biomarkers should be 
collected before dosing at Day 1 of 
all cycles, at the EOT visit and at 
PFS-FU. 
Including samples at PFS-FU 
independent of disease progression.  
1.3 Schedule of 
Activities (SoA) 
8.1 Study procedures 
 
  
Clarifications of cycle-specific 
assessments against information 
described in the protocol body for 
consistency, including adding 
separate rows in SoA for 
subsequent therapy review. 
Clarification 
1.3 Schedule of 
Activities (SoA) 
4.5.1Study 
Completion for a 
patient 
Clarification that patient study end 
date and primary reason for ending 
study will be collected. 
Clarification 


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1.3 Schedule of 
Activities (SoA) 
 
6.3.1 Study Drug 
Administration 
 
8.1.2.3 Procedures 
Day 8, 15 and 22 
If patient tolerability is good, i.e. 
no dose modifications, dose delays 
or need of supportive therapy (G-
CSF, blood or platelet transfusion) 
in the two preceding cycles, then 
Complete Blood Count 
assessments may be excluded at 
Day 8 and Day 22. 
To limit the number of mandatory visits 
for the patient during the cause of the 
study. 
2.2 Background 
Information on number of patients 
estimated with myeloma in the US 
has been updated with figures from 
2019. 
Isatuximab added as an approved 
drug for the treatment of Multiple 
Myeloma. 
 
Update with recent information. 
 
 
 
Recently approved treatment. 
2.3 Benefit/Risk 
Assessment 
New table added “Assessment of 
important potential risk” with 
important potential risks and 
mitigation strategy.  
Clarification of what the important 
potential risks that are associated with 
the study interventions and study 
procedures.  
4.3 Justification for 
Dose 
Reference added to the approved 
subcutaneous formulation Darzalex 
FASPROTM. 
FDA approval obtained in May 2020. 
5.1 Inclusion 
Criteria 
5.2 Exclusion 
Criteria 
See above. 
See above. 
6.1.1 Study 
Regimens and 
Administration 
Rewording of footnotes in table 
regarding pre-medication and 
dexamethasone administration. 
Clarification 
6.1.4 Daratumumab 
Administration (Arm 
A and B) 
Updated that the requirement of 
patients to remain in the clinic 
3 hours after their daratumumab 
administration is only for the first 
administration (Cycle 1 Day 1), 
and then up to investigators 
discretion for subsequent Cycles. 
 
Most administration related reactions 
occur following the first injection.  
6.1.4.1.2 Post-dose 
Medications  
Adding information about post-
dose administration of steroids for 
daratumumab. 
Alignment with prescribing 
information. 
 


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6.2.3.2 
Daratumumab 
Storage 
Mandatory filtration has been 
removed from the protocol and 
replaced by referring to Pharmacy 
manual. 
Filtration requirements will be 
described in the Pharmacy Manual. 
6.3.1 Study Drug 
Administration 
Adding information that if a 
patient’s tolerability is good in two 
preceding cycles, Visits at Day 8 
and Day 22 do not have to be 
completed. 
To reduce the number of visits for the 
patient. 
6.5.1 Required 
Concomitant 
Therapy 
6.5.2 Recommended 
Concomitant 
Therapy 
High risk patients are mandated, to 
receive pneumocystis prophylaxis. 
Alignment with Investigators Brochure.  
6.5.3 Prohibited 
Concomitant 
Therapy 
The use of live vaccines is 
prohibited during the study and for 
90 days after last dose of study 
treatment. 
 
Acetylsalicylic acid, at doses ≥ 1 g 
per dose or 3 g per day should be 
avoided due to an increased risk of 
bleeding in patients receiving 
dexamethasone. 
Update from 30 to 90 days at the 
request of competent authorities.  
 
 
 
Alignment with dexamethasone 
prescribing information.  
6.6.3.1 Dose 
Modifications for 
Melflufen and 
Daratumumab 
Clarification that patients with 
neutropenia should be monitored 
for signs of infection. 
Clarification 
6.6.3.2 Dose 
modifications for 
Dexamethasone 
(Arm A) 
Omeprazole has been replaced 
with proton pump inhibitors. 
Addition 
6.6.3.3 Dose 
Modifications for 
Daratumumab 
Clarified that Infusion Related 
Reactions is also used as the 
definition for systemic reactions to 
daratumumab subcutaneous 
injections. 
Added separate information about 
local reactions after administration. 
Clarification 
8.1.1 Procedures 
during screening 
Explanation of what myeloma 
history characteristics to be 
collected at screening.  
Clarification 
8.1.2.1 Procedures 
Day 1  
Duplicated information deleted. 
Duplicated information within the same 
section. 


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8.10.1 Minimal 
Residual Disease 
(MRD) assessment 
Details on MRD has been added. 
Clarification. 
8.4.7 Laboratory 
Test Abnormalities 
Removed “Induce clinical signs 
and symptoms” 
Clarification. If there are signs and 
symptoms these should be reported, not 
the lab value. 
8.11 
Immunophenotyping
/Immunoprofiling 
Clarification of heading to 
Immunophenotyping/Immunoprofi
ling. Immunoprofiling sample 
times corrected against SoA. 
Correction and clarification. 
9.2 Sample Size 
Determination 
Samples size has been updated 
based on 1:1 randomization. 
Revised study design from 2:1 to 1:1 
randomization and 90% power. 
 
9.3 Populations 
Clarification of the Per Protocol 
Analysis set that will be used for 
sensitivity analysis. 
Clarification 
9.4 Statistical 
Analyses 
Details added on the statistical 
analyses.  
Information added regarding 
efficacy analyses of the primary 
and secondary endpoints, 
multiplicity and pharmacokinetic 
data. 
Sub-section added about efficacy 
analyses of key secondary 
endpoints. 
Sub-section added about efficacy 
analyses of exploratory endpoints. 
Sub-section added about handling 
of dropouts and missing data. 
 
Addition of information. 
9.5 Interim Analyses Sub-section about Sample Size Re-
estimation has been deleted. 
Sample size revised. 
9.5.1 Data 
Monitoring 
Committee 
Added the DMC can recommend 
continuing the study, with or 
without modifications, or stop the 
study based on benefit/risk 
concerns. 
Addition of information. 


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Protocol OP-108 Version 2.1 
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Table 10-1
 
Protocol-
Required Laboratory 
Assessments 
Table 10-2 
Blood 
and Bone Marrow 
Volumes 
 
Hepatitis B, C and HIV screen 
only to be taken at screening. 
Pharmacokinetic, immunogenecity 
and immunoprofiling tests added to 
correspond to SoA. 
Clarification of timepoints as 
described above. 
Correction and clarification. 
 
 
10.1.3 Informed 
Consent Process 
Patients in Arm B who are eligible 
to crossover to treatment with 
melflufen, daratumumab and 
dexamethasone must sign an 
IRB/IEC/REB approved informed 
consent before the new treatment is 
started. 
Revised study design. 
Appendix 2: Clinical 
Laboratory Tests 
Central labs corrected with PK and 
biomarkers against SoA and Table 
8-2. 
Correction and clarification. 
Appendix 3:  
Optional crossover 
for patients in Arm 
B to treatment with 
melflufen, 
dexamethasone and 
daratumumab 
Schedule of activities, criteria for 
initiation of study procedures for 
patients in Arm B who crossover to 
treatment with melflufen, 
dexamethasone and daratumumab. 
Addition of information for crossover 
Appendix 4: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting 
COVID-19 reporting added. 
Addition of information related to 
COVID-19. 
Appendix 17 
Tick box added for 0 at No pain. 
Space for adding time added. 
Correction 
11 References 
Literature references in the 
protocol added into the Reference 
list. 
Correction 
Signature Page – 
Sponsor  
Change of Sponsor Clinical 
Operation Directors. 
Administrative update. 
Protocol 
Administrative updates. 
Administrative updates. 
 
 
 
 
 


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Protocol OP-108 Version 2.1 
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Changes Amendment 2 (non-substantial) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Signature Page – 
Sponsor  
Change of Sponsor Clinical Study 
Physician. 
Administrative update. 
Appendix 4: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting 
Assigned safety CRO changed from 
PSI to TFS 
 
SAE reporting email address added: 
safety.report@oncopeptides.com 
 
Safety CRO changed for the study 
from PSI to TFS 
 
 
Appendix 5: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Assigned safety CRO changed from 
PSI to TFS 
 
SAE reporting email address added: 
safety.report@oncopeptides.com 
 
Safety CRO changed for the study 
from PSI to TFS 
Protocol 
Administrative updates and 
corrected typos. 
Administrative updates. 
 
 


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Table of Contents 
1. 
Protocol Summary ........................................................................................................18 
1.1. 
Synopsis ..........................................................................................................................18 
1.2. 
Schema ............................................................................................................................28 
1.3. 
Schedule of Activities (SoA) ..........................................................................................29 
2. 
Introduction ...................................................................................................................38 
2.1. 
Study Rationale ...............................................................................................................38 
2.2. 
Background .....................................................................................................................38 
 
Multiple Myeloma ..........................................................................................................38 
 
Melflufen.........................................................................................................................39 
 
Daratumumab ..................................................................................................................41 
 
Melflufen and Daratumumab ..........................................................................................42 
2.3. 
Benefit/Risk Assessment ................................................................................................42 
3. 
Objectives and Endpoints ............................................................................................45 
4. 
Study Design ..................................................................................................................49 
4.1. 
Overall Design ................................................................................................................49 
 
Treatment duration ..........................................................................................................50 
4.2. 
Scientific Rationale for Study Design ............................................................................50 
4.3. 
Justification for Dose ......................................................................................................50 
4.4. 
End of Treatment Definition ...........................................................................................51 
4.5. 
End of Study Definition ..................................................................................................51 
 
Study Completion for a patient .......................................................................................51 
 
Study Definition ..............................................................................................................51 
5. 
Study Population ...........................................................................................................52 
5.1. 
Inclusion Criteria ............................................................................................................52 
5.2. 
Exclusion Criteria ...........................................................................................................53 
5.3. 
Lifestyle considerations ..................................................................................................55 
5.4. 
Screen Failures ................................................................................................................55 
5.5. 
Population Diversity .......................................................................................................55 
6. 
Study Intervention ........................................................................................................56 
6.1. 
Study Treatment Administered .......................................................................................56 
 
Study Regimens and Administration ..............................................................................57 
 
Melflufen Administration (Arm A) ................................................................................58 
 
Dexamethasone Administration (Arm A) .......................................................................59 
 
Daratumumab Administration (Arm A and B) ...............................................................60 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................62 
 
Melflufen.........................................................................................................................62 
 
Dexamethasone ...............................................................................................................63 
 
Daratumumab ..................................................................................................................64 
6.3. 
Measures to Minimize Bias ............................................................................................65 
 
Study Drug Administration .............................................................................................65 
 
Randomization ................................................................................................................65 
 
Data Access Plan.............................................................................................................65 
 
Medical Monitoring Plan ................................................................................................65 
 
Data Monitoring Committee ...........................................................................................65 
 
Independent Review Committee .....................................................................................66 
6.4. 
Study Treatment Compliance .........................................................................................66 


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6.5. 
Concomitant Therapy .....................................................................................................66 
 
Required Concomitant Therapy ......................................................................................66 
 
Recommended Concomitant Therapy .............................................................................67 
 
Prohibited Concomitant Therapy ....................................................................................68 
6.6. 
Dose Modification ..........................................................................................................68 
 
Criteria for initiation of therapy ......................................................................................69 
 
Dose Reduction Steps .....................................................................................................70 
 
Dose Modifications Based on Toxicity...........................................................................71 
6.7. 
Intervention after the End of the Study ...........................................................................76 
7. 
Discontinuation of Study Intervention and Patient 
Discontinuation/Withdrawal........................................................................................77 
7.1. 
Discontinuation of Study Treatment ...............................................................................77 
7.2. 
Patient Discontinuation/Withdrawal from the Study ......................................................77 
7.3. 
Lost to Follow Up ...........................................................................................................77 
8. 
Study Assessments and Procedures.............................................................................79 
8.1. 
Study procedures.............................................................................................................79 
 
Procedures during screening ...........................................................................................79 
 
Procedures during study treatment, all cycles.................................................................81 
 
Procedures after active study treatment  .........................................................................83 
8.2. 
Efficacy Assessments .....................................................................................................87 
 
Response Assessments ....................................................................................................87 
 
Skeletal X-rays and low-dose CT scans..........................................................................88 
 
Extramedullary Myeloma (plasmacytoma) Assessment .................................................88 
8.3. 
Safety Assessments .........................................................................................................88 
 
Physical Examinations ....................................................................................................88 
 
Vital Signs .......................................................................................................................89 
 
Electrocardiograms .........................................................................................................89 
 
Clinical Safety Laboratory Assessments ........................................................................89 
 
Medical History and Myeloma history including characteristics ...................................90 
 
Concomitant Therapy or Medication ..............................................................................90 
 
Eastern Cooperative Oncology Group Performance Status ............................................90 
 
Health Services and Hospitalizations ..............................................................................90 
8.4. 
Adverse Events and Serious Adverse Events .................................................................90 
 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................91 
 
Method of Detecting AEs ...............................................................................................91 
 
Follow-up of AEs, including SAEs ................................................................................91 
 
Regulatory Reporting Requirements for SAEs ...............................................................92 
 
Pregnancy ........................................................................................................................92 
 
Fatal Events .....................................................................................................................92 
 
Laboratory Test Abnormalities .......................................................................................92 
8.5. 
Treatment of Overdose ...................................................................................................93 
8.6. 
Pharmacokinetic assessments .........................................................................................94 
 
Pharmacokinetic assessment melphalan .........................................................................94 
 
Pharmacokinetic assessment daratumumab ....................................................................94 
8.7. 
Immunogenicity ..............................................................................................................95 
 
Immunogenicity of Daratumumab ..................................................................................95 
 
Immunogenicity of Recombinant Human Hyaluronidase ..............................................95 
8.8. 
Pharmacodynamics .........................................................................................................95 


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8.9. 
Genetics ..........................................................................................................................95 
8.10. 
Biomarkers ......................................................................................................................95 
 Minimal Residual Disease (MRD) assessment ...............................................................97 
 DNA/RNA Sequencing ...................................................................................................97 
 Biomarkers for myeloma-related bone disease ...............................................................97 
8.11. 
Immunophenotyping/Immunoprofiling ..........................................................................98 
8.12. 
Patient Reported Outcome assessments ..........................................................................98 
9. 
Statistical Considerations .............................................................................................99 
9.1. 
Statistical Hypotheses .....................................................................................................99 
9.2. 
Sample Size Determination ..........................................................................................100 
9.3. 
Populations....................................................................................................................101 
9.4. 
Statistical Analyses .......................................................................................................102 
 
Efficacy Analyses of the Primary Endpoint ..................................................................102 
 
Efficacy Analyses of Key Secondary Endpoints ..........................................................102 
 
Efficacy Analyses of other Secondary Endpoints .........................................................103 
 
Efficacy Analyses of Exploratory Endpoints ................................................................103 
 
Multiplicity ...................................................................................................................103 
 
Analyses of Pharmacokinetic Data ...............................................................................104 
 
Safety Analyses .............................................................................................................104 
 
Other Analyses ..............................................................................................................105 
 
Handling of dropouts and missing data ........................................................................105 
9.5. 
Interim Analyses ...........................................................................................................105 
 
Data Monitoring Committee .........................................................................................105 
 
Independent Review Committee ...................................................................................105 
10. 
Supporting Documentation and Operational Considerations ................................106 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ..............................................................................................................106 
 Regulatory and Ethical Considerations .........................................................................106 
 Financial Disclosure ......................................................................................................106 
 Informed Consent Process ............................................................................................106 
 Data Protection..............................................................................................................107 
 Dissemination of Clinical Study Data ...........................................................................107 
 Data Quality Assurance ................................................................................................107 
 Source Documents ........................................................................................................108 
 Study and Site Closure ..................................................................................................108 
 Publication Policy .........................................................................................................109 
10.2. 
Appendix 2: Clinical Laboratory Tests .........................................................................110 
10.3. 
Appendix 3:  Optional crossover for patients in Arm B to 
treatment with melflufen, dexamethasone and daratumumab ......................................117 
 Criteria for initiation of treatment following crossover ................................................117 
 Criteria Day 1, Subsequent cycles ................................................................................118 
 Dose Modification and Reduction Steps.......................................................................119 
 Study Procedures ..........................................................................................................119 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................................130 
10.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information ...................................................................................................................137 
10.6. 
Appendix 6: Eastern Cooperative Oncology Group (ECOG) 
Performance Scale ........................................................................................................141 


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10.7. 
Appendix 7: NCI CTCAE Version 5.0 .........................................................................142 
10.8. 
Appendix 8: IMWG Uniform Response Criteria ..........................................................143 
10.9. 
Appendix 9: Line of Therapy Definition ......................................................................146 
10.10. 
Appendix 10: ISS and R-ISS Score ..............................................................................147 
10.11. 
Appendix 11: Definition of Relapsed Disease per IMWG 
definitions .....................................................................................................................148 
10.12. 
Appendix 12: Assessment of Q-Tc interval ..................................................................149 
10.13. 
Appendix 13: Estimated Creatinine Clearance by Cockcroft- Gault 
Formula .........................................................................................................................149 
10.14. 
Appendix 14:  EQ-5D-3L .............................................................................................150 
10.15. 
Appendix 15:  EORTC QLQ-C30 ................................................................................150 
10.16. 
Appendix 16:  BPI-SF ..................................................................................................150 
10.17. 
Appendix 17:  NRS for measure of bone pain ..............................................................151 
10.18. 
Appendix 18:  Use of health services and hospitalization ............................................152 
10.19. 
Appendix 19: Abbreviations .........................................................................................153 
11. 
References ....................................................................................................................158 
 
List of Tables 
Table 1-1 
Study objectives and Endpoints .......................................................................... 19 
Table 1-2 
 Schedule of Activities (SoA) .............................................................................. 29 
Table 2-1 
Summary of melflufen treatment related Grade 3 or 4 AEs in O-12-M1 ........... 41 
Table 2-2 
Assessment of important Potential Risks ............................................................ 43 
Table 4-1 
Daratumumab Schedule, Arm A ......................................................................... 49 
Table 4-2 
Daratumumab Schedule, Arm B ......................................................................... 49 
Table 6-1 
Study Drugs ......................................................................................................... 56 
Table 6-2 
Study Treatment Arm A ...................................................................................... 58 
Table 6-3 
Study Treatment Arm B ...................................................................................... 58 
Table 6-4  
Dexamethasone dosing schedule ......................................................................... 60 
Table 6-5 
Dose Reduction Steps for Melflufen ................................................................... 70 
Table 6-6 
Dose Reduction Steps for Dexamethasone ......................................................... 71 
Table 6-7 
Dose Modification for Toxicity Related to Melflufen and Daratumumab .......... 72 
Table 6-8 
Dose Modification for Toxicity Related to Dexamethasone ............................... 74 
Table 8-1 
PK sampling timepoints melphalan ..................................................................... 94 
Table 8-2 
Summary of biomarker assessments ................................................................... 96 
Table 8-3 
Timepoints for patient reported outcome assessments ........................................ 99 
Table 9-1 
Sample Size Determination ............................................................................... 100 
Table 10-1 
Protocol-Required Laboratory Assessments ..................................................... 110 
Table 10-2 
Blood and Bone Marrow Volumes .................................................................... 115 


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Table 10-3 
Schedule of Activities (SoA) Crossover Arm B ............................................... 124 
Table 10-4 
Highly Effective Contraceptive Methods .......................................................... 138 
 


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1. 
Protocol Summary 
1.1. Synopsis 
Protocol Title: A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in 
combination with Daratumumab Compared with Daratumumab in Patients with Relapsed or 
Relapsed-Refractory Multiple Myeloma 
Short Title: An Open-label, Phase 3 Study of Melflufen with Daratumumab compared to 
Daratumumab in patients with RRMM   
Rationale: 
The outcome of relapsed/refractory multiple myeloma (RRMM) is still unsatisfactory despite 
recent improvements in treatment. Melphalan flufenamide (hereinafter referred to as melflufen) is 
a novel peptide-drug conjugate that is rapidly taken up by MM cells due to its high lipophilicity 
(Chauhan et al 2013, Wikström et al 2017). Once inside the myeloma cell, the activity of 
melflufen is determined by its immediate cleavage by peptidases into hydrophilic alkylator 
payloads that are entrapped (Wikström et al 2017, Gullbo et al 2003). Melflufen is 50-fold more 
potent than melphalan in myeloma cells in vitro due to the increase of intracellular alkylator 
activity (Chauhan et al 2013, Wikström et al 2017). Daratumumab is a monoclonal antibody 
targeting CD38 and has shown activity in RRMM as a single agent with limited hematological 
toxicity (Lokhorst 2014). The combination of melflufen, dexamethasone and intravenous 
daratumumab is explored in the clinical study OP-104 ANCHOR. Early data has shown promising 
efficacy and limited non-hematologic toxicity in line with previous experiences of melflufen in 
earlier studies. The aim of this Phase 3 study (OP-108) is to evaluate the drug combination 
melflufen, dexamethasone and daratumumab compared to daratumumab monotherapy in patients 
with RRMM. Daratumumab monotherapy is used as comparator since it is an approved treatment 
in the intended study population. Patients who received daratumumab monotherapy and have 
confirmed disease progression may receive the melflufen, daratumumab and dexamethasone 
combination as an optional treatment within the study. A subcutaneous co-formulation of 
daratumumab in combination recombinant human hyaluronidase PH20 has been evaluated versus 
intravenous daratumumab in a Phase 3 trial (Mateos et al 2019). Based on the data from that study 
(the COLUMBA trial), the subcutaneous formulation of daratumumab was approved in 2020 by 
FDA in US, EMA in Europe and MHRA in UK and will be used in both treatment arms in study 
OP-108.  
 
Objectives and Endpoints 
The objectives and endpoints for the study are presented in Table 1-1.  


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Table 1-1 
Study objectives and Endpoints 
Objectivesa 
Endpointsa 
Primary: 
To show superiority of progression free-survival 
(PFS) in patients treated with melflufen and 
dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
PFS (time from the date of randomization to the date of 
first documentation of confirmed progressive disease 
(PD) or death due to any cause).  
Key Secondary: 
 
To evaluate and compare Overall Response Rate 
(ORR) in patients treated with melflufen and 
dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
 
ORR (proportion of patients who achieve a best 
confirmed response of stringent Complete Response 
(sCR), Complete Response (CR), Very Good Partial 
Response (VGPR) or Partial Response (PR)). 
To evaluate and compare Duration of Response 
(DOR) in patients treated with melflufen and 
dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
 
DOR (time from the first evidence of confirmed 
assessment of sCR, CR, VGPR or PR to first confirmed 
disease progression, or death due to any cause. DOR is 
defined only for patients with a confirmed PR or better). 
To assess the safety and tolerability of melflufen 
and dexamethasone in combination with 
daratumumab compared to daratumumab alone. 
Frequency and Grade of treatment emergent adverse 
events (TEAE). 
Other Secondary: 
To evaluate and compare efficacy endpoints in 
patients treated with melflufen and dexamethasone 
in combination with daratumumab compared to 
daratumumab alone: 
• Best response during the study  
• Clinical benefit rate (CBR) 
• Duration of Clinical Benefit (DOCB) 
• Time to response (TTR) 
• Time to progression (TTP) 
• Time to next treatment (TTNT) 
• Overall survival (OS)  
Best Response (proportion of patients with sCR, CR, 
VGPR, PR, Minimal Response (MR), Stable Disease 
(SD), PD or non-evaluable).  
CBR (the proportion of patients who achieve a best 
confirmed response of sCR, CR, VGPR, PR or MR). 
DOCB (time from first evidence of confirmed 
assessment of sCR, CR, VGPR, PR, or MR to first 
confirmed disease progression, or to death due to any 
cause.) DOCB is defined only for patients with a 
confirmed MR or better. 
TTR (time from randomization to the date of the first 
documented confirmed response in a patient who has 
responded with ≥PR). 
TTP (time from the date of randomization to the date of 
the first documented confirmed PD). 
TTNT (time from randomization to the date of next 
anti-myeloma treatment or until death).  


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OS (time from date of randomization to death due to 
any cause). 
Exploratory: 
To assess minimal residual disease (MRD) in 
patients achieving a CR or VGPR in patients 
treated with melflufen and dexamethasone in 
combination with daratumumab compared to 
daratumumab alone.  
Assessment of MRD status by Next Generation 
sequencing (NGS) in patients who achieve a CR or 
VGPR.  
To evaluate the Progression Free Survival 
following next line of treatment (PFS-2) in 
patients treated with melflufen and dexamethasone 
in combination with daratumumab compared to 
daratumumab alone. 
PFS-2 (defined as time from randomization to 
progression on next line of treatment or death from any 
cause, whichever occurs first). 
To assess and compare the changes in pain in 
patients treated with melflufen and dexamethasone 
in combination with daratumumab compared to 
daratumumab alone. 
Value and changes in pain, in BPI-SF and Numeric 
Rating Scale (NRS) for measure of bone pain. 
To assess and compare responses in patients with 
extramedullary myeloma (plasmacytomas). 
Response rate (CR and PR) according to International 
Myeloma Working Group (IMWG) consensus criteria 
of extramedullary myeloma (plasmacytomas).  
To assess and compare use of health services and 
number and duration of hospitalizations in patient 
treated with melflufen and dexamethasone in 
combination with daratumumab compared to 
daratumumab alone, and in patients who crossover 
and receive treatment with melflufen, 
daratumumab and dexamethasone. 
Number of health services. 
Number and days of hospitalization. 
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). 
PK parameters of melphalan at selected time points. 
To assess the PK and immunogenicity of 
subcutaneous daratumumab. 
Serum daratumumab concentrations 
Incidence of antibodies to daratumumab 
To evaluate the immunogenicity of recombinant 
human hyaluronidase (rHuPH20) following 
subcutaneous daratumumab administration. 
Incidence of antibodies to rHuPH20 
To assess translational biomarkers that might 
predict response/non-response to the treatment, 
aid in monitoring of disease progression as well as 
improve understanding of mechanism of action. 
• DNA/RNA-based drug response biomarkers 
including but not limited to aminopeptidases 
and esterases.  


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• Serum levels of bone reabsorption related 
proteins including but not limited to TRACP‐
5b, PINP, Total RANK, Osteopontin, 
Osteocalcin, CTX, bone ALP.  
• Serum levels of cytokines IL-6, IL-10. 
• Immune profiling in peripheral blood including 
but not limited to T Reg., MDSC and NK cells. 
To assess and compare functional status and 
wellbeing based on patient reported outcome 
(PRO) assessments for patients treated with 
melflufen and dexamethasone in combination with 
daratumumab compared to daratumumab alone. 
Value and changes from baseline in EORTC QLQ-C30 
summary score, each scale of the EORTC QLQ-C30, 
EQ-5D utility index, each dimension of the EQ-5D-3L, 
and the Visual Analogue Scale (VAS) of the EQ-5D-
3L.  
To evaluate efficacy in patients in Arm B who 
crossover to treatment with melflufen, 
daratumumab and dexamethasone after 
progression on daratumumab 
• Overall response rate (ORR)  
• Duration of response (DOR) 
• Best response during the study  
• Clinical benefit rate (CBR) 
• Duration of Clinical Benefit (DOCB) 
• Time to response (TTR) 
• Time to progression (TTP) 
• Time to next treatment (TTNT) 
• Overall Survival (OS) 
 
ORR (proportion of patients who achieve a best 
confirmed response of stringent Complete Response 
(sCR), Complete Response (CR), Very Good Partial 
Response (VGPR) or Partial Response (PR)) after 
crossover. 
DOR (time from the first evidence of confirmed 
assessment (after crossover) of sCR, CR, VGPR or PR 
to first confirmed disease progression, or death due to 
any cause. DOR is defined only for patients with a 
confirmed PR or better). 
Best Response (proportion of patients with sCR, CR, 
VGPR, PR, Minimal Response (MR), Stable Disease 
(SD), PD or non-evaluable) after crossover. 
CBR (the proportion of patients who achieve a best 
confirmed response of sCR, CR, VGPR, PR or MR) 
after crossover. 
DOCB (time from first evidence of confirmed 
assessment of sCR, CR, VGPR, PR, or MR after 
crossover to first confirmed disease progression, or to 
death due to any cause.) DOCB is defined only for 
patients with a confirmed MR or better. 
TTR (time from crossover to the date of the first 
documented confirmed response in a patient who has 
responded with ≥PR). 
TTP (time from crossover to the date of the first 
documented confirmed PD). 
TTNT (time from crossover to the date of next anti-
myeloma treatment or until death). 
OS (time from crossover until death of any cause) 


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To assess and compare the changes in pain for 
patients in Arm B who crossover to treatment with 
melflufen, dexamethasone and daratumumab. 
Value and changes in pain, in BPI-SF and Numeric 
Rating Scale (NRS) for measure of bone pain. 
To assess and compare functional status and 
wellbeing based on patient reported outcome 
(PRO) assessments for patients in Arm B who 
crossover to treatment with melflufen, 
dexamethasone and daratumumab. 
Value and changes from crossover in EORTC QLQ-
C30 summary score, each scale of the EORTC QLQ-
C30, EQ-5D utility index, each dimension of the EQ-
5D-3L, and the Visual Analogue Scale (VAS) of the 
EQ-5D-3L.  
To assess the safety and tolerability of melflufen, 
dexamethasone and daratumumab treatment for 
patients in Arm B who crossover.  
Frequency and Grade of treatment emergent adverse 
events (TEAE). 
a) All tumor response and progression-dependent endpoints are assessed by the investigator and an Independent 
Review Committee (IRC) according to the International Myeloma Working Group Uniform Response 
Criteria (IMWG-URC) guidelines (Kumar et al 2016).   
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
1. Male or female, age 18 years or older;  
2. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol; 
3. A prior diagnosis of multiple myeloma with documented disease progression in need of 
treatment at time of screening;  
4. Double refractory to an immunomodulatory drug (IMiD) and a Proteasome Inhibitor 
(PI) (regardless of the number of prior lines of therapy), or have received at least 3 
prior lines of therapy including an IMiD and a PI (the definition of refractory includes 
intolerance to an IMiD/PI after at least two 28-day cycles of therapy); 
5. Prior treatment with daratumumab or another anti-CD38 antibody is allowed if the 
patient has: 
• Achieved at least PR and is not refractory to previous anti-CD38 antibody 
treatment 
• At least 6 months since last dose of anti-CD38 antibody prior to            
Cycle 1/Day 1 (C1/D1) 
• Not discontinued anti-CD38 antibody treatment due to related Grade ≥ 3 
toxicity    
6. Measurable disease defined as any of the following: 
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis 
(SPEP)  
•  ≥ 200 mg/24hr of monoclonal protein in the 24-hour urine collection by 
electrophoresis (UPEP)  
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to 
lambda free light chain (FLC) ratio 
7. Life expectancy of ≥ 6 months; 


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8. 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); 
9. Ability to understand the purpose and risks of the study, ability to participate in all the 
procedures required by the protocol and provide signed and dated informed consent;  
10. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula 
(QTcF) interval of ≤ 470msec;  
11. Adequate organ function with the following laboratory results during screening (within 
21 days) and immediately before study treatment administration on Cycle 1 Day 1: 
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth 
factors cannot be used within 10 days (14 days for pegfilgrastim) prior to 
initiation of study treatment) 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions 
during the 10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dL (Red Blood Cell (RBC) transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients 
diagnosed with Gilbert’s syndrome that have been reviewed and approved 
by the Medical Monitor 
• Aspartate transaminase/Aspartate aminotransferase (AST, also known as 
Serum Glutamic Oxaloacetic Transaminase (SGOT)) and Alanine 
transaminase/Alanine aminotransferase (ALT, also known as Serum 
Glutamic Pyruvic Transaminase (SGPT)) ≤ 3.0 x ULN 
• Renal function: Estimated creatinine clearance by Cockcroft- Gault formula 
of ≥ 45 mL/min  
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); 
 
13. a) Male patients: Male patient who agrees to use contraception as detailed in this 
protocol during the treatment period and for at least 3 months after the last dose of 
study treatment and refrain from donating sperm during this period.   
 
b) Female patients: A female patient is eligible to participate if she is not pregnant, 
not breastfeeding, and at least one of the following conditions applies: 
i. 
Not a woman of childbearing potential (WOCBP) or  
ii. 
A WOCBP who agrees to follow the contraceptive guidance in the protocol 
during the treatment period and for at least 3 months after the last dose of study 
treatment. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Primary refractory disease (i.e. never responded with at least MR to any prior therapy); 
2. Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies; 


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3. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 
second (FEV1) less than 50% of predicted normal; 
4. Moderate or severe persistent asthma within the past 2 years, or currently has 
uncontrolled asthma of any classification; 
5. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet 
count fails to increase by > 10,000 cells/mm3 after a transfusion of an appropriate dose 
of platelets);  
6. 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., 
heart failure class III or IV according to New York Heart Association (NYHA), 
cardiac angioplasty or stenting, myocardial infarction, unstable angina, significant 
cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 
thromboembolic event in the last 6 months); 
7. Known active infection that is uncontrolled (including symptomatic or asymptomatic 
COVID-19) or has required intravenous systemic therapy within 14 days of 
randomization. Patients who has required oral anti-infective treatment within 14 days 
of randomization should be discussed with the Medical Monitor;  
8. Other malignancy diagnosed or requiring treatment within the past 3 years with the 
exception of adequately treated basal cell carcinoma, squamous cell skin cancer, 
carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in 
active surveillance;  
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse compliance or follow-up evaluation; 
10. Human immunodeficiency virus (HIV) or active hepatitis C viral infection, either 
known or if detected during screening; 
11. Hepatitis B: both active (defined as HBsAg+) or non-active hepatitis B (defined as 
HBsAg-, Anti-HBs+, Anti-HBc+):  
• Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-
HBs+, Anti-HBc-).  
12. Concurrent known or suspected amyloidosis or plasma cell leukemia;   
13. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
14. Known central nervous system (CNS) or meningeal involvement of myeloma:   
15. Any of the following treatments, within the specified timeframe: 
• Previous cytotoxic therapies, including cytotoxic investigational agents, for 
multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of 
therapy. 
• The use of live vaccines within 30 days before initiation of therapy. 
• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy. 
• Other investigational therapies and monoclonal Antibody (mAb) within 4 weeks of 
initiation of therapy. 
• Prednisone up to but no more than 10 mg orally quaque die/one a day (q.d.) or its 
equivalent for symptom management of comorbid conditions is permitted but dose 


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should be stable for at least 7 days prior to initiation of therapy;   
16. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy 
(alopecia any grade and/or neuropathy Grade 1 without pain are permitted);   
17. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of 
therapy;   
18. Prior allogeneic stem cell transplantation with active graft-versus-host-disease; 
19. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of 
therapy (this does not include limited course of radiation used for management of bone 
pain within 7 days of initiation of therapy);   
20. Known intolerance to the required dose and schedule of steroid therapy, as determined 
by the investigator; 
21. Known hypersensitivity to any of the agents in this study including hyalonuridase 
22. Prior treatment with melflufen    
Overall Design: 
This is an open-label, randomized, international, multicenter Phase 3 trial which will enroll 
patients with RRMM who are either double refractory to an IMiD and a PI, or had at least 3 prior 
lines of therapy including exposure to both an IMiD and a PI. Patients will be randomized (1:1) to 
Arm A or Arm B. For each arm, treatment will be given in 28-day cycles and may be given in an 
outpatient treatment setting. Patients in Arm B may, after confirmed progressive disease, 
crossover and receive treatment with melflufen, dexamethasone and daratumumab and continue in 
the study.  
Arm A: 
• Melflufen 30 mg will be given as a 30-minute intravenous (i.v.) infusion. 
• Dexamethasone 40 mg weekly will be given per oral (p.o.). Patients ≥ 75 years should 
receive a reduced dose of dexamethasone (20 mg weekly).  
• Daratumumab 1800 mg will be given subcutaneously (s.c.) as a 15 mL injection over 3-5 
minutes with premedication for the prophylaxis of infusion reactions. 
Arm B:  
• Daratumumab 1800 mg will be given subcutaneously as a 15 mL injection over 3-5 
minutes with pre-medication for the prophylaxis of infusion reactions. Patients with 
confirmed disease progression after treatment in Arm B have the option to crossover and 
receive treatment with melflufen, dexamethasone and daratumumab.  
Number of Patients: 
240 patients are planned to be randomly assigned to study treatment and the final analysis will 
take place when 160 patients have experienced a PFS event. Randomization will be stratified by 
number of previous lines of treatment (<3 prior lines of treatment versus ≥3 prior lines of 
treatment) and previous treatment with daratumumab or another anti-CD38 antibody (no previous 
treatment versus previous treatment).  
Treatment Groups and Duration: 
The following tables summarizes the study drug administration schedule during each 28-day 
cycle. 
 


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Study Treatment Arm A: 
Melflufen 30 mg (i.v.) 
 
Daratumumab 1800 mg (s.c.)a 
 
Dexamethasone (p.o.)b 
 
All cycles: Day 1 
Cycle 1 and 2: Days 1, 8, 15 and 22 
Cycle 3 to 6: Days 1 and 15 
Cycle 7+: Day 1 
40 mg weekly for patients < 75 
years of age  
20 mg weekly for patients ≥75 
years of age  
a) Pre-medication should be administered to prevent infusion related reactions (see protocol).  
b) Prior to melflufen infusion in Cycle 1, oral dexamethasone may be substituted with i.v. dexamethasone 
during Cycle 1, at the investigator’s discretion, if this is the standard of care (SoC) of the study center.  For 
additional details on dexamethasone administration see protocol. 
 
Study Treatment Arm B: 
Daratumumab 1800 mg (s.c.)a, b 
 
Cycle 1 and 2: Days 1, 8, 15 and 22 
Cycle 3 to 6: Days 1 and 15 
Cycle 7+: Day 1 
a) Pre-medication should be administered to prevent infusion related reactions (see protocol). 
b) Patients with confirmed disease progression in Arm B have the option to receive melflufen, dexamethasone 
and daratumumab (dose and schedule as in Arm A). 
 
Dose modifications of each drug will be implemented for individual patient tolerability according 
to dose modification guidelines described in the protocol. This also applies to patients doing the 
crossover in the study. Patients unable to tolerate therapy following implementation of the 
guidelines will be permanently discontinued, unless in the opinion of the investigator and 
approved by the Medical Monitor, it is in the patient's best interest to continue therapy. In 
addition, patients discontinuing either melflufen or daratumumab in Arm A (or patients in Arm B 
who crossover to treatment with melflufen, dexamethasone and daratumumab), may continue with 
the remaining 2 study drugs according to the protocol, if in the best interest of the patient and 
approved by the Medical Monitor.   
Treatment duration: 
Patients in both treatment arms will receive treatment until there is documented PD according to 
the IMWG-URC guidelines (Kumar et al 2016), unacceptable toxicity, the patient/treating 
physician determines it is not in the patient’s best interest to continue, or patient’s withdrawal of 
consent. Confirmed PD (on two consecutive assessments if based on M-protein assessments) 
should be verified by the Medical Monitor prior to treatment discontinuation. Patients in Arm B 
with documented PD verified by the Medical Monitor may crossover and receive treatment with 
melflufen, dexamethasone and daratumumab (using the daratumumab dosing schedule 
corresponding to the cycle when disease progression occurred). Patients receiving therapy after 
crossing over will receive treatment until there is documented PD, unacceptable toxicity, the 


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patient/treating physician determines it is not in the patient’s best interest to continue, or patient’s 
withdrawal of consent. Confirmed PD should be verified by the Medical Monitor prior to 
treatment discontinuation. 
Study Assessments: 
All study visits and assessments are summarized in Schema (see Section Error! Reference 
source not found.) and Schedule of Activities (see Section 1.3). Study visits and assessments to 
be performed after patients cross over are summarized in a separate Schedule of Activities in 
Study Protocol Appendix 3.  
Independent Review Committee: 
All response assessments, including PD will be assessed by an Independent Review Committee 
(IRC) using the IMWG response criteria. The IRC members will be blinded to all treatment data 
(including investigator response) and perform their reviews in closed-meeting sessions.   
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.  
 


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1.2. Schema 
 
 


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1.3. Schedule of Activities (SoA) 
 
Table 1-2 
 
Schedule of Activities (SoA) 
Assessment 
Screening 
Day  
-21 to -1 
Regimen A and B, All Cycles 
(except where specified) 
 
 
End of 
Treatment 
Visit dd 
8 weeks 
after last 
dose of 
daratumu-
mab 
PFS -
FU ee 
OS and 
PFS-2- 
FU ff 
End of 
Study 
Day 1 
Day 4 
(Cycle 1 
and 3) cc 
Day 8 
Day 15 
Day 22 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±0 days 
±3 days ±3 days ±3 days ±3 days 
±3 days 
±7 days 
±7 days 
 
Informed consent a 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics b 
X 
 
 
 
 
 
 
 
 
 
 
Myeloma history including characteristics c X 
 
 
 
 
 
 
 
 
 
 
Physical examination d  
X 
X 
 
(X) 
(X) 
(X) 
X 
 
 
 
 
Vital signs e 
X 
X 
 
(X) 
(X) 
(X) 
X 
 
 
 
 
Pulmonary Function Tests  
X 
 
 
 
 
 
 
 
 
 
 


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Assessment 
Screening 
Day  
-21 to -1 
Regimen A and B, All Cycles 
(except where specified) 
 
 
End of 
Treatment 
Visit dd 
8 weeks 
after last 
dose of 
daratumu-
mab 
PFS -
FU ee 
OS and 
PFS-2- 
FU ff 
End of 
Study 
Day 1 
Day 4 
(Cycle 1 
and 3) cc 
Day 8 
Day 15 
Day 22 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±0 days 
±3 days ±3 days ±3 days ±3 days 
±3 days 
±7 days 
±7 days 
 
ECOG performance status 
X 
X 
 
 
 
 
X 
 
 
 
 
Pregnancy test f 
X 
X 
 
 
 
 
X 
Xf 
X f 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
M protein assessment (and myeloma 
response assessment from Cycle 2)g 
X 
X 
 
 
 
 
X 
 
X 
 
 
β2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
RBC typing and antibody screening h 
X 
 
 
 
 
 
 
 
 
 
 
Hematology i 
X 
X  
 
X 
X 
X 
X 
 
 
 
 
Chemistry j 
X 
X  
 
 
 
 
X 
 
(X) 
 
 
Hepatitis B, C and HIV screen  
X 
 
 
 
 
 
 
 
 
 
 


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Assessment 
Screening 
Day  
-21 to -1 
Regimen A and B, All Cycles 
(except where specified) 
 
 
End of 
Treatment 
Visit dd 
8 weeks 
after last 
dose of 
daratumu-
mab 
PFS -
FU ee 
OS and 
PFS-2- 
FU ff 
End of 
Study 
Day 1 
Day 4 
(Cycle 1 
and 3) cc 
Day 8 
Day 15 
Day 22 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±0 days 
±3 days ±3 days ±3 days ±3 days 
±3 days 
±7 days 
±7 days 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
Blood sample for DNA/RNA sequencing k 
 
X 
 
 
 
 
(X) 
 
(X) 
 
 
Blood sample for myeloma related bone 
disease biomarkers l 
 
X 
 
 
 
 
X 
 
X 
 
 
Bone marrow aspiration m 
X 
(X) 
 
 
 
 
(X) 
 
(X) 
 
 
12- lead Electrocardiogram n 
X 
 
 
 
 
 
X 
 
 
 
 
Chest X-ray o 
X 
 
 
 
 
 
 
 
 
 
 
Extramedullary myeloma (plasmacytoma) 
assessment p 
X 
(X) 
 
 
 
 
(X) 
 
(X) 
 
 
Lytic bone lesion assessment: skeletal X-
ray or low-dose CT q 
X 
(X) 
 
 
 
 
(X) 
 
(X) 
 
 


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Assessment 
Screening 
Day  
-21 to -1 
Regimen A and B, All Cycles 
(except where specified) 
 
 
End of 
Treatment 
Visit dd 
8 weeks 
after last 
dose of 
daratumu-
mab 
PFS -
FU ee 
OS and 
PFS-2- 
FU ff 
End of 
Study 
Day 1 
Day 4 
(Cycle 1 
and 3) cc 
Day 8 
Day 15 
Day 22 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±0 days 
±3 days ±3 days ±3 days ±3 days 
±3 days 
±7 days 
±7 days 
 
Randomization r 
X 
 
 
 
 
 
 
 
 
 
 
Criteria for initiation of therapy/new cycles  
X 
 
 
 
 
 
 
 
 
 
PRO assessments (EORTC QLQ-C30 and 
EQ-5D-3L) t 
 
X 
 
 
 
 
X 
 
X 
 
 
PRO Pain Assessments (BPI-SF, NRS) u 
 
X 
 
 
(X) 
 
X 
 
X 
 
 
Dexamethasone administration and review 
of patient compliance, Arm A only 
 
X 
 
X 
X 
X 
 
 
 
 
 
Melflufen administration, Arm A only  
 
X 
 
 
 
 
 
 
 
 
 
Daratumumab administration Arm A and 
Arm B according to treatment schedule  
 
X 
 
(X) 
(X) 
(X) 
 
 
 
 
 


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Assessment 
Screening 
Day  
-21 to -1 
Regimen A and B, All Cycles 
(except where specified) 
 
 
End of 
Treatment 
Visit dd 
8 weeks 
after last 
dose of 
daratumu-
mab 
PFS -
FU ee 
OS and 
PFS-2- 
FU ff 
End of 
Study 
Day 1 
Day 4 
(Cycle 1 
and 3) cc 
Day 8 
Day 15 
Day 22 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±0 days 
±3 days ±3 days ±3 days ±3 days 
±3 days 
±7 days 
±7 days 
 
Pharmacokinetic samples melphalan, 
Arm A only v 
 
XC1, C2 
 
 
 
 
 
 
 
 
 
Pharmacokinetic samples daratumumabw 
 
XC1, C3, C7, 
C12 
X 
 
 
 
X 
X 
 
 
 
Immunogenicity samples daratumumab x  
 
X C1, C7, 
C12 
 
 
 
 
X 
X 
 
 
 
Immunogenicity samples rHUPH20 x  
 
XC1, C7, 
C12 
 
 
 
 
X 
X 
 
 
 
Immunoprofiling samples y 
 
XC1, C6 
 
 
 
 
X 
 
 
 
 
Use of health services and hospitalization z X 
X 
 
 
 
 
X 
 
X 
 
 
Concomitant medications aa 
X 
 
X 
 
 
 
 


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Assessment 
Screening 
Day  
-21 to -1 
Regimen A and B, All Cycles 
(except where specified) 
 
 
End of 
Treatment 
Visit dd 
8 weeks 
after last 
dose of 
daratumu-
mab 
PFS -
FU ee 
OS and 
PFS-2- 
FU ff 
End of 
Study 
Day 1 
Day 4 
(Cycle 1 
and 3) cc 
Day 8 
Day 15 
Day 22 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±0 days 
±3 days ±3 days ±3 days ±3 days 
±3 days 
±7 days 
±7 days 
 
AE monitoring bb 
X 
 
X 
 
 
 
 
Subsequent therapy review gg 
 
 
 
 
 
X 
 
End of study information hh 
 
 
 
 
 
 
X 
 
(X)  Only if indicated (see footnotes and treatment schedule) 
 
C1 = Cycle 1; C2 = Cycle 2; etc. 
a) 
All patients must sign an (IRB/IEC/REB)-approved ICF within 28 days of randomization and prior to any study related procedures.  
b) Medical History including demographics, prior and current medical illness and conditions, prior surgical procedures. 
c) 
MM history including characteristics, date of initial diagnosis, International Staging System (ISS), Revised International Staging System (R-ISS) and 
cytogenetics at diagnosis (if previously evaluated). ISS and R-ISS stage at screening. Prior surgery, radiation and anticancer therapy, including start and 
stop dates, documentation of best response, date of progressive disease and relapsed or refractory status.   
d) A physical examination, including assessment for extramedullary myeloma will be conducted at screening, Day 1 of each cycle and End of Treatment 
(EOT) visit. A symptom directed physical examination will be conducted as needed during treatment period. 
e) 
Vital signs including blood pressure, pulse, respiratory rate, temperature will be assessed at screening, at each dosing day before melflufen dose and 
before and after daratumumab dosing and at EOT visit. Height will be assessed at screening only. Weight will be assessed at screening, Day 1 of each 
cycle and at EOT visit. 
f) 
All WOCBP must have a negative serum or urine pregnancy test prior to the initiation of therapy at each cycle. Pregnancy test will also be taken at EOT 
visit, 8 weeks after last dose of daratumumab and at 12 weeks after last dose of daratumumab. The 8 and 12-weeks urine test can be taken at home and 


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site can contact the patient for follow-up by phone. 
g) SPEP, UPEP, serum and urine Immunofixation ((IFE) if SPEP or UPEP are not detectable and to confirm a CR), quantitative immunoglobulins (Igs) 
and SFLC assay (only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hours and SPEP is < 0.5 g/dL]) are to be conducted at 
screening, pre-dose Cycle 1 Day 1 and prior to each cycle even if treatment is delayed. Quantitative Igs need to be repeated for patients with IgA or IgD 
myeloma for all response assessments. In the event treatment is delayed 2 weeks, response assessments are required to be repeated on the day the new 
cycle starts.  
 If treatment is discontinued at or beyond ≥ 6 weeks (Day 43) the response assessments should be repeated on the day of the decision (or as soon as 
possible ≥ 30 days after last dose of study drug) as part of the EOT visit. Daratumumab Interference Reflex Assay (DIRA) test should be conducted in 
patients with IgG kappa MM with SPEP 
o 
≤0.2 g/dl on 2 or more consecutive cycles   
OR 
o 
at zero, but persistently positive IFE for IgG kappa on 2 or more occasions 
h) Interference with cross-matching and red blood cell antibody screening: Type and screen patients prior to starting treatment. 
i) 
Hematology: Complete Blood Count (CBC) with differential, and platelet count should be taken at screening and at Day 1, 8, 15 and 22 of all cycles, 
prior to initiation of therapy, and at the EOT visit. If melflufen is discontinued and the partner therapy is continued, the schedule of CBC evaluations 
may be conducted at the investigator’s discretion but must at a minimum be performed on Day 1 of each subsequent cycle and before each dose of 
daratumumab. If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive therapy (G-CSF, blood or platelet transfusion) 
in the two preceding cycles, then CBC assessments may be excluded at Day 8 and Day 22. 
j) 
Chemistry should be taken at screening and at Day 1 of all cycles, at the EOT visit, prior to initiation of therapy. During PFS-FU serum calcium and 
albumin (corrected calcium) are required if evidence of PD.  
k) Blood sample for DNA/RNA sequencing should be collected before dosing at Cycle 1, at time of response (CR or VGPR), and at the time of disease 
progression. 
l) 
Blood sample for myeloma related bone disease biomarkers should be collected before dosing at Day 1 of all cycles, at the EOT visit and at PFS-FU. 
m) Bone marrow aspirate (BMA) to be collected at screening for % plasma cells, morphology, cytogenetics by Interphase Fluorescence In Situ 
Hybridization (iFISH), and for exploratory biomarker analysis. A repeat sample is required in patients with suspected CR/VGPR to confirm response 
and for MRD assessment. A BMA sample may be needed to confirm disease progression, if taken, samples will also be used for biomarker analysis See 
Protocol and Laboratory manual. 
n) A 12-lead ECG will be performed at screening and EOT visit. Q-Tc interval to be assessed by Fridericia formula. 
o) Chest X-ray is optional if low-dose Computerized Tomography (CT) is performed for skeletal assessment and will only be performed at baseline. If 
performed within 6 weeks from initiation of therapy, repeat of assessment is only needed if clinically relevant. 
p) Known or suspected extramedullary myeloma (plasmacytomas) are to be assessed, with the same method at screening and every 2 cycles up to disease 
progression. 
q) Lytic bone lesion assessment: skeletal X-ray or low-dose CT scan should be performed at screening if previous skeletal survey > 6 weeks from initiation 
of therapy and when clinically indicated. Limited X-rays may be performed to confirm PD. 
r) 
Treatment cannot begin prior to randomization and must begin ≤ 5 days after randomization. The 5 day window is included in the 21 days screening 
period, i.e., if treatment starts 5 days after randomization, randomization has to be done latest at day 16 after Screening visit. 
s) 
Evaluate if the treatment should be given, delayed or held. See Protocol for details. 


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t) 
EORTC QLQ-C30 and EQ-5D-3L should be completed 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. See Protocol for details. 
u) BPI-SF and NRS for measure of bone pain. The patient should complete the questionnaires prior to any procedures, and prior to dexamethasone dosing, 
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.  
BPI-SF should be completed first and if patient has experienced pain, the NRS for measure of bone pain should be completed. The questionnaires 
should be submitted to patients at Day 1 and Day 15 of Cycle 1-3. From Cycle 4, the questionnaires should be submitted to patient on Day 1 of each 
cycle. The questionnaires should also be submitted at the time of EOT visit, at the time of disease progression and at the time of starting a new treatment 
(Day 1 of new treatment). See Protocol for details. 
v) Melphalan pharmacokinetic (PK) samples will be collected in patients in Arm A. Samples will be drawn in connection to the first two melflufen 
treatment cycles, 5–10 minutes after the end of the melflufen infusion, 1 hour after the end of the melflufen infusion (+/- 5 min window acceptable) and 
2-4 hours after the end of the melflufen infusion (as late as possible within the time frame).  
w) Daratumumab PK samples will be collected in patients in Arm A and Arm B at pre-dose on Day 1 of Cycle 1, 3, 7, and 12, on Day 4 in Cycles 1 and 3 
and at EOT visit and at 8 weeks after the last dose of daratumumab. Not applicable for patients in Arm B after crossover to treatment with melflufen, 
dexamethasone and daratumumab.  
x) Serum samples for immunogenicity (daratumumab and rHuPH20) to be collected in both Arm A and Arm B pre-dose on Day 1 of Cycle 1, 7, and 12 
and at EOT visit and at 8 weeks after the last dose of daratumumab. Not applicable for patients in Arm B after crossover to treatment with melflufen, 
dexamethasone and daratumumab.  
y) Whole blood samples will be collected pre-dose on Cycle 1 Day 1, Cycle 6 Day 1 and at the EOT visit. 
z) 
Use of health services and days of hospitalization will be completed by the patient at screening, on Day 1 of each cycle, at time of EOT visit and at 
follow-up until start of new treatment. To be completed prior to any procedures on the day of the visit and prior to being told anything related to health. 
aa) Concomitant medications and procedures: All blood products and medications within 21 days prior to first dose until the EOT visit should be recorded. 
bb) SAEs will be collected from signing of the ICF until 30 days after last dose of study treatment or initiation of subsequent therapy whichever occurs first. 
AEs will be collected from the start of study treatment until 30 days after the last dose of any study drug (melflufen, dexamethasone or daratumumab) or 
initiation of subsequent therapy whichever occurs first. 
cc) Day 4 is a visit for daratumumab PK sampling and will be performed when possible to schedule on weekdays. 
dd) EOT visit should be scheduled 30 days after last dose of study treatment or as soon as possible if the decision to remove patient from therapy occurs 
later than 30 days after last dose (such as in the case of a prolonged cycle). 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 (this also applies to crossover treatment for 
patients in Arm B). For patients who are randomized but withdraw from study, for any reason, prior administration of any study drug, the EOT visit 
should be completed as soon as possible after decision to remove patient from study (including withdrawal of consent to study treatment) has been 
made. For patients in Arm B who crossover to treatment with melflufen, dexamethasone and daratumumab, the EOT visit could be done at the same day 
as the initiation visit for the new treatment  Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT visit are to be followed until resolution (≤ 
Grade 2) or initiation of subsequent therapy.     
ee) Schedule the first assessment 4 weeks after the EOT visit. Patients who discontinue therapy for reasons other than disease progression should continue 


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to have monthly disease assessments done until documented disease progression or initiation of subsequent therapy. Confirmed disease progression 
requires 2 consecutive M protein assessments at any time (including the same day for SPEP/FLC). The second assessment must be a separate serum and 
urine sample. If the second consecutive M protein sample can only be obtained after the start of subsequent therapy, it may be used as confirmation of 
PD. 
ff) Following confirmed disease progression or initiation of subsequent therapy, follow-up for PFS-2, overall survival status and second primary 
malignancies will take place every three months +/- 7 days for at least 24 months. 
gg) Subsequent therapy review including regimen (all individual drugs), start and stop dates. If PD has not been confirmed prior to the initiation of 
subsequent therapy, the reason for the subsequent therapy, best response, and date of disease progression per investigator review. 
hh) Patient study end date and primary reason for ending the study will be collected. 
 
 


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2. 
Introduction 
Melphalan flufenamide (hereinafter referred to as melflufen) is a novel peptide-drug conjugate 
designed for targeted enrichment of alkylating moieties in tumor cells and belongs to a novel 
class of drugs called peptide-drug conjugates.   Once monthly intravenous (iv) melflufen, in 
combination with weekly dexamethasone, has shown encouraging clinical results in relapsed and 
refractory multiple myeloma (RRMM) patients (see current Investigator’s Brochure (IB) of 
melflufen for details).  Initial promising data from the OP-104 Anchor study established the 
maximum tolerated dose for testing the combination of melflufen and daratumumab in RRMM 
patients.   
2.1. Study Rationale 
The outcome in relapsed/refractory multiple myeloma is still unsatisfactory despite recent 
improvements in treatment. Thus, new therapeutic options are needed. Melflufen is a peptide-
conjugated alkylator that is rapidly taken up by MM cells due to its high lipophilicity (Chauhan 
et al 2013, Wickström et al 2017). Once inside the myeloma cell, the activity of melflufen is 
determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are 
entrapped (Wikström et al 2017, Gullbo et al 2003). Melflufen is 50-fold more potent than 
melphalan in myeloma cells in vitro due to the increase of intracellular alkylator activity 
(Chauhan et al 2013, Wickström et al 2017). The ongoing clinical study OP-104 ANCHOR 
evaluates the combination of melflufen, dexamethasone and daratumumab in patients with 
RRMM previously treated with 1-4 lines of therapy and refractory to an immunomodulatory 
agent (IMiD) and/or a proteasome inhibitor (PI). Promising efficacy has been shown, with a 
median ORR of 76% and a median immature progression-free survival (PFS) of 14.3 months 
(ASH poster #3124 of abstract Ocio et al 2019). Grade 3/4 adverse events were mainly 
cytopenias with limited non-hematologic toxicity. These results are in line with previous 
experiences of melflufen in combination with dexamethasone only in earlier clinical studies in 
RRMM. It is therefore reasonable to confirm the efficacy of this drug combination in a Phase 3 
trial in a patient population that reflects the approved indication for daratumumab as 
monotherapy including an option for patients randomized to daratumumab monotherapy to 
crossover and receive treatment with melflufen, daratumumab and dexamethasone after 
documented disease progression. The study will use the subcutaneous formulation of 
daratumumab, which was approved in 2020 by FDA in US, EMA in Europe and MHRA in UK. 
2.2. Background 
 
Multiple Myeloma 
Multiple myeloma is a malignancy of differentiated plasma cells that mainly affects older 
patients, with a median age at onset of 65 to 70 years and a slight male predominance. MM is the 
second most common hematologic malignancy and 32,270 patients were estimated to be 
diagnosed with myeloma in the United States in 2019, with a 5-year survival of 52.2% (SEER 
2019).   


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The disease is characterized by clonal proliferation of plasma cells in the bone marrow and the 
production of excessive amounts of a monoclonal immunoglobulin (usually of the IgG or IgA 
type or free urinary light chain [paraprotein, M-protein or M-component]). Patients with MM 
may experience significant decrement to quality of life, including bone pain, bone fractures, 
fatigue, anemia, infections, hypercalcemia, and compromised renal function (including renal 
failure) (Jordan et al. 2014). The disease course for MM varies with the disease stage at 
diagnosis, cytogenetic profile, as well as age and patient comorbidities. Survival in myeloma is 
significantly variable depending on host factors, tumor burden, biology and response to treatment 
(Chng et al. 2014). However, the disease remains ultimately fatal.   
There are currently 7 classes of approved drugs for the treatment of MM, including steroids 
(prednisone and dexamethasone), IMiDs (thalidomide, lenalidomide and pomalidomide), PIs 
(bortezomib, carfilzomib and ixazomib), histone deacetylase inhibitors (panobinostat), 
conventional chemotherapy (melphalan, cyclophosphamide, doxorubicin), including high dose 
melphalan with autologous stem-cell transplantation (ASCT), monoclonal antibodies 
(elotuzumab, daratumumab and isatuximab) and nuclear export inhibitors (selinexor). The 
selection of treatment in relapsed/refractory multiple myeloma is challenging. The National 
Comprehensive Cancer Network (NCCN) guidelines (NCCN 2.2019) and a recent overview 
published in the Mayo Clinic Proceedings (Kumar et al 2016) detail an array of single agent, 
doublet and triplet combination regimens that can be considered. Patients for whom stem cells 
were cryopreserved early in the disease course, and who are transplant candidates, may benefit 
from ASCT as salvage therapy (Cavo et al. 2011). In general, MM patients will receive an 
average of 4 to 8 different treatment regimens during their life span.   
Improvements in therapies have significantly increased the expected life span for these patients, 
especially for younger patients (Kristinsson et al 2014). However, despite the availability of 
effective therapies, the optimal combinations and sequencing of these agents with other therapies 
and with one another is still unclear. Only 20 to 30% of the RRMM patients typically respond to 
any particular treatment and ultimately patients relapse from all available options. Given the 
inevitable relapses seen in these patients, new approaches to therapy are clearly still needed.   
 
Melflufen 
Melflufen, a first-in-class peptide-drug conjugate, is rapidly taken up by MM cells due to its high 
lipophilicity (Wickström et al. 2017). Once inside the myeloma cell, melflufen is immediately 
cleaved by peptidases, leading to entrapment of the hydrophilic alkylator payloads. (Wickström 
et al 2017, 2010, Gullbo et al 2003).  
In primary patient-derived MM tumor cells, melflufen demonstrated approximately 50-100 fold 
higher efficacy than melphalan, explained by the 50-fold higher intracellular concentration of 
alkylating moieties achieved after melflufen vs. melphalan exposure in the culture (Chauhan 
2013, Ray 2016, Wickström et al. 2017). 
Mechanistic studies have shown that melflufen induces rapid, irreversible DNA damage; 
accumulation of reactive oxygen species and apoptosis associated with mitochondrial 
dysfunction and release of cytochrome c, activation of caspases and poly adenosine diphosphate 
(ADP) ribose polymerase cleavage. Moreover, melflufen inhibits angiogenesis and MM cell 
migration. (Chauhan et al. 2013, Ray et al 2016, Strese et al. 2013).   


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Importantly, in vitro studies in MM cell lines resistant to dexamethasone, bortezomib, and 
melphalan have demonstrated melflufen efficacy at same concentrations as observed in the 
parental, non-resistant cell lines (Chauhan 2013). Likewise, in the in vivo efficacy studies with 
different human tumors, including MM, superior antitumor activity yet seemingly comparable 
toxicity of melflufen was observed compared to equimolar dosage of melphalan (Wickström et 
al. 2007, Chauhan et al. 2013).  
Melflufen has been evaluated in combination with low dose dexamethasone in patients with 
relapsed/refractory myeloma in a Phase 1/2 clinical trial (O-12-M1, NCT01897714). The trial 
established the recommended dose at 40 mg of melflufen every 28 days combined with 40 mg 
dexamethasone weekly. Based on the 45 patients treated with 40 mg melflufen every 28 days in 
combination with weekly dexamethasone, the ORR (PR or better) was 31% and the CBR (MR or 
better) was 49%. The patients had a median of 4 prior lines of therapy, including IMiD, PIs and 
alkylators. The median PFS was 5.7 months based on 41 events, and the overall survival (OS) 
was 20.7 months based on 23 events in the 45 patients (Richardson et al, 2017).   
There are also ongoing clinical studies in RRMM patients, including a Phase 2 study in patients 
refractory to pomalidomide and/or daratumumab (OP-106 HORIZON, NCT02963493), a Phase 
1/2 study where melflufen and dexamethasone are combined with daratumumab or bortezomib 
(OP-104 ANCHOR, NCT03481556), and a randomized Phase 3 study (OP-103 OCEAN, 
NCT03151811) comparing melflufen and dexamethasone to pomalidomide and dexamethasone.   
The safety profile of melflufen suggested by preclinical studies is supported by clinical data from 
the completed O-12-M1 and ongoing clinical trials.   
As of 6 February 2019, 263 patients with RRMM had received at least one dose of melflufen.  
The most common treatment emergent adverse events (TEAE) in the trials O-12-M1 and OP-106 
(HORIZON) were hematological events, such as thrombocytopenia, neutropenia and anemia. 
This is not unexpected since hematological events are common both as a consequence of the 
disease of MM and of treatment with alkylators. These events were assessed to be dose-related, 
reversible and monitorable. 
Treatment related Grade 3 and 4 AEs were reported in 37 out of 45 patients (82%) in the O-12-
M1 trial. Those related to melflufen and occurring in ≥ 5% of the patients are presented in Table 
2-1. 


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Table 2-1 
Summary of melflufen treatment related Grade 3 or 4 AEs in O-12-M1  
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 
Thrombocytopenia 
Neutropenia 
Anemia 
Lymphopenia 
 
36 (80) 
26 (58) 
26 (58) 
19 (42) 
3 (7) 
 
19 (42) 
17 (38) 
11 (24) 
0 (0) 
1 (2) 
There were no non-hematological Grade 3/4 AEs which were reported in >5% of the patients.   
Taken together, clinical and preclinical data support that melflufen delivers a higher anti-tumor 
activity compared with equimolar administration of the alkylator melphalan but with a similar 
safety profile.   
Please see the IB for melflufen for further information.   
 
Daratumumab 
Daratumumab is a ﬁrst-in-class, human immunoglobulin G1 kappa (IgG1κ) mAb that binds to 
malignant cells expressing CD38 with high afﬁnity and induces tumor cell death through several 
immune-mediated mechanisms. Daratumumab was initially approved in RRMM as monotherapy 
based on results from study GEN501 (Lokhorst et al. 2014, Usmani et al. 2016) and the SIRIUS 
study (Lonial et al. 2016, Usmani et al. 2016). The combined results showed an overall response 
rate to daratumumab of 31% in a heavily pretreated population (Usmani et al. 2016). Some of the 
responses were deep (4.7% of the patients had a CR or better) and durable (median duration of 
response [PR or better] was 7.6 months). Daratumumab is also approved in RRMM in 
combination with lenalidomide and dexamethasone (Dimopoulos et al, 2016), or bortezomib and 
dexamethasone (Palumbo et al. 2016), for the treatment of patients with multiple myeloma who 
have received at least one prior therapy, and in combination with pomalidomide for patients who 
have received at least two previous lines of therapy (Chari et al. 2017).  In newly diagnosed MM 
patients considered ineligible for stem cell transplant, daratumumab was studied and 
subsequently approved in combination with bortezomib, melphalan and dexamethasone (Mateos 
et al. 2018). These studies reported that the addition of daratumumab to these therapies improved 
response rates while increased toxicity mainly consisted of daratumumab-related infusion 
reactions, including when combined with the alkylating agent melphalan, and resulted in 
approval for daratumumab in these combinations. The Phase 1b PAVO (MMY-1004) study 
evaluated subcutaneously-administered daratumumab in combination with the recombinant 


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human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. The 
safety and PK profile were similar with lower rate of infusion-related reactions compared with 
the IV formulation (Usmani et al. 2019). This has later been confirmed in the Phase 3 
COLUMBA trial that showed non-inferiority in terms of ORR and a lower rate of infusion-
related reactions for the subcutaneous formulation (Mateos et al. 2019). 
Daratumumab is a targeted immunotherapy directed toward cells that express high levels of 
CD38, such as plasma cells from patients with multiple myeloma. Once binding to CD38 occurs, 
daratumumab induces cell death through diverse immune-mediated mechanisms (complement-
dependent cytotoxicity [CDC], antibody-dependent cell-mediated cytotoxicity [ADCC], antibody 
dependent cellular phagocytosis [ADCP]), and induction of apoptosis (de Weers 2011, Overdijk 
2015. 
Translational biomarker studies of Phase 1 and Phase 2 multiple myeloma daratumumab patient 
samples (GEN501 and MMY2002, respectively) reveal immunomodulatory effects of 
daratumumab (Krejcik 2016). Daratumumab leads to the elimination of highly 
immunosuppressive subsets of CD38+ T-regulatory cells (Tregs), CD38+ myeloid derived 
suppressor cells (MDSCs), and CD38+ B regulatory cells (Bregs). It has also been shown that 
daratumumab may modulate the enzymatic activity of CD38 and may lead to a reduction in 
immunosuppressive adenosine levels (Horenstein 2016). 
 
Melflufen and Daratumumab 
The safety and efficacy of melflufen in combination with daratumumab and dexamethasone is 
being evaluated in a Phase 1/2a trial (OP-104 ANCHOR). RRMM patients included in this study 
have previously received 1-4 previous lines of therapy and must be refractory to an IMiD or a PI 
or to both. Preliminary data from the 33 patients treated with melflufen 30 mg (n=6) or 40 mg 
(n=27) in combination with daratumumab and dexamethasone has shown a safety profile 
consistent with previous trials, with Grade 3/4 treatment-related AEs reported in 27 (82%) 
patients, and thrombocytopenia (n=21, 64%) and neutropenia (n=20, 61%) being most 
commonly reported treatment-related AEs. At a data cutoff (8 October 2019) the ORR was 76% 
in all treated patients and median immature PFS was 14.3 months (ASH poster #3124 of Ocio et 
al 2019). 
2.3. Benefit/Risk Assessment 
Although the incorporation of novel agents such as PIs and IMiDs has significantly improved 
outcomes of patients suffering from multiple myeloma, myeloma is not yet curable and new 
treatment options are needed. Ongoing trials in RRMM with melflufen and dexamethasone with 
or without daratumumab has shown promising efficacy. It is therefore reasonable to evaluate 
whether patients with relapsed-refractory MM may receive benefit from the drug combination of 
melflufen, dexamethasone and daratumumab in a patient population that reflects the approved 
indication for daratumumab as monotherapy. The safety profile of melflufen and dexamethasone 
has been consistent and manageable throughout the trials, with thrombocytopenia and other 
hematologic toxicity being most frequent.  


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The prognosis is poor in patients progressing while on treatment with daratumumab (Gandhi et 
al. 2019), therefore it is feasible to include an option to crossover and receive treatment with the 
melflufen, daratumumab and dexamethasone. 
Important potential risks with the study drugs are presented in Table 2-2. More detailed 
information about the known and expected benefits and risks of melflufen, dexamethasone and 
daratumumab can be found in the IBs for melflufen and daratumumab respectively and the 
Summary of Product Characteristics / US Prescribing Information for dexamethasone.   
Table 2-2 
Assessment of important Potential Risks  
Important Potential 
Risk  
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention (s) 
Infections 
Severely ill MM patients are at 
increased risk of developing 
infections and infections are 
common adverse events with 
melflufen, dexamethasone and 
daratumumab. There may be a 
further increased risk for 
infections when concomitantly 
administering all three drugs. 
Patients should be monitored for 
signs of infection as part of SoC 
and as part of regular follow-up 
during the clinical study. 
NCCN guidelines (2020) (see 
Section 6.5.2) on infectious 
prophylaxis should be closely 
followed.  
Thrombocytopenia, 
Neutropenia, and 
Anemia 
Thrombocytopenia, neutropenia, 
and anemia are known 
consequences of MM but also 
common, adverse drug reactions 
associated with melflufen and 
daratumumab.  
Patients should be monitored as 
part of SoC and as part of regular 
follow-up during the clinical 
study. 
Careful attention is to be paid to 
the monitoring of blood counts. 
General supportive measures, 
together with appropriate blood 
and platelet transfusions as well 
as hematopoietic growth factors 
should be administered if 
necessary (see Section 6.5.2). 


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Severe and/or serious 
systemic 
infusion/administration-
related reactions, 
including anaphylactic 
reaction 
 
Both systemic administration-
related reactions, including 
severe or life-threatening 
reactions, and local injection-site 
reactions can occur with 
daratumumab.  
Patients should be observed 
carefully during daratumumab 
administrations for systemic 
administration-related reactions, 
especially following the first 
injection. 
Prophylactic treatment required 
prior to daratumumab to 
minimize or to treat 
administration related reactions 
can be found in Section 6.1.4.1. 
Daratumumab should be 
administered by a healthcare 
professional, with immediate 
access to emergency equipment 
and appropriate medical support 
to manage infusion reactions, if 
they occur. 
Study Procedures 
Placement of central 
line, including Port-A-
Cath and peripherally 
inserted central catheter 
(PICC) line  
A central line is needed for the 
administration of melflufen. 
Known risks with placement of 
central lines include 
pneumothorax, vascular 
perforation, catheter associated 
thrombosis, and central line 
infections. 
Central lines will be placed at 
centers well trained and 
experienced in the procedure. 
Patients will be monitored for 
signs of complications as part of 
SoC. 
 


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3. 
Objectives and Endpoints   
Objectivesa 
Endpointsa 
Primary: 
To show superiority of progression free-survival 
(PFS) in patients treated with melflufen and 
dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
PFS (time from the date of randomization to the date of 
first documentation of confirmed progressive disease 
(PD) or death due to any cause).  
Key Secondary: 
 
To evaluate and compare Overall Response Rate 
(ORR) in patients treated with melflufen and 
dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
 
ORR (proportion of patients who achieve a best 
confirmed response of stringent Complete Response 
(sCR), Complete Response (CR), Very Good Partial 
Response (VGPR) or Partial Response (PR)). 
To evaluate and compare Duration of Response 
(DOR)in patients treated with melflufen and 
dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
 
DOR (time from the first evidence of confirmed 
assessment of sCR, CR, VGPR or PR to first confirmed 
disease progression, or death due to any cause. DOR is 
defined only for patients with a confirmed PR or better). 
To assess the safety and tolerability of melflufen 
and dexamethasone in combination with 
daratumumab compared to daratumumab alone. 
Frequency and Grade of treatment emergent adverse 
events (TEAE). 
Other Secondary: 
To evaluate and compare efficacy endpoints in 
patients treated with melflufen and dexamethasone 
in combination with daratumumab compared to 
daratumumab alone: 
• Best response during the study 
• Clinical benefit rate (CBR) 
• Duration of Clinical Benefit (DOCB) 
• Time to response (TTR) 
• Time to progression (TTP) 
• Time to next treatment (TTNT) 
• Overall survival (OS)  
Best Response (proportion of patients with sCR, CR, 
VGPR, PR, Minimal Response (MR), Stable Disease 
(SD), PD or non-evaluable).  
CBR (the proportion of patients who achieve a best 
confirmed response of sCR, CR, VGPR, PR or MR). 
DOCB (time from first evidence of confirmed 
assessment of sCR, CR, VGPR, PR, or MR to first 
confirmed disease progression, or to death due to any 
cause.) DOCB is defined only for patients with a 
confirmed MR or better. 
TTR (time from randomization to the date of the first 
documented confirmed response in a patient who has 
responded with ≥PR). 


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TTP (time from the date of randomization to the date of 
the first documented confirmed PD). 
TTNT (time from randomization to the date of next 
anti-myeloma treatment or until death).  
OS (time from date of randomization to death due to 
any cause). 
Exploratory: 
To assess minimal residual disease (MRD) in 
patients achieving a CR or VGPR in patients 
treated with melflufen and dexamethasone in 
combination with daratumumab compared to 
daratumumab alone.  
Assessment of MRD status by Next Generation 
sequencing (NGS) in patients who achieve a CR or 
VGPR.  
To evaluate the Progression Free Survival 
following next line of treatment (PFS-2) in 
patients treated with melflufen and dexamethasone 
in combination with daratumumab compared to 
daratumumab alone. 
PFS-2 (defined as time from randomization to 
progression on next line of treatment or death from any 
cause, whichever occurs first). 
To assess and compare the changes in pain in 
patients treated with melflufen and dexamethasone 
in combination with daratumumab compared to 
daratumumab alone. 
Value and changes in pain, in BPI-SF and Numeric 
Rating Scale (NRS) for measure of bone pain. 
To assess and compare responses in patients with 
extramedullary myeloma (plasmacytomas). 
Response rate (CR and PR) according to International 
Myeloma Working Group (IMWG) consensus criteria 
of extramedullary myeloma (plasmacytomas).  
To assess and compare use of health services and 
number and duration of hospitalizations in patient 
treated with melflufen and dexamethasone in 
combination with daratumumab compared to 
daratumumab alone, and in patients who crossover 
and receive treatment with melflufen, 
daratumumab and dexamethasone. 
Number of health services. 
Number and days of hospitalization. 
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). 
PK parameters of melphalan at selected time points. 
To assess the PK and immunogenicity of 
subcutaneous daratumumab. 
Serum daratumumab concentrations. 


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Incidence of antibodies to daratumumab. 
To evaluate the immunogenicity of recombinant 
human hyaluronidase (rHuPH20) following 
subcutaneous daratumumab administration. 
Incidence of antibodies to rHuPH20. 
To assess translational biomarkers that might 
predict response/non-response to the treatment, 
aid in monitoring of disease progression as well as 
improve understanding of mechanism of action. 
• DNA/RNA-based drug response biomarkers 
including but not limited to aminopeptidases 
and esterases.  
• Serum levels of bone reabsorption related 
proteins including but not limited to TRACP‐
5b, PINP, Total RANK, Osteopontin, 
Osteocalcin, CTX, bone ALP.  
• Serum levels of cytokines IL-6, IL-10. 
• Immune profiling in peripheral blood including 
but not limited to T Reg., MDSC and NK cells. 
To assess and compare functional status and 
wellbeing based on patient reported outcome 
(PRO) assessments for patients treated with 
melflufen and dexamethasone in combination with 
daratumumab compared to daratumumab alone. 
Value and changes from baseline in EORTC QLQ-C30 
summary score, each scale of the EORTC QLQ-C30, 
EQ-5D utility index, each dimension of the EQ-5D-3L, 
and the Visual Analogue Scale (VAS) of the EQ-5D-
3L.  
To evaluate efficacy in patients in Arm B who 
crossover to treatment with melflufen, 
daratumumab and dexamethasone after 
progression on daratumumab. 
• Overall response rate (ORR)  
• Duration of response (DOR) 
• Best response during the study  
• Clinical benefit rate (CBR) 
• Duration of Clinical Benefit (DOCB) 
• Time to response (TTR) 
• Time to progression (TTP) 
• Time to next treatment (TTNT) 
• Overall Survival (OS) 
 
ORR (proportion of patients who achieve a best 
confirmed response of stringent Complete Response 
(sCR), Complete Response (CR), Very Good Partial 
Response (VGPR) or Partial Response (PR)) after 
crossover. 
DOR (time from the first evidence of confirmed 
assessment (after crossover) of sCR, CR, VGPR or PR 
to first confirmed disease progression, or death due to 
any cause. DOR is defined only for patients with a 
confirmed PR or better). 
Best Response (proportion of patients with sCR, CR, 
VGPR, PR, Minimal Response (MR), Stable Disease 
(SD), PD or non-evaluable) after crossover. 
CBR (the proportion of patients who achieve a best 
confirmed response of sCR, CR, VGPR, PR or MR) 
after crossover. 
DOCB (time from first evidence of confirmed 
assessment of sCR, CR, VGPR, PR, or MR after 
crossover to first confirmed disease progression, or to 


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death due to any cause.) DOCB is defined only for 
patients with a confirmed MR or better. 
TTR (time from crossover to the date of the first 
documented confirmed response in a patient who has 
responded with ≥PR). 
TTP (time from crossover to the date of the first 
documented confirmed PD). 
TTNT (time from crossover to the date of next anti-
myeloma treatment or until death). 
OS (time from crossover until death of any cause). 
To assess and compare the changes in pain for 
patients in Arm B who crossover to treatment with 
melflufen, dexamethasone and daratumumab. 
Value and changes in pain, in BPI-SF and Numeric 
Rating Scale (NRS) for measure of bone pain. 
To assess and compare functional status and 
wellbeing based on patient reported outcome 
(PRO) assessments for patients in Arm B who 
crossover to treatment with melflufen, 
dexamethasone and daratumumab. 
Value and changes from crossover in EORTC QLQ-
C30 summary score, each scale of the EORTC QLQ-
C30, EQ-5D utility index, each dimension of the EQ-
5D-3L, and the Visual Analogue Scale (VAS) of the 
EQ-5D-3L.  
To assess the safety and tolerability of melflufen, 
dexamethasone and daratumumab treatment for 
patients in Arm B who crossover.  
Frequency and Grade of treatment emergent adverse 
events (TEAE). 
a) All tumor response and progression-dependent endpoints are as assessed by the investigator and IRC 
according to the IMWG-URC guidelines (Kumar et al. 2016).   


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4. 
Study Design 
4.1. Overall Design 
This is an open-label, randomized, international, multicenter Phase 3 trial which will enroll 
patients with relapsed or relapsed-refractory MM who are either double refractory to an IMiD 
and a PI, given alone or in combination or had at least 3 prior lines of therapy including being 
exposed to both an IMiD and a PI. The patients will be randomized in a 1:1 fashion into either 
one of two treatment arms, Arm A and Arm B. Patients who receive daratumumab in Arm B and 
have a confirmed disease progression will have the option to crossover and receive treatment 
with melflufen, daratumumab and dexamethasone..  
Arm A: 
In Arm A melflufen i.v. 30 mg will be administered on Day 1 in every 28-day cycle in 
combination with daratumumab s.c. 1800 mg according to the schedule in Table 4-1. 
dexamethasone 40 mg p.o. (20 mg p.o. for patients ≥ 75 years) will be given weekly (see Section 
6.1.3 and Table 6-4). 
Pre-medication for the prophylaxis of infusion reactions and post-medication should be 
administered according to Section 6.1.4.1.  
Table 4-1 
Daratumumab Schedule, Arm A 
Cycles  
Days 
1 and 2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7 + 
1 
 
Arm B: 
In Arm B daratumumab will be given at the dose of 1800 mg s.c. according to the schedule in 
Table 4-2. Pre-medication for the prophylaxis of infusion reactions and post-medication should 
be administered according to Section 6.1.4.1. 
Table 4-2 
Daratumumab Schedule, Arm B 
Cycles  
Days 
1 and 2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7 + 
1 
a) Patients with confirmed disease progression in Arm B have the option to receive melflufen, 
dexamethasone and daratumumab (dose and schedule as in Arm A). 


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Treatment duration 
Patients in both treatment arms will receive treatment until any of the following events is 
reached. This also applies for patients in Arm B who crossover and receive treatment with 
melflufen, daratumumab and dexamethasone: 
• there is documented PD according to the IMWG-URC guidelines (Kumar et al.2016 to be 
confirmed on two consecutive assessments (if PD due to increase in M-protein), and 
verified by the Medical Monitor prior to treatment discontinuation, see Appendix 8. to be 
confirmed on two consecutive assessments (if PD due to increase in M-protein), and 
verified by the Medical Monitor prior to treatment discontinuation, see Appendix 8.  
• unacceptable toxicity. 
• the patient/treating physician determines it is not in the patient’s best interest to continue. 
• patient’s withdrawal of consent.  
4.2. Scientific Rationale for Study Design 
In the Phase 1/2 trial (OP-104 ANCHOR) investigating melflufen and dexamethasone with either 
bortezomib or daratumumab, the melflufen+dexamethasone+daratumumab combination in 
patients previously treated with an IMiD and a PI and refractory or intolerant to an IMiD, PI, or 
both, has demonstrated a safety profile consistent with data in previous studies evaluating 
melflufen and dexamethasone. In the daratumumab-containing regimen, Grade 3/4 AEs have 
been mainly hematological, including thrombocytopenia (64%) and neutropenia (61%) in the 33 
included patients. Promising efficacy has been demonstrated with an ORR of 76% and a median 
immature PFS of 14.3 months (ASH poster #3124 of abstract Ocio et al 2019).   
Although the incorporation of novel agents such as PIs and IMiDs has significantly improved 
outcomes of patients suffering from multiple myeloma, myeloma is not yet curable and new 
treatment options are needed, especially for patients who have progressed during therapies 
containing PIs and/or IMiDs. Melflufen has a unique mechanism of delivering an alkylating 
payload to MM cells. Given the demonstrated efficacy of melflufen and dexamethasone and 
promising early results in the clinical study OP-104 ANCHOR, melflufen is an appropriate 
candidate for confirmation of efficacy and safety in a triple-drug combination. The study is 
intended to support a regulatory submission for a marketing authorization of melflufen in 
combination with daratumumab and dexamethasone in a patient population where daratumumab 
as monotherapy is approved and is considered a reasonable treatment option (NCCN Guidelines 
v 2 2020). The poor prognosis in patients refractory to daratumumab (Gandhi et al. 2019) and the 
demonstrated activity of melflufen in daratumumab-refractory patients (Richardson et al. 2019) 
makes it reasonable to include a crossover option with melflufen, daratumumab and 
dexamethasone for patients in the daratumumab arm with documented disease progression.  
The assumptions regarding sample size are described in Section 9.2.   
4.3. Justification for Dose 
The dosing schedule of melflufen 40 mg i.v. in combination with dexamethasone was previously 
established in the Phase 1/2 trial O-12-M1 and has subsequently been used in the Phase 2 trials 
OP-106 HORIZON and OP-107 BRIDGE as well as in the Phase 3 OP-103 OCEAN trial.  


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The dosing schedule of melflufen, dexamethasone and daratumumab is based on emerging data 
from the Phase 1/2a OP-104 ANCHOR trial in RRMM in which two dose levels of melflufen are 
evaluated: 30 and 40 mg. In this study, the recommended Phase 2 dose of melflufen was 
determined to be 40 mg i.v. on day 1 in a 28-day cycle in combination with daratumumab 
16 mg/kg i.v. and dexamethasone 40 mg weekly (20 mg for patients ≥ 75 years). The ORR at the 
30 mg and 40 mg dose levels were similar, 83% and 74% respectively. However, at the 40 mg 
dose level more frequent dose reductions were needed to manage thrombocytopenias, resulting 
in a similar dose intensity (cumulative dose) as the lower 30 mg level. The benefit-risk profile 
was therefore considered more favorable for the 30 mg melflufen dose level in this combination, 
and this dose was chosen for the proposed Phase 3 study.   
The recommended dose for subcutaneous daratumumab is 1800 mg daratumumab (and 30,000 
units hyaluronidase) when administered as monotherapy or in combinations with other agents 
including PIs and IMiDs, with appropriate pre- and post-medications (Darzalex FASPROTM 
(daratumumab and hyaluronidase-fihj) injection, for subcutaneous use see US prescribing 
information and Summary of Product Characteristics (SmPC)). In the COLUMBA trial the 
subcutaneous formulation of daratumumab at a fixed dose demonstrated non-inferiority 
compared to i.v. daratumumab in terms of ORR, with less infusion-related reactions (Mateos et 
al. 2019).  
4.4. End of Treatment Definition 
A patient is considered to have completed study treatment when all study drugs (melflufen, 
dexamethasone and daratumumab) are discontinued for any reason. 
4.5. End of Study Definition 
 
Study Completion for a patient 
A patient is considered to have completed the study if he/she has completed all visits for the 
study including follow up visits for time to next anti-myeloma treatment, PFS-2 and overall 
survival.   
A patient is also considered to end the study when they withdraw from the study for any reason 
prior to completion. 
Patient study end date and primary reason for ending study will be collected. 
 
Study Definition  
The end of the study is defined as the date when the last patient completes the last study visit 
(which may be a follow-up visit), or the date the Sponsor determines to terminate the study.   


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Patients in this study will have a diagnosis of MM, be double refractory to an IMiD and a PI or 
have received at least 3 prior lines of therapy including at least one IMiD and one PI, and must 
meet all entry criteria defined in Sections 5.1 and 5.2 below.   
5.1. Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
1. Male or female, age 18 years or older;  
2. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol; 
3. A prior diagnosis of multiple myeloma with documented disease progression in need 
of treatment at time of screening;  
4. Double refractory to an IMiD and a PI (regardless of the number of prior lines of 
therapy), or have received at least 3 prior lines of therapy including an IMiD and a PI 
(the definition of refractory includes intolerance to an IMiD/PI after at least two 
28-day cycles of therapy); 
5. Prior treatment with daratumumab or another anti-CD38 antibody is allowed if the 
patient has:   
•     Achieved at least PR and is not refractory to previous anti-CD38 
antibody treatment 
•     At least 6 months since last dose of anti-CD38 antibody prior to Cycle 
1/Day 1 (C1/D1)  
•     Not discontinued anti-CD38 antibody treatment due to related Grade ≥ 3 
toxicity                                                                                      
6. Measurable disease defined as any of the following: 
• Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis 
(SPEP)  
•  ≥ 200 mg/24hr of monoclonal protein in the 24-hour urine collection by 
electrophoresis (UPEP)  
• Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to 
lambda free light chain (FLC) ratio 
7. Life expectancy of ≥ 6 months; 
8. 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); 
9. Ability to understand the purpose and risks of the study, ability to participate in all the 


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procedures required by the protocol and provide signed and dated informed consent;  
10. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula 
(Q-TcF) interval of ≤ 470 msec;  
11. Adequate organ function with the following laboratory results during screening 
(within 21 days) and immediately before study treatment administration on Cycle 1 
Day 1: 
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) 
(Growth factors cannot be used within 10 days (14 days for pegfilgrastim) 
prior to initiation of study treatment) 
• Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusions 
during the 10 days prior to initiation of therapy) 
• Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted) 
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients 
diagnosed with Gilbert’s syndrome that have been reviewed and approved 
by the Medical Monitor 
• AST (also known as SGOT) and ALT (also known as SGPT) ≤ 3.0 x ULN 
• Renal function: Estimated creatinine clearance by Cockcroft- Gault 
formula of ≥ 45 mL/min 
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); 
a) 
Male patients: Male patient that agrees to use contraception as 
detailed in  
 
 


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13. Appendix 5 of this protocol during the treatment period and for at least 3 months after 
the last dose of study treatment and refrain from donating sperm during this period.   
 
Female patients: A female patient is eligible to participate if she is not 
pregnant (see  
 
 


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b) Appendix 5), not breastfeeding, and at least one of the following conditions applies: 
Not a woman of childbearing potential (WOCBP) as defined in  
 
 


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i. 
Appendix 5 or 
A WOCBP who agrees to follow the contraceptive guidance in  
 
 


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ii. 
Appendix 5 during the treatment period and for at least 3 months after the last 
dose of study treatment. 
5.2. Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Primary refractory disease (i.e. never responded with at least MR to any prior therapy);  
2. Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies; 
3. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 
second (FEV1) less than 50% of predicted normal; 
4. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled 
asthma of any classification; 
5. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet 
count fails to increase by > 10,000 cells/mm3 after a transfusion of an appropriate dose of 
platelets);  
6. 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., heart failure class III or 
IV according to New York Heart Association (NYHA), cardiac angioplasty or stenting, 
myocardial infarction, unstable angina, significant cardiac conduction system abnormalities, 
uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months); 
7. Known active infection that is uncontrolled (including symptomatic or asymptomatic 
COVID-19) or has required intravenous systemic therapy within 14 days of randomization. 
Patients who has required oral anti-infective treatment within 14 days of randomization 
should be discussed with the Medical Monitor;  
8. Other malignancy diagnosed or requiring treatment within the past 3 years with the 
exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma 
in-situ of the cervix or breast or very low and low risk prostate cancer in active 
surveillance;  
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse 
compliance or follow-up evaluation; 
10. Human immunodeficiency virus or active hepatitis C viral infection, either known or if 
detected during screening; 
11. Hepatitis B: both active (defined as HBsAg+) or non-active hepatitis B (defined as HBsAg-, 
Anti-HBs+, Anti-HBc+):  
• Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, 
Anti-HBs+, Anti-HBc-).  
12. Concurrent known or suspected amyloidosis or plasma cell leukemia;   
13. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
14. Known CNS or meningeal involvement of myeloma:   
15. Any of the following treatments, within the specified timeframe: 


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• Previous cytotoxic therapies, including cytotoxic investigational agents, for 
multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation 
of therapy. 
• The use of live vaccines within 30 days before initiation of therapy. 
• IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy. 
• Other investigational therapies and mAb within 4 weeks of initiation of 
therapy. 
• Prednisone up to but no more than 10 mg orally q.d. or its equivalent for 
symptom management of comorbid conditions is permitted but dose should be 
stable for at least 7 days prior to initiation of therapy;   
16. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (alopecia 
any grade and/or neuropathy Grade 1 without pain are permitted);   
17. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of 
therapy;   
18. Prior allogeneic stem cell transplantation with active graft-versus-host-disease; 
19. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of 
therapy (this does not include limited course of radiation used for management of bone pain 
within 7 days of initiation of therapy);   
20. Known intolerance to the required dose and schedule of steroid therapy, as determined by 
the investigator; 
21. Known hypersensitivity to any of the agents in this study including hyalonuridase 
22. Prior treatment with melflufen   
5.3. Lifestyle considerations 
No restrictions are required. 
5.4. Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently eligible to be randomized. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE).   
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if appropriate and in consultation and approval of the Medical Monitor.   
5.5. 
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 patient factors 
in subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist. Investigators are encouraged to recruit a diverse population. 


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6. 
Study Intervention 
Study intervention is defined as treatment with melflufen, dexamethasone and daratumumab in 
Arm A and daratumumab in Arm B. Both treatments are intended to be administered to a study 
patient according to the study protocol.   
Treatment will be given in 28-day cycles and may be given in an outpatient setting.  
6.1. Study Treatment Administered 
See Table 6-1 for an overview of the study drugs and their respective characteristics.   
 
Table 6-1 
Study Drugs 
Study Drug Name: 
 
Melflufen  
Daratumumab 
Dexamethasone 
Pharmaceutical 
form: 
 
Powder for solution 
for infusion 
Solution for injection 
Tablet 
Unit dose 
strength(s)/ 
20 mg 
16 mL of solution 
which includes 120 
mg/mL of 
daratumumab, in 
combination with 
rHuPH20 
[2000 U/mL] 
4 mg 
Dosage: 
30 mg  
1800 mg 
40 mg (20 mg for patients 
≥75 years) 
Route of 
Administration  
Intravenous (i.v.) via 
central catheter 
Subcutaneous (s.c.) 
Oral (p.o.)a 


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Study Drug Name: 
 
Melflufen  
Daratumumab 
Dexamethasone 
Packaging and 
Labeling 
 
melflufen powder for 
solution for infusion 
is filled in 50 mL 
glass vials with grey 
rubber stoppers and 
flip-off seals.   
The vials will be 
delivered in boxes 
containing enough 
vials for several 
administrations. 
Each vial and box 
will be labeled as 
required per country 
requirement. 
daratumumab (s.c) is 
supplied as a single 
use, sterile, liquid 
product in a glass vial 
closed with a stopper 
and aluminum seal 
with a gray plastic 
flip off cap. Each vial 
and box will be 
labeled as required 
per country 
requirement. 
dexamethasone (p.o.) will 
be supplied by 
Oncopeptides AB to all 
countries except the USA. 
There are 20 tablets in each 
package. 
Where supplied, it will be 
labeled as required per 
country requirement. 
Storage conditions 
Refrigerated 2°C – 
8°C (36°F–46°F)  
Protected from light   
Refrigerated 2°C – 
8°C (36°F–46°F)  
Protected from light 
Ambient 15°C–25°C 
(59°F–77°F)  
Further 
information 
Investigator’s 
Brochure and 
Pharmacy Manual 
Investigator’s 
Brochure and 
Pharmacy Manual 
Summary of Product 
Characteristics (SmPC) or 
Prescribing Information, 
as well as Pharmacy 
Manual 
a) For patients in Arm A: Oral dexamethasone may be substituted with i.v. dexamethasone in cycle 1, at the 
investigator’s discretion if this is the standard of care of the study center.   
 
Study Regimens and Administration 
Patients will be randomized (1:1) to Arm A (melflufen+dexamethasone+daratumumab) or Arm 
B (daratumumab). Treatment will be given in cycles and may be given in an outpatient treatment 
setting. Each cycle is 28 days.   
Arm A: 
• Melflufen 30 mg will be given as a 30-minute i.v. infusion.   
• Dexamethasone 40 mg weekly will be given p.o. Patients ≥75 years old should receive a 
reduced dose of dexamethasone (20 mg weekly).  
• Daratumumab 1800 mg will be given s.c. as a 15 mL injection over 3-5 minutes with pre-
medication for the prophylaxis of infusion reactions.   
 


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Arm B:  
• Daratumumab 1800 mg will be given s.c. as a 15 mL injection over 3-5 minutes with pre-
medication for the prophylaxis of infusion reactions. Patients with confirmed disease 
progression in Arm B have the option to crossover to treatment with melflufen, 
dexamethasone and daratumumab (dose and schedule as in Arm A). 
Table 6-2 and Table 6-3 summarize the study drug administration schedule during each 28-day 
cycle. 
 
Table 6-2 
Study Treatment Arm A 
Melflufen dose (i.v.) 
 
Daratumumab dose (s.c.)a 
 
Dexamethasone doseb (p.o.)c 
 
All cycles: Day 1  
Cycle 1 and 2: Days 1, 8, 15 and 22 
Cycle 3 to 6: Days 1 and 15 
Cycle 7+: Day 1 
40 mg weekly for patients < 75 
years  
20 mg weekly for patient ≥ 75 
years  
 
a) Pre-medication should be administered to prevent infusion/administration related reactions (see Section 
6.1.4.1)    
b) For additional details on dexamethasone administration see Section 6.1.3.  
c) Prior to melflufen infusion in Cycle 1, oral dexamethasone may be substituted with i.v. dexamethasone 
during cycle 1 at the investigator’s discretion, if this is the standard of care of the study center.  
 
 
Table 6-3 
Study Treatment Arm B 
Daratumumab dosea b(s.c.) 
 
Cycle 1 and 2: Days 1, 8, 15 and 22 
Cycle 3 to 6: Days 1 and 15 
Cycle 7+: Day 1 
a) Pre-medication should be administered to prevent infusion related reactions (see Section 6.1.4.1).   
b) Patients with confirmed disease progression in Arm B have the option to crossover and receive melflufen, 
dexamethasone and daratumumab (dose and schedule as in Arm A). 
 
 
Melflufen Administration (Arm A) 
Prophylactic treatment with anti-emetic drug(s) prior to melflufen administration is 
recommended. Subsequent anti-emetic drugs against delayed emesis should be administered at 


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the discretion of the investigator. Concomitant medication shall be documented in the 
concomitant medication page in the electronic case report form (eCRF).   
On days when melflufen and daratumumab are scheduled on the same day melflufen should be 
administered first.   
Melflufen should be administered as a 30-minute i.v. infusion through a central catheter (Port A 
Cath, PICC line or central venous 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.   
Before infusion: 
• Document vital signs prior to start of infusion. 
• Prepare the central catheter by flushing with approximately 20 mL of 0.9% sodium 
chloride .  
Infusion: 
• The melflufen should be administered as a 30-minute intravenous infusion. 
• Record start and stop time for infusion. 
After infusion: 
• First, flush the central catheter with approximately 20 mL of 0.9% sodium chloride. 
Then follow with additional flushing as per institutional guidelines if necessary. 
The planned and actual administered dose, as well as the start and stop time for the infusion, 
should be documented in the source documents and on the appropriate eCRF page. See Section 
6.2 for preparation, handling, storage and accountability. Refer to the Pharmacy Manual for 
details on melflufen preparation and administration.   
 
Dexamethasone Administration (Arm A) 
Dexamethasone 40 mg p.o. (20 mg p.o. for patients ≥ 75 years) will be given weekly for all 
patients in Arm A. Dexamethasone should always be administered prior to melflufen when both 
melflufen and daratumumab is given (i.e. on Day 1 of each cycle).  
Additional steroids may be given as needed to prevent or treat hypersensitivity reactions at the 
investigator’s discretion and as per the Standard of Care (SoC) for the site. Table 6-4 outlines the 
dexamethasone doses and schedule for administration. 


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Table 6-4  
Dexamethasone dosing schedule 
Dexamethasone dosing on days when melflufen and daratumumab are givena  
All Cycles Day 1  
patients < 75 years of age 
40 mg prior to melflufen administration  
patients ≥ 75 years of age 
20 mg prior to melflufen administration 
Dexamethasone dosing on days when only daratumumab is givena 
Cycle 1 and 2: Days 8, 15 and 22 
Cycle 3 to 6: Day 15 
patients < 75 years of age 
40 mg prior to daratumumab 
administration 
 
patients ≥ 75 years of age 
20 mg prior to daratumumab 
administration 
Dexamethasone dosing on weeks when no other drug is given 
Cycle 3 to 6: Days 8 and 22 
Cycle 7+ Days 8, 15 and 22 
patients < 75 years of age 
40 mg weekly 
patients ≥ 75 years of age 
20 mg weekly 
a) Prior to daratumumab administration in Cycle 1, oral dexamethasone may be substituted with i.v. 
dexamethasone during Cycle 1, at the investigator’s discretion, if this is the standard of care of the study 
center.   
 
Daratumumab Administration (Arm A and B) 
Daratumumab will be given at the dose of 1800 mg daratumumab (in combination with 
rHuPH20 [2000 U/mL]) administered s.c. by manual push [15 mL] over 3-5 minutes at 
alternating left/right abdominal sites. Pre- and post-medications should be administered for the 
prophylaxis of infusion/related reactions (see Section 6.1.4.1). Vital signs should be measured 
pre-dose and post-dose on all dosing days. Patients shall remain in the clinic 3 hours after their 
first daratumumab administration (Cycle 1 Day 1) and up to investigator’s discretion for 
following Cycles. 
6.1.4.1. 
Daratumumab Pre-dose and Post-dose Medications 
6.1.4.1.1. Pre-dose Medications 
In an effort to prevent administration related reactions, all patients will receive the following 
medications 1 to 3 hours prior to each daratumumab administration (1 hour prior to study drug 
administration is preferred): 
• An antipyretic: paracetamol (acetaminophen) 650-1000 mg i.v. or p.o. 
• An antihistamine: diphenhydramine 25-50 mg i.v. or p.o., or equivalent. Avoid i.v. use 
of promethazine. 
• Corticosteroids (long acting or intermediate-acting) 
o Arm A (melflufen, dexamethasone and daratumumab): 


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Dexamethasone is a part of the background regimen and will serve as the steroid for 
premedication. No additional corticosteroid pre-medication is needed 
o Arm B (daratumumab): 
Dexamethasone  20 mg (or equivalent corticosteroid) i.v. or p.o. Following the 
second injection, the dose of the corticosteroid may be reduced to dexamethasone 12 
mg i.v. or p.o,. 
For patients in Arm B who receive melflufen, dexamethasone and daratumumab 
treatment after crossover, no additional corticosteroid pre-medication is needed.  
• Pre-dose administration of a leukotriene inhibitor (montelukast 10 mg p.o., or 
equivalent) is optional on Cycle 1 Day 1 and can be administered up to 24 hours before 
administration as per investigator’s discretion. 
If necessary, all p.o. pre-dose medications may be administered outside of the clinic on the day 
of administration, provided they are taken within 3 hours before administration.  
6.1.4.1.2. Post-dose Medications  
Administer the following post-dose medications: 
o Arm A (melflufen, dexamethasone and daratumumab):  
Consider administering dexamethasone at a dose of less than or equal to 4 mg orally 
beginning of the day after administration of daratumumab.  
o Arm B (daratumumab):  
Administer dexamethasone 4 mg (or equivalent corticosteroid) orally for 2 days, 
starting the day after the administration of daratumumab. 
If the patient does not experience a major systemic administration-related reaction after the first 
3 doses of daratumumab, consider discontinuing the administration of corticosteroids (except the 
background regimen-specific corticosteroid). 
For patients with a higher risk of respiratory complications (e.g., patients with mild asthma or 
patients with COPD who have an FEV1<80% at screening or developed FEV1 <80% during the 
study without any medical history) the following post-dose medications should be considered: 
• Antihistamine (diphenhydramine or equivalent) 
• Leukotriene inhibitor (montelukast or equivalent) 
• Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
• Control medications for lung disease (e.g., inhaled corticosteroids ± long-acting β2 
adrenergic receptor agonists for patients with asthma; long-acting bronchodilators such 
as tiotropium or salmeterol ± inhaled corticosteroids for patients with COPD) 
Investigators may prescribe bronchodilators, H1-antihistamines, and corticosteroids that are 
deemed necessary to provide adequate supportive care in the event a bronchospasm occurs after 
patients are released from the hospital/clinic. If an at-risk patient experiences no major 
administration-related reactions, then these post-dose medications may be waived after 4 doses at 
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Any post-dose medication will be administered after the administration has completed. 
 
6.2. Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drugs received and any discrepancies are reported 
and resolved before use of the study drug.   
2. Only patients enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study drugs. All study drugs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized 
site staff. 
3. The investigator is responsible for study drug accountability, reconciliation, and record 
maintenance, i.e. receipt reconciliation, and final disposition record. Drug accountability 
will be reviewed by the CRO monitor during site visits and at the completion of the 
study. A copy of the drug destruction policy and the completed drug log should be 
provided to the CRO monitor upon request. 
4. At study close-out, and as appropriate during the study, all unused study drug packaging 
and any associated supplies should be discarded according to the site drug destruction 
policy following review and approval of the site CRO monitor. A copy of the drug 
destruction policy and the completed drug accountability log should be provided to the 
CRO monitor. 
5. Further guidance and information for the final disposition of unused study drugs are 
provided in the Pharmacy Manual.   
 
 
Melflufen 
6.2.1.1. 
Melflufen Packaging and Labeling 
Melflufen is formulated as a sterile lyophilized powder for solution for infusion (containing 
melflufen and the excipient sucrose). The drug product, melflufen powder for solution for 
infusion, is filled in 50 mL glass vials with grey rubber stoppers and flip-off seals. Each vial 
contains 20 mg of melflufen. These will be delivered in paper boxes containing enough vials for 
several administrations.   
Please refer to the Pharmacy Manual for further details on packaging and labeling. 
6.2.1.2. 
Melflufen Storage 
Melflufen must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access. Upon receipt, the temperature log should be checked, and notice given to 
supplier of the condition of the shipment. Melflufen shall be stored at 2°C – 8°C (36°F–46°F) 
(refrigerated) protected from light.   


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6.2.1.3. 
Melflufen Supply 
Melflufen will be provided by Oncopeptides AB.   
6.2.1.4. 
Melflufen Special Handling 
Melflufen is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and 
handling melflufen solutions. The use of gloves and other appropriate protective clothing is 
recommended. In case of skin contact, wash the affected area immediately and thoroughly with 
soap and water for at least 15 minutes. If product contacts eye, immediately flush eye thoroughly 
with water for at least 15 minutes. Always contact a physician after any form of body contact. 
All materials that have been used for preparation should be disposed of according to standard 
practices.   
6.2.1.5. 
Melflufen Drug Preparation 
Note:  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.   
• Melflufen is administered i.v. through a central catheter, which should be inserted 
according to standard local practice. All patients must have an acceptable catheter for 
infusion (Port A Cath, PICC line or CVC).   
• Melflufen degrades in solution. It is very important to adhere to the timelines for 
preparation that are outlined in the Pharmacy Manual. This requires very good 
coordination between staff at the pharmacy and the patient treatment area. Careful 
attention and documentation of the preparation procedures and time frames are 
required.   
• Melflufen is reconstituted in 40 mL 5% glucose infusion solution per 20 mg vial of 
melflufen. The reconstituted melflufen is diluted to 250 mL in 0.9% sodium chloride 
infusion solution and should be refrigerated immediately, see Pharmacy Manual for 
detailed instructions. 
 
Dexamethasone 
6.2.2.1. 
Dexamethasone Packaging and Labeling 
Dexamethasone (p.o.) will be supplied as a 4 mg tablet with 20 tablets in each package by 
Oncopeptides AB to all countries except the USA. Where supplied, it will be labeled as 
required per country requirement. No additional labeling is required for the use of commercial 
dexamethasone in the USA.  
6.2.2.2. 
Dexamethasone Storage 
Dexamethasone is to be stored at controlled room temperature. Consult the package insert or 
SmPC for dexamethasone for additional storage and usage instructions. Upon receipt, the 
temperature log should be checked, and notice given to supplier of the condition of the 
shipment.    


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6.2.2.3. 
Dexamethasone Supply 
Oral dexamethasone will be supplied by Oncopeptides AB to sites located outside the USA. 
USA sites will use commercially available dexamethasone supplies. 
 
Daratumumab 
6.2.3.1. 
Daratumumab Packaging and Labeling 
Daratumumab is a colorless to yellow, preservative-free solution for injection. Each single use 
drug product vial contains approximately 16 mL of solution which includes 120 mg/mL of 
daratumumab. Daratumumab will be labeled for investigational use according to local 
regulations. 
6.2.3.2. 
Daratumumab Storage 
Store the drug product vial in a refrigerator at 2°C – 8°C (36°F–46°F). Protect from light during 
refrigerated storage. Protection from light is not needed during dose preparation of 
administration. Do not freeze or shake the drug product vial or prepared drug syringe. This 
product contains no preservative. Upon receipt, the temperature log should be checked, and 
notice given to supplier of the condition of the shipment. Please refer to the Pharmacy Manual 
for specifications.  
Do not store any unused portion of the injection solution for reuse. Any unused product or waste 
material should be disposed of in accordance with local requirements.   
6.2.3.3. 
Daratumumab Supply  
Daratumumab will be supplied by Oncopeptides AB. 
Please refer to the Pharmacy Manual for complete details on drug supply and ordering 
procedures. 
6.2.3.4. 
Daratumumab Drug Preparation 
Daratumumab drug product vials should be stored at 2°C – 8°C (36°F–46°F) and protected from 
light. The drug product vials should be kept in original carton until assigned for use. Drug 
product vials should not be frozen or shaken. 
Remove drug product vial from the 2°C – 8°C (36°F–46°F) storage and equilibrate at room 
temperature for at least 30 minutes (from the time the vial is removed from 2°C – 8°C (36°F–
46°F) storage until preparation of a syringe. The vial must not be stored at room temperature and 
room light for more than 24 hours including equilibration time before first vial puncture.  
NOTE: The maximum allowable time at room temperature and room light from puncturing the 
vial to administering the syringe contents to the patient is 4 hours. 
Refer to the Pharmacy Manual for detailed instructions for preparation and requirements for 
administration.   


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6.3. Measures to Minimize Bias 
 
Study Drug Administration 
The study drug administration is more frequent in treatment arm A, i.e. dexamethasone dosing on 
weeks when no other drug is given, see Table 6-4. There is a potential risk that these additional 
visits may not be attended for pragmatic and logistic reasons. In addition, patients who have not 
required any dose modification or delays, G-CSF and transfusions during the last two cycles may 
skip visits at Day 8 and Day 22, and it is possible that this may be more common for patients in 
treatment Arm B. This may introduce bias in reporting of data. Special attention will therefore be 
given to frequency of visits not attended during data review and final analysis. 
A potential bias may also be introduced from varying frequency and degree of drug interruptions 
due to adverse events, as a result of differences between treatment arms regarding expected 
adverse events. This may lead to varying intensity of drug exposure as well as unbalanced timing 
of assessments between treatment arms. Special attention will therefore be given to this potential 
bias during data review and final analysis. 
 
Randomization 
Patients will be randomly assigned to study treatment through an Interactive Web Response 
System (IWRS) system. This provides automated confirmation of assignments and 
documentation. It also assures inventory management and real-time reporting of study 
enrollment status.  
The randomization will be stratified to minimize bias in endpoints due to differences in baseline 
characteristics between the investigational arm and the control arm. The randomization will be 
stratified by number of previous lines of treatment (<3 prior lines of treatment versus ≥3 prior 
lines of treatment) and previous treatment with daratumumab or another anti-CD38 antibody (no 
previous treatment versus previous treatment).   
 
Data Access Plan 
This is a randomized controlled study where the open-label treatment allocation is unblinded for 
investigators and other personnel involved in monitoring and data validation. To minimize the 
potential bias from review and processing of unblinded data, the access to data will be restricted 
to varying degrees by study roles. Access to data and processes for data management reports are 
specified in a separate Data Access Plan. 
 
Medical Monitoring Plan 
Patients’ eligibility will be verified by the Medical Monitor before randomization to assure 
consistency and documentation of medical judgements related to the eligibility criteria. Processes 
pertaining to this activity are described in a separate Medical Monitoring Plan.  
 
Data Monitoring Committee 
Safety and tolerability will be reviewed during the study by an independent Data Monitoring 
Committee (DMC) as described in Section 9.5.1. 


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Independent Review Committee 
All response assessments will be done by investigators based on IMWG guidelines. These 
guidelines will ensure consistency of response assessments across patients and sites. As a 
sensitivity analysis, an Independent Review Committee (IRC) will also evaluate the response 
assessments as described in Section 9.5.2.  
6.4. Study Treatment Compliance 
Compliance with melflufen and daratumumab will be assured by administration of the study 
treatment under the supervision of the investigator or his/her designee and should be documented 
in the study drug administration and accountability records. Compliance with dexamethasone (in 
Arm A) will be verified by accountability, patient inquiry and documented in the source 
documents and eCRF, as well as in a patient diary. 
6.5. Concomitant Therapy 
Any blood products, medications and vaccines (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the patient is receiving within 21 days prior 
to the initiation of therapy or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
 
Required Concomitant Therapy 
• Anti-viral prophylaxis 
It is required that patients receive prophylaxis against herpes zoster using oral acyclovir 
(400 mg twice daily) or valacyclovir (500 mg twice daily) or equivalent antiviral therapy 
per institutional guidelines and at the discretion of the site investigator, unless the patient 
develops a hypersensitivity to the agents.   
Reactivation of Hepatitis B: See Section 6.6.3, regarding management of patients at risk 
for, or diagnosed with, reactivation of hepatitis B. 
 
• Contraceptive measures 
Males and females of child-bearing potential shall be required to use effective contraceptive 
methods (or abstinence) prior to initiation of study drug, while on therapy and for 3 months 
after the last dose of study drug. The best method should be determined in consultation with 
the Investigator. See  
 
 


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Appendix 5. 
 
• Pneumocystis prophylaxis  
All patients are recommended, and high risk patients are mandated, to receive 
pneumocystis prophylaxis, see Section 6.5.2. 
 
Recommended Concomitant Therapy 
• Pneumocystis prophylaxis: 
All patients are recommended, and high risk patients are mandated, to receive 
pneumocystis prophylaxis concomitant treatment according to the National 
Comprehensive Cancer Network (NCCN) or institutional guidelines:  
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf 
o Trimethoprim/sulfamethoxazole – Prophylaxis: single or double strength daily or 
double strength 3 times per week. The dose and administration schedule 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. Alternative 
pneumocystis prophylaxis regimens should be considered 
 
• 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  
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  
 
• Thrombocytopenia and neutropenia are known consequences of MM but also the most 
common expected AEs associated with melflufen. Careful attention is to be paid to the 
monitoring of blood counts. General supportive measures, together with appropriate 
blood and platelet transfusions and hematopoietic growth factors should be 
administered if necessary. It is recommended, at the investigator’s discretion, that 
platelet transfusion should be avoided within ≤ 5 days of the next dose in order to 
assess endogenous platelet recovery and avoid the possibility of excessive 
myelosuppression (Excluding Cycle 1, Day 1 which adheres to the guidelines in 
Section 6.6.1.1 for use of growth factors and platelet transfusions prior to the first dose 
of therapy).   
• Prophylactic treatment with anti-emetic(s) prior to melflufen administration is 
recommended. Subsequent anti-emetic drugs against emesis should be administered at 
the discretion of the investigator.   


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• Prophylactic treatment required prior to daratumumab to minimize or to treat infusion 
related reactions can be found in Section 6.1.4.1. 
• Patients should receive full supportive care while on study at the investigator’s 
discretion, including red blood cell transfusions, anti-emetics, anti-diarrheals and 
analgesics etc.   
• Bisphosphonate therapy i.v. or p.o. should be administered if indicated in accordance 
with institutional guidelines.   
• Other prophylactic treatment for patient related concomitant conditions or risks may be 
considered.   
 
Prohibited Concomitant Therapy 
• Concurrent therapy with any approved or investigative anticancer therapeutic drug 
with activity against MM, including alpha interferon and/or chronic use of 
clarithromycin, is not allowed.   
• Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel 
disease) > prednisone 10 mg/day (or its equivalent) are not permitted. However, 
steroids required for the treatment of daratumumab infusion related reactions are 
permitted. Topical and inhaled corticosteroids are permitted.  
• Other investigative agents should not be used during the study.   
• Radiation therapy, unless only to a limited area for bone pain to a pre-existing lesion 
– this may be considered in consultation with and approval by the Medical Monitor.   
• The use of live vaccines is prohibited during the study and for 90 days after last dose 
of study treatment.   
• Thrombopoietin receptor agonists are not permitted. Platelet transfusions are allowed 
in case of thrombocytopenia. 
• The prophylactic use of Granulocyte-colony stimulating factor (G-CSF) and platelet 
transfusions are not permitted to render the patient eligible for trial participation 
except as described within the inclusion criteria Section 5.1. 
• Acetylsalicylic acid, at doses ≥ 1 g per dose or 3 g per day should be avoided due to 
an increased risk of bleeding in patients receiving dexamethasone. 
6.6. Dose Modification 
Dose modifications are permitted during the study according to guidelines described below.   
• Toxicity should be assessed using the common terminology criteria for adverse events 
(CTCAE) version 5.0 (See Appendix 7). 
• All dose modifications should be based on the worst preceding toxicity. 
• Each AE should be attributed to a specific drug, if possible, so that the dose 
modifications can be made accordingly. 


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• Dose modification of one agent and not the others is appropriate if toxicity is related 
primarily to one of the agents.  
• No dose escalations are permitted in any given patient once a dose level has been 
reduced.   
• Dose modifications different from those stated in the protocol should only be made in 
consultation with the Medical Monitor or Sponsor; unless required for immediate patient 
safety.   
• Administration of the study treatment should be discontinued in the event of a TEAE that 
persists despite appropriate dose modifications or any other AE that, in the opinion of the 
investigator, warrants discontinuation. 
• All interruptions or changes to study treatment administration must be recorded in the 
eCRF. 
• In case of dose reduction of any study therapy, the dose should not be re-escalated to the 
higher dose once the AE resolves.   
 
Criteria for initiation of therapy 
6.6.1.1. 
Day 1, Cycle 1 
Prior to initiation of therapy, patients must continue to meet eligibility criteria including ECOG 
performance status of ≤ 2 and the Cycle 1 Day 1 laboratory results must also meet the entry 
criteria as follows:   
• ANC ≥ 1,000 cells/ mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days 
[14 days for pegfilgrastim] 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). Thrombopoietin receptor agonists are not permitted, see 
Section 6.5.3.   
• Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted).  
• Total Bilirubin ≤ 1.5 x upper limit of normal, except patients diagnosed with Gilbert’s 
syndrome that have been reviewed and approved by the Medical Monitor. 
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN 
• Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min 
(Appendix 13). 
Criteria for initiation of a crossover in Arm B after confirmed disease progression have been 
specified in Appendix 3.  
6.6.1.2. 
Day 1, Subsequent cycles 
• ANC must be ≥ 1,000 cell/mm3 (1.0 x109/L). For administration of growth factors see 
Section 6.5.2. 
• All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except 
peripheral neuropathy Grade 1 without pain, alopecia and fatigue ≤ Grade 2). 


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• Absence of daratumumab IRR that require discontinuation (Grade 4 or Grade 3 on three 
occurrences in the previous cycle see Section 6.6.3.3.1.   
• Platelet count: 
o Arm A (melflufen, dexamethasone and daratumumab): Platelet count must 
be ≥ 50,000 cell/mm3 (50.0 x 109/L) (platelet transfusions not recommended 
within ≤ 5 days of dosing (see Section 6.5.2). For patients in Arm A that have 
discontinued melflufen but remain on daratumumab and dexamethasone the 
platelet count must be ≥ 25,000 cell/mm3 (25.0 x 109/L) 
o Arm B (daratumumab): Platelet count must be ≥ 25,000 cell/mm3 (25.0 x 109/L) 
(platelet transfusions not recommended within ≤ 5 days of dosing (see Section 
6.5.2). 
If these criteria are not met on the scheduled Day 1, the new cycle should be held, and patients 
should be re-evaluated weekly. Refer to Section 6.6.3 for guidelines on dose modification due to 
drug related toxicity.   
The maximum amount of time for which study therapy may be held due to drug related toxicity 
is 28 days from a scheduled Day 1 (Day 57). If study treatment is not administered for more than 
28 days due to drug related toxicity the patient will be removed from the study treatment and 
enter follow up phase. If the patient was clearly benefiting from therapy, the patient may be able 
to continue treatment at the Investigator’s discretion and in consultation with the Medical 
Monitor, after resolution of the AE.  This also applies to the patients who crossover.   
 
Dose Reduction Steps 
6.6.2.1. 
Dose Reduction Steps for Melflufen 
Dose modifications of melflufen for drug related toxicity are permitted. Multiple dose reductions 
are permitted however, the lowest dose permitted is 10 mg (see (Table 6-5). If a patient is unable 
to tolerate the lowest dose of melflufen due to drug related toxicity the patient must be 
withdrawn from treatment. No dose increases after previous dose reductions are allowed. Prior to 
each cycle of melflufen the criteria for initiation of therapy must be met (see Section 6.6.1). 
Patients who discontinue treatment with melflufen in Arm A for any reason may continue 
treatment with daratumumab and dexamethasone. In the event that melflufen is discontinued and 
the partner therapy is continued, the schedule of CBC and platelet evaluations may be conducted 
at the investigator’s discretion but must at a minimum be performed Day 1 of each subsequent 
cycle and before each dose of daratumumab.  


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Table 6-5 
Dose Reduction Steps for Melflufen 
Starting dose  
Dose reduction 
Step - 1 
Dose reduction 
Step – 2 
Dose reduction 
Step – 3 
30 mg 
20 mg 
15 mg 
10 mg 
6.6.2.2. 
Dose Reduction Steps for Dexamethasone 
Table 6-6 outlines the dose reduction steps for dexamethasone. Dose reductions of 
dexamethasone other than those listed in Table 6-6 or discontinuation may be considered in 
consultation with the Medical Monitor. Table 6-8 outlines the dose modification guidelines for 
toxicity related to dexamethasone.  
Table 6-6 
Dose Reduction Steps for Dexamethasone 
Starting dose 
Dose reduction Step - 1 
Dose reduction Step - 2 
40 mg 
20 mg 
12 mg 
20 mg 
12 mg 
4 mg 
6.6.2.3. 
Dose Reduction Steps for Daratumumab  
There are no dose reduction steps for daratumumab. A patient who discontinues treatment with 
daratumumab due to AEs, except from hematologic toxicity, in Arm A may continue treatment 
with melflufen and dexamethasone, after consultation with Medical Monitor.  
 
Dose Modifications Based on Toxicity 
6.6.3.1. 
Dose Modifications for Melflufen and Daratumumab 
Melflufen is a potent myelosuppressive agent, and it is essential that careful attention be paid to 
the monitoring of blood counts. General supportive measures, together with appropriate red 
blood cell and platelet transfusions and hematological growth factors, should be instituted if 
necessary. It is recommended, at the investigator’s discretion, that platelet transfusion should be 
avoided within 5 days of the next dose of melflufen in order to assess endogenous platelet 
recovery and avoid the possibility of excessive myelosuppression. Table 6-7 outlines the dose 
modification for toxicity related to melflufen and daratumumab.  
Patients with neutropenia should be monitored for signs of infection as described in section 6.5.2  
Patients who discontinue treatment for a study related AE including abnormal laboratory value 
must be followed as described in Section 8.1.3.   
 
 
 


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Table 6-7 
Dose Modification for Toxicity Related to Melflufen and Daratumumab 
Toxicity 
Cycle Day 
Action with Melflufen 
Action with 
Daratumumab 
Hematologic Toxicity – Supportive therapy with platelets and growth factors is permitted 
according to the guidelines in Section 6.5. 
ANC 
<1000 mm3  
(<1.0 x 109 /L) 
Platelet count  
<50,000 mm3  
(<50.0 x 109 /L) 
Day 1 
Hold, evaluate weekly and 
resume therapy when 
criteria for initiation of a 
new cycle are met 
(Section 6.6.1) 
Hold, evaluate weekly 
and resume therapy when 
criteria for initiation of a 
new cycle are met  
For patients in Arm B 
and patients in Arm A 
that have discontinued 
melflufen, dosing may 
continue if platelets are 
>25,000 mm3 (>25.0 x 
109 /L) (Section 6.6.1). 
First occurrence - if 
resolved in ≤ 14 days 
same dose may be 
resumed. Dose reduction 
or delay may be 
considered. 
No dose reduction of 
daratumumab is 
permitted. 
If resolved in > 14 days or 
a subsequent occurrence, 
dose reduction is required. 
 
ANC  
< 500 mm3  
(0.5 x 109/L) 
Platelet count  
<25,000 mm3  
(<25.0 x 109 /L) 
Day 8, 15 or 
22 (see 
Section 
6.1.4) for 
daratumumab 
schedule) 
Not applicable 
Hold until resolved to ≤ 
Grade 2 within the cycle 
(see Section 6.1.4) for 
daratumumab schedule) 
Non-hematologic Toxicity 
Reactivation of HBV 
Any Day 
 
Hold until the infection is 
adequately controlled. If 
the benefits outweigh the 
risks, study treatment 
may be resumed with 


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concomitant antiviral 
prophylaxis as per local 
standard of care. Consult 
a liver disease specialist 
as clinically indicated.  
Grade 3 drug related 
non-hematologic 
toxicity 
Day 1 
Hold, evaluate weeklya 
and resume therapy when 
criteria for initiation of a 
new cycle are met (see 
Section 6.6.1).  
 
Reduce dose if attributed 
to melflufenc 
 
Hold and evaluate with 
next scheduled 
administration.   
Resume therapy within 
the cycle if resolved to ≤ 
Grade 1 or baseline or 
hold for remainder of 
cycle and resume therapy 
when criteria for 
initiation of a new cycle 
are met (see Section 
6.6.1). 
Grade 3 drug related 
non-hematologic 
toxicity 
Any day 
during a 
cycle 
If attributed to melflufen, 
reduce by one dose level 
when criteria for a new 
cycle are metb 
No dose reduction is 
permitted, refer to 
Section 6.6.3.3.1 for 
management of infusion-
related reactions 
Grade 4 drug related 
non-hematologic 
toxicity  
Any day 
Discontinue therapy 
Discontinue therapy 
a) If cycle prolongation of more than 28 days (beyond Day 57) is needed, study treatment is to be 
discontinued unless in the investigator’s opinion the patient is benefitting from therapy. Continuation must 
be discussed with the Medical Monitor on a case by case basis. 
b) A dose reduction may not be required if: 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 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). This must be discussed with the Medical Monitor on a case by case 
basis.   
c) Alternate dose modification may be considered in discussion with the Medical Monitor. Continued dosing 
with or without dose reduction of melflufen may be considered after contact with the Medical Monitor in 
case of non-study drug related cycle prolongations (for example: influenza).   
6.6.3.2. 
Dose modifications for Dexamethasone (Arm A) 
Dose modifications for dexamethasone are permitted. If a patient is unable to tolerate 
dexamethasone due to dexamethasone related toxicity, dexamethasone may be further reduced or 


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discontinued following consultation with the Medical Monitor. In the event of a cycle delay, 
unrelated to dexamethasone toxicity, dexamethasone may be continued weekly at the 
investigator’s discretion.   
Table 6-8 
Dose Modification for Toxicity Related to Dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1–2  
(requiring medical 
management) 
Treat with Histamine 2 receptor (H2) 
blockers, sucralfate, or proton pump 
inhibitors (PPIs) . If symptoms persist despite 
above measures, decrease dexamethasone 
dose by 1 dose level. 
Gastrointestinal  ≥ Grade 3 
(requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled. Restart and decrease 
one dose level of current dose along with 
concurrent therapy with H2 blockers, 
sucralfate, or PPIs. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal Acute pancreatitis 
Discontinue dexamethasone and do not 
resume. 
Cardiovascular 
Edema 
 ≥ Grade 3 (limiting function 
and unresponsive to therapy 
or anasarca) 
Diuretics as needed. Decrease 
dexamethasone dose by 1 dose level; if 
edema persists despite above measures, 
decrease dose by another dose level. 
Discontinue dexamethasone and do not 
resume if symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood 
alteration  
 ≥ Grade 3 (interfering with 
function +/- interfering with 
activities of daily living) 
Hold dexamethasone until symptoms resolve.  
Restart with one dose level reduction. If 
symptoms persist despite above measures, 
discontinue dexamethasone and do not 
resume. 
Musculoskeletal Muscle weakness  
 ≥ Grade 3 (symptomatic 
and interfering with function 
+/- interfering with activities 
of daily living) 
Decrease dexamethasone dose by one dose 
level. If weakness persists despite above 
measures, decrease dose by one additional 
dose level. Discontinue dexamethasone and 
do not resume if symptoms persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 or 
higher 
Treatment with insulin or oral hypoglycemics 
as needed. If uncontrolled despite above 
measures, decrease dose by one dose level 
until levels are satisfactory. 


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Alternate dose modification may be considered in discussion with the Medical Monitor.  
6.6.3.3. 
Dose Modifications for Daratumumab 
There are no dose reductions for daratumumab. 
6.6.3.3.1.  Management of Infusion Related Reactions 
Both systemic administration-related reactions, including severe or life-threatening reactions, 
and local injection-site reactions can occur with subcutaneous daratumumab. To be consistent 
with the IB for daratumumab as well as available prescribing information, the definition 
Infusion-related reactions (IRRs) is used for systemic reactions related to daratumumab 
administration, also when daratumumab is given as an injection over time in this protocol and 
not as an infusion. Patients should be observed carefully during daratumumab administrations for 
systemic administration-related reactions, especially following the first and second injections. 
Daratumumab should be administered by a healthcare professional, with immediate access to 
emergency equipment and appropriate medical support to manage infusion reactions if they 
occur. 
If an IRR develops during daratumumab administration, the administration should be temporarily 
interrupted. Patients who experience AEs during daratumumab administration should be treated 
for their symptoms. Patients should be treated with paracetamol (acetaminophen), antihistamine, 
or corticosteroids, as needed. Intravenous saline may be indicated. For bronchospasm, urticaria, 
or dyspnea, patients may require antihistamines, oxygen, corticosteroids, or bronchodilators. For 
hypotension, patients may require vasopressors. In the event of a life-threatening IRR (which 
may include pulmonary or cardiac events) or an anaphylactic reaction, daratumumab should be 
discontinued.The most common local reaction after daratumumab administration has been 
injection site erythema. Monitor for local reaction and consider symptomatic management. 
Infusion-related Reactions of Grade 1 or Grade 2 
If the investigator assesses a Grade 1-2 IRR to be related to administration of study treatment, 
then the daratumumab administration should be interrupted. When the patient’s condition is 
stable, daratumumab administration may be restarted at the investigator's discretion. 
If the patient experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from onset, then the patient must be permanently discontinued from daratumumab 
treatment. 


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Infusion-related Reactions of Grade 3 or Higher 
For IRR AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the daratumumab 
administration must be stopped, and the patient must be observed carefully until resolution of the 
AE or until the intensity of the event decreases to Grade 1, at which point the daratumumab 
administration may be restarted at the investigator’s discretion. 
If the intensity of the AE returns to Grade 3 after restart of the daratumumab administration, then 
the patient must be permanently discontinued from daratumumab treatment. 
For IRR AEs that are Grade 4, the daratumumab administration must be stopped, and the patient 
permanently discontinued from daratumumab treatment. 
Recurrent Infusion-related Reactions 
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of 
bronchospasm) recurs during or within 24 hours after a subsequent daratumumab administration, 
the patient must be permanently discontinued from daratumumab treatment. 
6.6.3.3.2. Daratumumab precautions 
Daratumumab binds to CD38 on RBCs and results in a positive Indirect Antiglobulin Test 
(Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for 
up to 6 months after the last daratumumab infusion. daratumumab bound to RBCs masks 
detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s 
ABO and Rh blood type are not impacted.   
Notify blood transfusion centers of this interference with serological testing and inform blood 
banks that the patient has received daratumumab according to local requirements. Type and 
screen RBC prior to starting daratumumab, see Section 8.1.1.   
 
6.7. Intervention after the End of the Study 
There is no planned intervention following the end of the study.   


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7. 
Discontinuation of Study Intervention and Patient 
Discontinuation/Withdrawal  
7.1. Discontinuation of Study Treatment  
Patients may be withdrawn from study treatment if any of the following occur: 
• His/her own request at any time.  
• At the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons.   
• Any of the events outlined in Section 4.1.1 Treatment duration 
• Requiring other anticancer therapeutic drug, corticosteroids for non-malignant conditions, 
other investigative agent, live vaccine, or dialysis, as further detailed in Section 6.5.3.  
• Confirmed pregnancy. 
• Lost to follow-up. 
• An incidence or a seriousness of SAEs in this study or other studies indicating a potential 
danger for the patient’s health caused by the study treatment. 
In the event of patient withdrawal from study treatment the reason(s) for withdrawal of study 
treatment 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. 
As for any other reason to discontinue treatment, the patient can still continue in follow up 
(unless consent has been withdrawn for study participation and not only for treatment).    
See the SoA for data to be collected at the time of treatment discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.2. Patient Discontinuation/Withdrawal from the Study 
• A patient may withdraw from the study at any time at his/her own request. 
• If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent, if 
allowed as per local regulations. 
• If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
• The reason(s) for withdrawal of study participation and the date at which the decision is 
made should be documented. 
7.3. Lost to Follow Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 


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• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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8. 
 Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Study procedures and their 
timing for patients who crossover are summarized in the SoA in Appendix 3. Protocol 
waivers or exemptions are not allowed.   
• Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.   
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.   
• All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.   
• Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.   
8.1. Study procedures 
 
Procedures during screening 
Potential patients will be contacted to determine their interest in participating in this study. All 
patients must sign and date an IRB/IEC/REB approved informed consent form within 28 days of 
enrollment and prior to any study related procedure and enrollment. After providing written 
informed consent, the patients will be evaluated for eligibility by screening tests and conformity 
to study inclusion and exclusion criteria.   
Once a patient is determined to be eligible for screening and satisfy all initial inclusion and 
exclusion criteria (Sections 5.1 and 5.2), screening procedures will be performed as listed below. 
If at any point during screening, a finding disqualifies the patient from study participation, no 
further screening tests will be performed.   
The screening visit will occur within 21 days before randomization and treatment must begin ≤ 5 
days after randomization but not before. The following assessments will be performed at the 
screening visit:   
• Demographics 
o Date of birth, age, gender, race and ethnicity   
• Medical history, including the following:   
o Prior and current medical illness and conditions   
o Prior surgical procedures   
• Myeloma history including  
o Characteristics (including heavy chain or light chain subtype, evidence of EMD 


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or lytic bone lesions) 
o Date of initial diagnosis   
o ISS and R-ISS stage and cytogenetics at diagnosis (if previously evaluated)   
o ISS and R-ISS stage at time of screening 
o All prior myeloma treatment, also including surgery and/or radiation, 
documenting:   
• start and stop dates   
• assessment of best response   
• date of progressive disease and relapsed or refractory status   
• Physical examination, including assessment for extramedullary myeloma. Baseline 
symptoms and residual toxicity from previous therapy, including neuropathy.   
• Vital signs including height, weight, blood pressure, pulse, respiratory rate and temperature.   
• ECOG performance status   
• Pregnancy test, only for WOCBP   
• RBC typing and antibody screening; Inform blood banks that the patient will receive 
daratumumab, according to local practice. See Section 6.6.3.3.2.  
• 12- lead electrocardiogram (ECG); Q-Tc interval to be assessed by Fridericia formula   
• Blood tests;  
o Hematology: CBC with differential and platelet count 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric 
acid, blood urea nitrogen [BUN](or urea), creatinine, estimated creatinine 
clearance (by Cockcroft-Gault Formula), glucose (fasting), ALT (SGPT), AST 
(SGOT), alkaline phosphatase, total protein, total bilirubin, albumin, and lactate 
dehydrogenase (LDH). 
o Coagulation: Prothrombin time (PT), international normalized ratio (INR). 
o β2-microglobulin   
• M protein assessments, see Section 8.2.1. 
• Hepatitis B screening: HBsAg, Anti-HBs, Anti-HBc 
• Hepatitis C screening: Anti-HCV 
• HIV screening: Anti-HIV1/2 and HIV1/2 antigen 
• Pulmonary function test: spirometry  
• Urinalysis 
• Bone marrow aspiration; The aspirate will be used for the following assays and should be 
divided into aliquots with the below priority order. Refer to Laboratory Manual for additional 
information.   
1. 
% plasma cells and morphology (smear)  
2. 
The rest of the aspirate should be divided into aliquots in the following order: 
i. 1 mL for possible MRD assessment (first draw) 
ii. 4 mL for cytogenetics by interphase Fluorescence In-Situ Hybridization 
(iFISH), karyotyping and DNA/RNA sequencing.  
• Review prior/concomitant medications   
• Extramedullary myeloma assessment. If imaging is used the method must provide 
bidimensional measurements with same method to be used throughout the study. 


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• Chest X-ray (optional if low-dose CT is performed for skeletal assessment). If performed 
within 6 weeks from initiation of therapy, repeat only needed if clinically indicated. 
• Skeletal X-ray or low-dose CT scan; required if previous assessment is > 6 weeks from 
initiation of therapy. 
• Inclusion/Exclusions criteria review 
• Use of health services and hospitalization   
• SAE monitoring 
The Investigator will review each patient’s screening data and document the patient’s 
acceptability for study participation. The patient may be enrolled upon approval by the Medical 
Monitor.   
For patients who fail screening, the Investigator will record demographics and reason for screen 
fail, eligibility criteria and any SAE in the appropriate sections of the eCRF and note the reason 
for exclusion. These documents and the patient’s signed informed consent form will be retained 
in the study files. 
 
Procedures during study treatment, all cycles 
The following procedures will be performed during active study treatment at the times specified. 
All procedures are applicable at all cycles unless otherwise specified.   
8.1.2.1. 
Procedures Day 1 
• Criteria for initiation of therapy should be fulfilled, see Section 6.6.1.  
• PRO assessments (EORTC QLQ-C30 and EQ-5D-3L), prior to any study visit activities 
(tests, examination or treatment). The questionnaires should be administered even if the 
treatment is not given, see Section 8.12. 
• PRO pain assessments (BPI-SF and NRS for measure of bone pain), prior to study visit 
activities (tests, examination or treatment). BPI-SF should be completed first and if patient 
has experienced pain, the NRS for measure of bone pain should be completed. The 
questionnaires should be administered even if the treatment is not given, see Section 8.12.   
• Physical examination; including assessment for extramedullary myeloma. Plasmacytomas 
that can be followed by physical examination should also be evaluated at each cycle with 
measurements documented in the source documents.  
• Vital signs, including blood pressure, pulse, respiratory rate, temperature, should be assessed 
before melflufen dose as well as before and after daratumumab dosing. Weight should be 
assessed prior to melflufen dose.  
• ECOG performance status   
• Pregnancy test; only for WOCBP   
• Blood tests: 
o Hematology: CBC with differential and platelet count 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric 
acid, blood urea nitrogen [BUN](or urea), serum creatinine, estimated creatinine 
clearance (by Cockcroft-Gault Formula), glucose (non-fasting), ALT (SGPT), 
AST (SGOT), alkaline phosphatase, total protein, total bilirubin, albumin, and 
lactate dehydrogenase (LDH).  


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o Blood sample for DNA/RNA sequencing should be collected before dosing at 
Cycle 1 day 1  and at the time of response (CR or VGPR) and at the time of 
disease progression.  
o Blood sample for myeloma related bone disease biomarkers should be collected 
before dosing. 
See Laboratory Manual for additional information.   
• Bone marrow aspiration; at the time of CR/VGPR and if needed to confirm disease 
progression, the below samples should be obtained in the following order and sent to the 
central laboratory for analysis. See Laboratory Manual for additional information. 
1. 
% plasma cells and morphology including immunohistochemistry 
2. 
3 mL for MRD assessment (not applicable in case of suspected PD) 
3. 
DNA/RNA sequencing 
• Concomitant medications review   
• M-protein assessments described in Section 8.2.1 is planned pre-dose Day 1 of each cycle 
(day 29 of prior cycle) and with assessment of myeloma response from Cycle 2. If treatment 
is delayed, an assessment should still be made at day 29 and should be repeated prior to next 
cycle if the delay is 2 weeks or longer, and to confirm any response or PD.  
• Extramedullary myeloma assessment; Known or suspected plasmacytomas should be 
assessed, using the same method as at screening, every 2 cycles up to disease progression. 
• Skeletal X-ray or low-dose CT scan; as clinically indicated. 
• Administration of study treatment; see Section 6.1.   
• Pharmacokinetic blood samples for melphalan; for patients in Arm A, cycle 1 and 2 only (see 
Section 8.6.1). 
• Pre-dose pharmacokinetic blood samples for daratumumab for patients in Arm A and Arm B, 
cycle 1, 3, 7 and 12. 
• Pre-dose serum samples for immunogenicity (daratumumab) for patients in Arm A and Arm 
B, cycle 1, 7 and 12. 
• Pre-dose serum samples for immunogenicity (rHuPH20) for patients in Arm A and Arm B, 
cycle 1, 7 and 12. 
• Pre-dose whole blood samples for immunoprofiling at Cycle 1 and Cycle 6. 
• Use of health services and hospitalization   
• AE monitoring   
 
8.1.2.2. 
Procedures Day 4 (Cycle 1 and 3) 
Pharmacokinetic blood samples for daratumumab for patients in both Arm A and B (Cycle 1 and 
3 only) when possible to schedule on weekdays. 
8.1.2.3. 
Procedures Day 8, 15 and 22  
• If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive 
therapy (G-CSF, blood or platelet transfusion) in the two preceding cycles, then Day 8 and 
Day 22 visits do not have to be completed. Pain assessments (BPI-SF and NRS for measure 
of bone pain), prior to any study visit activities (tests, examination or treatment) on Day 15 of 
cycles 1-3. BPI-SF should be completed first and if patient has experienced pain, the NRS for 


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measure of bone pain should be completed. The questionnaires should be administered even 
if the treatment is not given.     
• Physical examination: symptom directed as needed during treatment.   
• Vital signs; including blood pressure, pulse, respiratory rate, temperature, to be assessed 
before and after each daratumumab administration (see Section 6.1.4 for daratumumab 
administration schedule).  
• Blood tests: 
o Hematology: CBC with differential and platelet count. If patient tolerability is 
good, i.e. no dose modifications, dose delays or need of supportive therapy (G-
CSF, blood or platelet transfusion) in the two preceding cycles, then Complete 
Blood Count assessments may be excluded at Day 8 and Day 22. 
• See Laboratory manual for additional information. Concomitant medications review 
• Administration of study treatment, see Section 6.1. 
• AE monitoring 
8.1.2.4. 
Procedures if melflufen is discontinued 
If melflufen is discontinued and the partner therapy is continued, the schedule of assessments 
should continue as outlined in the SoA, Section 8.1.2 and 8.1.3. The schedule of CBC and 
platelet evaluations may be conducted at the investigator’s discretion but must at a minimum be 
performed on Day 1 of each subsequent cycle and before each dose of daratumumab. Patients 
who discontinue melflufen and continue to be treated with the other drugs in the Regimen should 
also be followed for response, PFS, PFS-2 and OS. 
 
Procedures after active study treatment  
Patient will be treated until progressive disease (confirmed PD should be verified by Medical 
Monitor prior to discontinuation of therapy), unacceptable toxicity, consent withdrawal, or if the 
patient/treating physician determines it is not in the patient’s best interest to continue. Patients in 
Arm B with documented disease progression may have the option to crossover and receive 
treatment with melflufen, dexamethasone and daratumumab.   
An EOT visit will be scheduled within 30 days of the last dose of study drug. Patients that 
discontinue therapy for reasons other than disease progression will enter PFS follow-up. Patients 
who discontinue therapy for disease progression in Arm A will enter PFS-2 follow-up. Once 
disease progression has occurred, patients will enter the OS follow-up. Patient in Arm B will 
enter OS follow-up directly after confirmed disease progression in PFS follow-up. Patients in 
Arm B who are eligible for the crossover may have a combined EOT/initiation of crossover visit 
within 28 days of the last daratumumab dose in Arm B. Refer to SoA in Appendix 3 for details.   
Patients with Grade 3 or 4 thrombocytopenia or neutropenia should be followed until resolution 
to ≤ Grade 2 or start of subsequent therapy. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, not expected to resolve or the patient is lost to 
follow-up (as defined in Section 7.3).  
Patients who withdrew consent for treatment will continue to be followed for disease progression 
and/or survival unless they explicitly withdraw consent for these procedures. 
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required at each time point. 
8.1.3.1. 
Procedures at End of Treatment Visit 
EOT visit should be scheduled 30 days (accepted time window ±3 days) after last dose of study 
treatment or as soon as possible if the decision to remove patient from therapy occurs later than 
30 days after last dose (such as in the case of a prolonged cycle). For patients who are 
randomized but withdraw from study, for any reason, prior administration of any study drug the 
EOT visit should be completed as soon as possible after decision to remove patient from study 
(including withdrawal of consent to study treatment) has been made. 
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. For patients 
in Arm B who are eligible to crossover, the EOT visit should occur as soon as possible after 
confirmed disease progression and it may be combined with the initiation of the crossover visit 
(see SoA Appendix 3 for more details).  
Patients progressing while on treatment, require 2 consecutive M protein assessments at any time 
(including the same day for SPEP/FLC). The confirmed PD should be verified by the Medical 
Monitor 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). Patients in Arm B need to 
have the second assessment obtained before start of crossover.  
• PRO assessments (EORTC QLQ-C30 and EQ-5D-3L), prior to any examination/procedure. 
If the EOT is for a reason other than PD, the assessments should be continued, on any on-site 
visit, each month until PD and/or start of new anti-myeloma treatment. 
• PRO pain assessments (BPI-SF and NRS for measure of bone pain), prior to any 
examination/procedure. BPI-SF should be completed first and if patient has experienced 
pain, the NRS for measure of bone pain should be completed. If the EOT is for a reason other 
than PD, the assessments should be continued, on any on-site visit, each month until PD 
and/or start of new anti-myeloma treatment. 
• Physical examination; including and assessment for extramedullary myeloma.  
• Vital signs; including weight, blood pressure, pulse, respiratory rate and temperature. 
• ECOG performance status. 
• Pregnancy test; only for WOCBP. 
• 12-lead ECG, Q-Tc interval to be assessed by Fridericia formula.   
• Blood tests;   
o Hematology: CBC with differential and platelet count. 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric 
acid, blood urea nitrogen [BUN](or urea), serum creatinine, estimated creatinine 
clearance) (by Cockcroft-Gault Formula), glucose (non-fasting), ALT (SGPT), 
AST (SGOT), alkaline phosphatase, total protein, total bilirubin, albumin, and 
lactate dehydrogenase (LDH). 
• Blood sample for DNA/RNA sequencing should be collected in case of disease progression 
or response (CR or VGPR). 
• Blood sample for myeloma related bone disease biomarkers should be collected in case of 
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• Bone marrow samples to be taken if needed to confirm disease progression.  
See Laboratory Manual for additional information. 
• M protein and myeloma response assessments, see Section 8.2.1   
• Extramedullary myeloma assessment; known or suspected plasmacytomas should be 
assessed until disease progression. 
• Skeletal X-ray or low dose CT scan; as clinically indicated. 
• Concomitant medications review   
• AE monitoring; Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT visit are 
to be followed until resolution (≤ Grade 2) or initiation of subsequent therapy. All SAEs, will 
be followed until resolution, stabilization, the event is otherwise explained, not expected to 
resolve or the patient is lost to follow-up (as defined in Section 7.3). 
• Pharmacokinetic blood samples for daratumumab  
• Serum samples for immunogenicity (daratumumab) 
• Serum samples for immunogenicity (rHuPH20). 
• Whole blood samples for immunoprofiling. 
• Use of health services and hospitalization   
 
 
8.1.3.2. 
Procedures 8 weeks after last dose of daratumumab 
• Pharmacokinetic blood samples for daratumumab.  
• Serum samples for immunogenicity (daratumumab). 
• Serum samples for immunogenicity (rHuPH20). 
• Pregnancy test; only for WOCBP. 
• Instruct WOCBP to do a urine pregnancy test at home 12 weeks after last dose of 
daratumumab. 
These samples are not required for patients in Arm B who enter the crossover. 
 
8.1.3.3. 
Procedures during follow up 
8.1.3.3.1. Progression Free Survival Follow-Up 
• PRO assessments (EORTC QLQ-C30 and EQ-5D-3L), should be completed monthly on any 
on-site follow-up visit until PD and/or start of new anti-myeloma treatment. If PD and start 
of next treatment occur at the same time, only one assessment is required at that time. If the 
new treatment starts during OS follow-up, an additional assessment must be completed at 
that time. 
• PRO pain assessments (BPI-SF and NRS for measure of bone pain), monthly on any on-site 
follow-up visit until PD and/or start of new anti-myeloma treatment. If PD and start of next 
treatment occur at the same time, only one assessment is required at that time. If the new 
treatment starts during OS follow-up, an additional assessment must be completed at that 
time. BPI-SF should be completed first and if patient has experienced pain, the NRS for 
measure of bone pain should be completed.  
•   Blood sample for DNA/RNA sequencing should be collected at time of response (CR or 
VGPR) and at the time of disease progression. 


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• Blood sample for myeloma related bone disease biomarkers should be collected at PFS-FU. 
See Laboratory manual for additional information 
• Bone marrow samples to be taken if needed to confirm disease progression. 
• Extramedullary myeloma assessment; Known or suspected plasmacytomas should be 
assessed every 2 months until disease progression.  
• Skeletal X-ray or low dose CT scan; as clinically indicated. 
• M protein and myeloma response assessment;  
o Monthly until confirmed disease progression or initiation of next anti-myeloma 
treatment, for patients who discontinue study treatment for reasons other than disease 
progression. 
o Confirmed disease progression requires 2 consecutive M protein assessments at any 
time (including the same day for SPEP/FLC). The second assessment must be a 
separate serum and urine sample. If the second consecutive M protein sample only can 
be obtained after the start of subsequent therapy, it may be used as confirmation of 
PD. 
o The first assessment should be performed 4 weeks after the EOT visit. Serum calcium, 
albumin (corrected calcium) required if this is the presenting symptom of disease 
progression.  
o When disease progression has been confirmed, the patients will enter PFS-2 follow up. 
• Second primary malignancies follow-up. 
• For WOCBP: Collect and record any result of a urine pregnancy home test performed 12 
weeks after last dose of daratumumab on the following PFS-FU if not done separately by 
phone. 
• Use of health services and hospitalization   
 
8.1.3.3.2. Procedures during PFS-2 follow up 
Following documented disease progression on the study treatment, the patients will be followed 
for progression on the next line of treatment and secondary primary malignancies every 3 months 
+/-7days. Patients in Arm B with confirmed disease progression who continue and crossover to 
treatment with melflufen, daratumumab and dexamethasone will not be followed for PFS-2.  
During the follow up the below assessments should be recorded:  
• Subsequent therapy review; 
 
o Regimen (all individual drugs) 
o Start and stop dates  
o If PD has not been confirmed prior to the initiation of subsequent therapy, the reason for 
the subsequent therapy should be documented.   
o Best response  
o Date of disease progression per investigator review. 
• Second primary malignancies follow-up. 
 


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8.1.3.3.3. Procedures during Overall Survival follow-up 
Following PFS, patients will be contacted every 3 months +/- 7 days for OS for 24 months. 
Follow-up may be completed by phone, email, site visit or other method of contact. Death 
information from public sources, e.g. death registry, obituary listing, etc. can also be used when 
it is available and verifiable.   
PFS-2 and OS will be captured every 3 months until median PFS-2 has been reached, or a 
minimum of 24 months. Following 24 months, annual follow up of OS might be conducted and 
information can then be captured outside the eCRF, and as an addendum to the study report.   
8.2. Efficacy Assessments  
Time points for all efficacy assessments are provided in Section 8.1.    
 
Response Assessments 
Samples for response assessments should be sent to the central laboratory for analysis, except 
where specified, see also  central Laboratory Manual for instructions.   
• M protein assessments: 
o FLC levels (kappa/lambda) including dFLC (difference between involved FLC and 
uninvolved FLC) and FLC ratio (involved FLC/uninvolved FLC).   
 FLC assessment is not required in the presence of measurable SPEP and/or 
UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 mg/24 hours). 
 FLC is required to confirm sCR, regardless of type of measurable disease. 
o Electrophoresis 
 SPEP 
 UPEP 
o Immunofixation (IFE) 
 Serum immunofixation; 
- 
To be performed at baseline and at any time when M protein by SPEP 
becomes non-detectable to confirm CR. 
- 
Quantitative immunoglobulins should be included for patients with IgA 
and IgD myeloma. 
 Urine immunofixation 
- 
To be performed at baseline and at any time when M protein by UPEP 
becomes not detectable to confirm CR. 
o Daratumumab Immunofixation reflex Assay (DIRA) test, for patients with IgG kappa 
MM with M-protein assessment by SPEP. 
 ≤0.2 g/dL on 2 or more consecutive cycles.  
or 
 Not detectable M-protein, but persistently positive IFE for IgG kappa on 2 or 
more occasions. 
N.B. As daratumumab is a monoclonal IgG kappa antibody, the SPEP and IFE can be 
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• Serum calcium (corrected calcium to be performed at local laboratory). 
• Bone Marrow Aspirate: In patients with suspected CR or VGPR to confirm response and 
for MRD assessment, by next generation sequencing (NGS) .   
 
Skeletal X-rays and low-dose CT scans 
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 to or in place of conventional X-ray with 
the same technique to be used with each evaluation. Limited X-rays may be performed as 
clinically indicated to confirm PD.   
 
Extramedullary Myeloma (plasmacytoma) Assessment 
Known or suspected extramedullary myeloma (plasmacytomas) are to be assessed at screening, 
every 2 cycles and every 2 months during PFS-follow- up to disease progression.  
• Method(s) of evaluation should be able to provide bidimensional measurements and must 
be defined at baseline (for lesions present at screening); methods may include, CT scan or 
MRI physical examination or photography. Once the method is selected, extramedullary 
myeloma lesions should be evaluated with the same method throughout the trial.   
• Lesions will be assessed according to IMWG-URC guidelines (Kumar et al 2016). Other 
lesions, including visceral lesions should be evaluated by CT, scan or MRI as 
appropriate. 
• For skin lesions, only measurable lesions with a caliper should be reported. 
• Lesions that are evaluable but not measurable should be reported. These lesions should 
disappear completely in case of CR or increase in size in order to be reported as cause for 
disease progression.   
8.3. Safety Assessments  
Time points for all safety assessments are provided in Section 8.1, SoA and in Appendix 3 for 
patients in Arm B doing the crossover. 
 
Physical Examinations 
A physical examination, including assessment for extramedullary myeloma will be conducted at 
screening, Day 1 of each cycle and at the EOT visit. A symptom directed physical examination 
will be conducted as needed during treatment period. Plasmacytomas that can be followed by 
physical examination are to be evaluated on Day 1 of each cycle. The timing of the assessment is 
described in Section 8.1.   
The outcome of the assessments will be recorded as “normal” or “abnormal”. Abnormal findings 
will be assessed as “clinically significant” or “not clinically significant”. Clinically significant 
findings prior to first dose of study drug will be documented as Medical History. Clinically 
significant findings after screening will be documented as AE/SAEs. An asymptomatic abnormal 
physical examination finding should only be reported as an AE if it is clinically significant or if 
it fulfils the criteria for an SAE. If an abnormal physical examination finding is associated with 


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clinical signs and symptoms, the sign/symptom should be reported as an AE and the associated 
physical examination finding should be considered additional information.   
 
Vital Signs 
Vital signs will be measured, at the timepoint specified in Section 8.1 and SoA, will include 
height, weight, temperature, systolic and diastolic blood pressure, pulse and respiratory rate.   
The outcome of the assessments will be recorded as “normal” or “abnormal”. Abnormal findings 
will be assessed as “clinically significant” or “not clinically significant”. An asymptomatic 
abnormal vital sign finding should only be reported as an AE if it is clinically significant, or if it 
fulfils the criteria for an SAE. Vital sign abnormalities should only be reported using one event 
term. For example – a high blood pressure recording (systolic blood pressure of 180 mm Hg) and 
hypertension, both should not be used to record the AE. If an abnormal vital sign value is 
associated with clinical signs and symptoms, the sign/symptom should be reported as an AE and 
the associated vital sign result should be considered additional information. 
 
Electrocardiograms 
12-lead ECGs will be taken as outlined in Section 8.1 in supine position, after the patient has 
been lying down for at least three minutes. Q-Tc interval should be assessed by Fridericia 
formula. The Investigator (or a qualified observer at the investigational site) will interpret the 
ECG using one of the following categories: “normal” or “abnormal”. Abnormal findings will be 
assessed as “clinically significant” or “not clinically significant”.   
An asymptomatic abnormal ECG finding should only be reported as an AE if it is clinically 
significant or if it fulfils the criteria for an SAE. ECG abnormalities should only be reported 
using one event term. For example, an ECG recording of a rapid heart rate (a PR interval of 
120 ms) and tachycardia, both should not be used to record the AE.   
 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and Section 8.1 and SoA 
for the timing and frequency. All protocol-required laboratory safety assessments, as defined in 
Appendix 2, must be conducted in accordance with the Laboratory Manual and the SoA. For 
patients in Arm B who continue and crossover to treatment with melflufen, daratumumab and 
dexamethasone, see SoA in Appendix 3.  
A screening test 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 Investigator’s discretion or upon request of the Medical 
Monitor). Patients are required to have all laboratory evaluations completed at the study center 
during Cycle 1. Starting at Cycle 2, the 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. 
The investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 


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laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are defined in Section 8.4.7. 
All protocol specified laboratory assessments performed in addition to protocol specified time 
points must be recorded in the eCRF.  
Other laboratory values from non-protocol specified laboratory assessments considered clinically 
significant by the investigator, as defined in Section 8.4.7 or supportive of understanding the 
patient’s condition related to an AE or SAE must be recorded in the eCRF. See Section 8.4.7.1 
for additional laboratory reporting guidelines.  
8.3.4.1. 
Hepatitis and HIV assessments 
Hepatitis B, Hepatitis C and HIV assessments are required at screening. Patients with Hepatitis B 
both active (defined as HBsAg+) and non-active (HBsAg-, Anti-HBs+, Anti-HBc+), active 
Hepatitis C or HIV infections are excluded. 
 
Medical History and Myeloma history including characteristics 
A complete medical history will include evaluation for past or present cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, metabolic, lymphatic, 
hematologic, immunologic, dermatologic, psychiatric, and genitourinary disorders, medical-, 
surgical- and radiation history, and review of any other diseases or disorders. 
 
Concomitant Therapy or Medication 
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
required, recommended and prohibited medications are found in Section 6.5. 
 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status (Appendix 6) will be assessed 
at screening, at Cycle 1 Day 1, prior to administration of study treatment and at the EOT visit.  
 
Health Services and Hospitalizations 
Number of health services, and number and days of hospitalizations will be assessed from 
screening, on Day 1 of each cycle, at time of EOT visit and at follow up until start of new 
treatment. 
8.4. Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study treatment or study procedures, or that 
caused the patient to discontinue the study treatment.   


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Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the signing of the informed consent form (ICF) until 30 days 
after the last administration of any study drug. In patients not receiving any study drug, every 
SAE occurring until date of documentation of screen failure OR date of documentation of EOT 
must be reported.  
All AEs will be collected from the first dose of study drug until 30 days after the last study drug 
administration. 
AEs, including SAEs, attributable to subsequent therapy should not be recorded.   
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF and not on the AE section, unless it is an SAE.   
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in   Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting. The investigator will submit any updated SAE data to the Sponsor or 
designee within 24 hours of information being available.   
Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT visit are to be followed until 
resolution (≤ Grade 2) or initiation of subsequent therapy. All SAEs, will be followed until 
resolution, stabilization, the event is otherwise explained, not expected to resolve or the patient is 
lost to follow-up (as defined in Section 7.3). In addition to this, Investigators are not obligated to 
actively seek information regarding new AEs, including SAEs, after the EOT visit. However, if 
the investigator learns of any SAE, including a death, at any time after a patient has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor or designee.   
The method of recording, evaluating, and assessing causality of AEs, including SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.   
 
Method of Detecting AEs 
Care will be taken not to introduce bias when detecting AEs, including SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.   
 
Follow-up of AEs, including SAEs 
After the initial AE/SAE, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT 
visit are to be followed until resolution (≤ Grade 2) or initiation of subsequent therapy. All SAEs, 
will be followed until resolution, stabilization, the event is otherwise explained, not expected to 
resolve or the patient is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is given in Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting. 


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Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the safety of a 
study treatment under clinical investigation are met.   
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
An investigator who receives an Individual Case Safety Report, safety line listing or any other 
specific safety information from the Sponsor will review and then file it along with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements.   
 
Pregnancy 
Details of all pregnancies, that occur after the start of treatment until 3 months after last dose of 
study drug administration, in female patients and female partners of male patients will be 
collected.   
If a pregnancy is reported, the investigator should inform the Sponsor or designee within 24 
hours from learning of the pregnancy and should follow the procedures outlined in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered as SAEs. 
 
Fatal Events 
Death is an outcome of a serious adverse event and not a serious adverse event in itself. When 
death is an outcome, the event(s) resulting in death should be reported (e.g., “pulmonary 
embolism” with a fatal outcome). The appropriate diagnosis or term should be recorded and 
assigned severity Grade 5; 
In instances of death due to “Disease Progression” the cause of death should be indicated as the 
event or condition resulting in death to the extent possible (e.g., “respiratory failure” due to 
progressive MM);   
Deaths that occur later than 30 days after the last study drug administration should be reported as 
SAEs only if assessed as related to the study treatment. 
 
Laboratory Test Abnormalities 
Laboratory abnormalities are usually not recorded as AEs; however clinically significant 
laboratory abnormalities must be recorded as AEs (or serious AEs) if they meet the definition of 
an AE (or serious AE) as described in Appendix 4: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting.   


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Clinically significant laboratory abnormalities are those that: 
• Require concomitant therapy  
• Require medical intervention 
• Require change in study treatment 
• Investigator considers clinically significant for any reason 
The Investigator will record the grade of the clinically significant laboratory abnormality and 
will evaluate its relationship to the study drug and clinical condition. Laboratory AEs should be 
recorded using only one event term per event such as thrombocytopenia for low platelet count 
but not as both (thrombocytopenia and low platelet count). 
A positive COVID-19 (SARS-CoV-2) test should always be considered clinically significant. 
Reporting of COVID-19 infections is described in Appendix 4: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. Additional Laboratory 
Reporting Guidelines 
Extra attention should be given to reporting all Grade 3 and 4 platelet and neutrophil counts.  
They must be: 
• Collected and reported during the study period and the EOT visit; 
• Ongoing Grade 3 and 4 platelet and ANC values at the time of the EOT visit are to be 
followed until resolution (≤ Grade 2), or stabilization, or initiation of a subsequent therapy;  
• All ANC and platelet counts collected during the treatment period and until the EOT visit, 
i.e. both those collected at protocol specified time points and any additional time points 
(unscheduled assessments), must be reported in the eCRF and if applicable also as an 
AE/SAE;  
• All ANC and platelet counts associated with an SAE regardless of the nature of the event, 
must be reported in the details of the SAE report; 
• Supportive care such as platelet transfusions and G-CSF given for an AE or prophylactic 
reasons must be reported in the eCRF and if applicable also in the SAE report.   
Other laboratory values from non-protocol specified laboratory assessments considered 
clinically significant by the investigator, as defined in Section 8.4.7 or support understanding 
the patient’s condition related to an AE or SAE must be recorded in the eCRF. 
8.5. Treatment of Overdose 
For this study, any dose of melflufen greater than 30 mg per cycle (including 30 mg administered 
< 28 days [+/-3day window]) will be considered an overdose. 
The ponsor recommends supportive treatment with close observation of CBC in particular to 
platelets and neutrophil count in case of an overdose. Prophylactic measures and/or treatment of 
thrombocytopenia or neutropenia should be considered in the event of an overdose. Refer to 
concomitant therapy Section 6.5 for further guidance on antimicrobial prophylaxis in the case of 
severe neutropenia. 
In the case of an overdose of daratumumab or dexamethasone, please refer to the IB, Product 
information and SmPC, respectively for guidance.   


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In the event of an overdose (melflufen, dexamethasone or daratumumab), the investigator 
should:   
1. Contact the Medical Monitor immediately.   
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities until they no 
longer can be detected systemically (return to ≤ Grade 3).   
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.   
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient.   
8.6. Pharmacokinetic assessments  
 
Pharmacokinetic assessment melphalan 
PK samples will be collected in patients in Arm A. Three plasma samples for determination of 
melphalan concentrations will be drawn in each of the first two melflufen treatment cycles 
(Cycle 1 and 2), at the following time points according to Table 8-1:   
 
Table 8-1 
PK sampling timepoints melphalan 
 
Cycle 1 and 2 
Sample 1, timepoint 
5-10 minutes after the end of melflufen infusion   
Sample 2, timepoint 
1 hour after the end of melflufen infusion (+/- 5 min window 
allowed)  
Sample 3 timepoint 
2-4 hours after the end of melflufen infusion (as late as 
possible within the time frame) 
All PK samples must be drawn peripherally and not from the central catheter. Refer to the 
Laboratory Manual for details on sample collection and processing.  
 
Pharmacokinetic assessment daratumumab 
All PK samples must be drawn peripherally and not from the central catheter. Refer to the 
Laboratory Manual for details on sample collection and processing.  
Daratumumab PK samples will be collected in patients in Arm A and Arm B at pre-dose on Day 
1 of Cycle 1, 3, 7, and 12, on Day 4 in Cycles 1 and 3 and at End of treatment visit and at 8 
weeks after the last dose of daratumumab. Daratumumab PK samples will not be collected in 
patients in Arm B who crossover to treatment with melflufen, daratumumab and dexamethasone 
after they have initiated their new treatment regimen.  


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8.7. Immunogenicity 
 
Immunogenicity of Daratumumab 
Serum samples to be collected in both treatment arms at pre-dose on Day 1 of Cycle 1, 7, and 12, 
at the EOT and at visit 8 weeks after the last dose of daratumumab. It will be the same blood 
draw as for daratumumab PK. Daratumumab immunogenicity samples will not be collected in 
patients in Arm B who crossover to treatment with melflufen, daratumumab and dexamethasone 
after they have initiated their new treatment regimen.   
Refer to the Laboratory Manual for details on sample collection and processing.  
 
Immunogenicity of Recombinant Human Hyaluronidase 
Plasma for rHuPH20 immunogenicity will be collected in both treatment arms at pre-dose on 
Day 1 of Cycles 1, 7, and 12, at the EOT and at visit 8 weeks after the last dose of daratumumab. 
Plasma for rHuPH20 immunogenicity will not be collected in patients in Arm B who crossover 
to treatment with melflufen, daratumumab and dexamethasone after they have initiated their new 
treatment regimen.  
Refer to the Laboratory Manual for details on sample collection and processing.  
8.8. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9. Genetics 
Cytogenetic characterization of MM by karyotyping and iFISH and biomarker analysis (MRD 
assessment and DNA/RNA sequencing) described in Appendix 2Appendix 2Appendix 2 are 
planned to be conducted. No other genetic analysis will be performed as part of this study.  
8.10. Biomarkers 
Collection of samples for biomarker research is a part of the study and the following samples are 
required and will be collected from all patients in this study as specified in the SoA and in Table 
8-2. Samples are planned to be tested to identify biomarkers that predict the treatment outcome 
and detect patient subgroups that are likely to respond to the study drug(s). Analysis such as 
outlined in Table 8-2 and Sections 8.10.1, 8.10.2 and 8.10.3 are planned but may not be 
conducted if deemed as obsolete during later stages of the study; other exploratory analyses may 
be added based on emerging new findings. 


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Table 8-2 
Summary of biomarker assessments 
Marker 
Tissue 
Timepoint 
Method 
Purpose of 
analysis 
Minimal Residual Disease 
(MRD) 
Bone Marrow 
- Screening 
- At the time of response 
(CR and VGPR) 
Next Generation 
Sequencing 
Indicator of 
clinical outcomes 
and response to 
therapy. 
Novel biomarkers 
including expression of 
aminopeptidases/esterases 
 
Bone Marrow 
- Screening 
- At the time of response 
(CR and VGPR) 
- At the time of disease 
progression 
DNA/RNA 
sequencing 
Identify novel 
biomarkers that 
may predict 
response. 
 
Blood  
 
- Pre-dose, Cycle 1 day 
1. 
- At the time of response 
(CR and VGPR) 
 
- At the time of disease 
progression 
Circulating tumor 
cells DNA/RNA 
sequencing 
Biomarkers for myeloma-
related bone disease: 
TRACP‐5b 
Total RANK 
PINP 
Osteopontin 
Osteocalcin 
IL-6 
IL-10 
CTX 
Bone ALP 
 
Blood (serum) - Pre-dose, Day 1 of all 
cycles 
- End of treatment visit 
- During PFS-FU 
ELISA 
Surveillance of 
therapy effects on 
bone disease 
progression. 
Immunoprofiling 
Blood 
-Pre-dose Cycle 1 Day 1 
- Cycle 6 Day 1 
- End of treatment visit 
ELISA/flow 
cytometry 
Identify 
biomarkers of 
biologic activity of 
the therapy in 
specific 
subpopulations of 
immune cells. 
 
Samples may be stored for a maximum of 5 years (or according to local regulations) following 
the last patient’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to study treatment.  


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Minimal Residual Disease (MRD) assessment   
Minimal Residual Disease (MRD) refers to the number of malignant cells that remain in a patient 
during and following treatment. It is a reliable indicator of clinical outcomes and response to 
myeloma therapies (Kumar et al 2016). To follow the minimal residual disease in the treated 
patients, a diagnostic assay is used which utilizes next generation sequencing (NGS) to identify 
frequency and distribution of clonal sequences consistent with a malignant cell population in the 
bone marrow samples. MRD will be determined by detection and tracking of clonal 
rearrangement of immunoglobulin heavy chain variable region  (IGH FR1/FR2, FR3, and IGK) 
using most up to date Illumina platform at the time of the analysis with currently verified 
minimum sensitivity of 10−5 and achievable sensitivity of 10-6. 
Bone marrow aspirate, 1 mL, should be taken at screening and 3 mL at response (CR and VGPR) 
and sent to the central laboratory for analysis. Refer to the Laboratory Manual for complete 
details on sample collection, processing, storage and shipping. 
 
 
DNA/RNA Sequencing  
Sequencing studies are planned to be conducted using next generation sequencing. This will 
enable the evaluation of changes in DNA/transcriptome profiles that may correlate with 
biological response to the treatment (Jang et al. 2019). Aminopeptidases/esterases expression 
levels will be investigated in order to find correlations with observed response, in addition, it 
may be possible to identify novel biomarkers associated with response or disease progression. 
Due to possible challenges in obtaining an adequate amount of bone marrow aspirate for 
DNA/RNA analysis, an alternative experimental approach is taken utilizing single-cell RNA 
sequencing of circulating tumor cells, though minimally-invasive alternative, for monitoring 
tumor burden and response to treatment (Bustoros et al. 2017). 
For this approach 10 mL of blood will be collected and sent to the central laboratory for analysis, 
at the following timepoints (see Laboratory Manual for details): 
- 
Pre-dose, Cycle 1 Day 1 
- 
At the time of response (CR or VGPR) 
- 
At the time of disease progression (at EOT Visit or during PFS follow-up) 
   
Bone marrow aspirate and blood samples will not be used for other reasons than the 
identification of novel biomarkers by sequencing analysis. Samples may be stored for up to 5 
years. 
 
Biomarkers for myeloma-related bone disease  
Biomarkers that reflect the activity of the cell types in the bone marrow microenvironment 
contributing to myeloma-related bone disease are suitable for surveillance of response, treatment 
effects, and disease progression (Bhutani et al. 2015).  
Biomarkers planned to be analyzed, all previously reported increased in myeloma patients and 
correlated with the extent of bone disease, include: 


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• TRACP‐5b  
• PINP 
• Total RANK 
• Osteopontin 
• Osteocalcin 
• IL-6/IL-10 
• CTX/bone ALP ratio  
A blood sample, 7.5 mL, for serum isolation will be collected, and sent to the central laboratory 
for analysis, at the following timepoint (see Laboratory Manual for details): 
- 
Day 1 of all treatment cycles 
- 
EOT Visit 
- 
PFS-FU Visits 
Biomarkers will be measured in undiluted serum using a validated enzyme-linked 
immunosorbent assay (ELISA) according to the standard manufacturer's protocols. Serum 
samples will not be used for other reasons than to evaluate the performance of the biomarkers in 
the prediction of therapy response. Samples may be stored for up to 5 years. 
8.11. Immunophenotyping/Immunoprofiling 
The goal of the biomarker analysis is to evaluate the pharmacodynamics and aid in evaluating 
the drug-clinical response relationship.  
Evaluation of blood biomarkers may provide evidence for biomarkers of biologic activity of 
melfulfen+daratumumab in patients with MM. Flow cytometry will be performed to 
immunophenotype T-cells and to characterize changes in CD38+ Tregs and CD38+ MDSCs in 
response to treatment. These cells have been shown to express CD38 and can be depleted by 
daratumumab in patients with multiple myeloma (Krejcik 2016) and play a role in 
daratumumab’s mechanism of action. 
Serum samples for immunoprofiling will be collected in both treatment arms pre-dose on Day 1 
of Cycle 1,  Day 1 of Cycle 6, and at the EOT visit. 
8.12. Patient Reported Outcome assessments  
Patient reported outcome assessments include EORTC QLQ-C30, EQ-5D-3L, BPI-SF, NRS for 
measure of bone pain and use of health services and hospitalization. The patient should complete 
the questionnaires prior to any procedures on the day of the visit and prior to any study visit 
activities (tests, examination or treatment). The questionnaires should be administered even if the 
treatment is not given. If the patient wishes to have the questions read out loud and then answer 
orally, and the study personnel write the answers on the questionnaires, this is acceptable. 
For pain assessment the BPI-SF should be completed first and only if the patient confirms pain 
has been experienced, the NRS for measure of bone pain should be completed. The NRS for 
measure of bone pain is a non-validated questionnaire about experienced muscle pain and bone 
pain. 


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Table 8-3 
Timepoints for patient reported outcome assessments 
Timepoint 
EORTC QLQ-
C30 
EQ-5D-3L 
BPI-SF 
 
NRS for 
measure of bone 
pain 
(in case patient 
indicated pain in 
BPI-SF) 
Health services 
and 
hospitalization 
Screening 
 
 
 
X 
Day 1, All cycles 
X 
X 
X 
X 
Day 15, Cycle 1-3 
 
X 
X 
 
End of treatment 
visit 
X 
X 
X 
X 
Follow Up until 
Start of new 
Treatment 
X 
X 
X 
X 
Crossover  
(Refer to SoA 10.3) 
X 
X 
X 
X 
 
If PD/EOT and start of next anti-myeloma treatment occur at the same time, only one assessment 
is required at that time. If the EOT is for a reason other than PD, the assessments should be 
continued, on any on-site visit, each month until PD and/or start of new treatment. If the new 
treatment starts during OS follow-up an additional assessment must be completed at that time. 
See Section 8.1.   
9. 
Statistical Considerations  
9.1. Statistical Hypotheses 
The primary objective with this study is to show superiority of PFS in patients treated with 
melflufen and dexamethasone in combination with daratumumab (Arm A) compared to 
daratumumab alone (Arm B). Superiority will be demonstrated if the p-value from the statistical 
test is lower than 0.05 (i.e. the upper limit of the 95 % confidence interval for the hazard ratio is 
<1). All statistical tests will be two-sided, and have a null hypothesis of no difference between 
treatment arms for the applicable endpoint. See Section 9.4.5 for a description of multiplicity 
adjustments. 


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9.2. Sample Size Determination  
The sample size of 200 patients was calculated based on achieving 90% power to observe a 
statistically significant result for comparing the treatment arms in terms of PFS, using a log-rank 
test for two survival curves and the parameter assumptions presented in Table 9-1 
Assuming a dropout rate of approximately 15%, it is anticipated to randomize 120 patients in 
each treatment arm, to a total number of 240 patients.  
The randomization will be stratified by number of previous lines of treatment (<3 prior lines of 
treatment versus ≥3 prior lines of treatment) previous treatment with daratumumab or another 
anti-CD38 antibody (no previous treatment versus previous treatment).  
The final analysis will take place when 160 patients have experienced a PFS event. 
 
.Table 9-1 
Sample Size Determination 
Parameter 
Assumption 
Power 
90% 
Significance level 
5%, two-sided 
Hazard Ratio (Arm A / Arm B) 
0.60 
Distribution of survival curves 
Exponential 
Method  
Lakatos normal approximation 
Accrual time 
24  months 
Follow up time 
6 months after last patient randomized 
Total study time 
18 months 
Median PFS for Arm A 
6.7 months 
Median PFS for Arm B 
4.0 months 
The assumptions for this sample size estimation are based on  preliminary data from an ongoing 
Phase 1/2 study (ANCHOR OP-104) and a pooled analysis of two open-label Phase 1/2 studies 
of daratumumab monotherapy (IB for melflufen, Usmani et al. 2016). 


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9.3. Populations 
For purposes of analysis, the following populations are defined: 
Analysis Population 
Description 
Enrolled Population 
Includes all screened patients, i.e. patients having completed 
assessments and procedures during screening as outlined in 
Section 8.1.1. The Enrolled population will include 
randomized patients and  non- randomized patients (defined 
as screening failures) and will be used for summaries of 
disposition.   
Full analysis set (FAS) 
Includes all patients who are randomized. Analyses will be 
performed according to the treatment assigned at 
randomization. The primary endpoint and all secondary 
efficacy endpoints will be based on FAS. 
Safety Analysis Set 
Includes all patients in the FAS with at least one exposure to 
any study drug. Analyses will be performed according to the 
treatment actually received. 
Pharmacokinetic Analysis Set Includes all patients in FAS who received at least 1 dose of 
daratumumab or for melflufan  includes all patients in FAS 
who received at least 1 dose of melflufen and have 3 samples 
with measurable concentrations in at least one treatment cycle.  
Analyses will be performed according to the treatment 
actually received. 
Per Protocol Analysis Set 
 
The Per Protocol Analysis Set includes all patients in the FAS 
who have received at least 1 dose of study medication. 
Patients who have  important protocol deviations, related to 
critical eligibility criteria, the assessment of efficacy or the 
safety of the patient who could significantly impact the 
interpretation of study result, will be excluded from the PPAS. 
The PPAS will be used for sensitivity analyses of selected 
efficacy variables as described later in the SAP. 
Analyses will be performed according to the treatment 
actually received. 
QoL Analysis Set 
All patients who received at least 1 dose of melflufen or 
daratumumab respectively and have evaluable changes in QoL 
parameters. Analyses will be performed according to the 
treatment actually received. 


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9.4. Statistical Analyses 
The statistical analyses outlined in this section will be further described in the Statistical 
Analysis Plan (SAP). Statistical analyses will be performed using programming in SAS® 
version 9.4 or higher, and will be presented as summary tables, 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.   
 
Efficacy Analyses of the Primary Endpoint 
The primary endpoint PFS is defined as the duration in months from the date of randomization 
until first documentation 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 conventions adapted from the FDA Guidance for Industry, Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics and the FDA Guidance for 
Industry, Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics.  
The primary statistical analysis of PFS will be performed using a  Log-rank test stratified by the 
randomization stratification factors. The Cox proportional hazard will be used to estimate the 
hazard ratio for melflufen+dexamethasone+daratumumab versus daratumumab and its 95% 
CI.The distribution of PFS will be summarized using Kaplan-Meier method. The median PFS 
will be estimated for each treatment arm as  the 50th percentile of the corresponding Kaplan-
Meier estimates. 95% CI will be based on the log(-log(survival)) distribution. 
 
 
Efficacy Analyses of Key Secondary Endpoints 
The analysis of the key secondary efficacy endpoints will be performed using statistical methods 
with multiple control describe in section 9.4.5  
There are two key secondary endpoints: 
1. ORR (proportion of patients who achieve a best confirmed response of stringent 
Complete Response (sCR), Complete Response (CR), Very Good Partial Response 
(VGPR) or Partial Response (PR)). 
2. DOR (time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to 
first confirmed disease progression, or death due to any cause. DOR is defined only for 
patients with a confirmed PR or better). 
ORR will be presented together with 95% exact binomial confidence intervals based on the 
Clopper-Pearson method. The treatment groups will be compared using the Cochran-Mantel 
Haenszel test stratified by the randomization stratification factor. DOR will be performed using 
Kaplan-Meier method. The median time to event will be estimated for each treatment arm from 
the 50th percentile of the corresponding Kaplan-Meier estimates. 95% confidence intervals will 
be based on the log(-log(survival)) distribution. 


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Efficacy Analyses of other Secondary Endpoints 
Response rates ( Best response and CBR  ) and other dichotomous parameters will be presented 
together with 95% exact binomial confidence intervals based on the Clopper-Pearson method. 
The treatment groups will be compared using the Cochran-Mantel Haenszel test stratified by the 
randomization stratification factor.  
Time-to-event analyses ( DOCB, TTR, TTP,TTNT and OS ) will be performed using Kaplan-
Meier method. The median time to event  will be estimated for each treatment arm from the 50th 
percentile of the corresponding Kaplan-Meier estimates. 95% confidence intervals will be based 
on the log(-log(survival)) distribution.  
 
Efficacy Analyses of Exploratory Endpoints 
Response rates (CR and PR) and other dichotomous parameters will be presented together with 
95% exact binomial confidence intervals based on the Clopper-Pearson method. The treatment 
groups will be compared using the Cochran-Mantel Haenszel test stratified by the randomization 
stratification factors.  
Time-to-event analyses (PFS-2) will be performed using Kaplan-Meier method. The median time 
to event will be estimated for each treatment arm from the 50th percentile of the corresponding 
Kaplan-Meier estimates. 95% confidence intervals will be based on the log(-log(survival)) 
distribution. Stratified log-rank test will be applied for PFS-2 the same way as for the primary 
PFS analysis. 
The number and percentage of patients with MDR or not in patient achieve CR or better will be 
presented. 
For EQ-5D-3L the number and percentage of patients for each score within the dimension will 
be presented, including shift table from baseline to post-baseline assessments. 
Changes in parameters for QoL (QLQ-C30 summary score, each scale of the EORTC QLQ-C30, 
EQ-5D-3L utility index, each dimension of the EQ-5D-3L, EQ-5D-3L VAS, BPI-SF and NRS) 
will be analyzed using repeated-measures mixed-models. Changes in QoL parameters will be 
dependent variables, treatment arm will be fixed effect, and treatment cycle will be repeated 
effect. QoL parameters and additional fixed effects will be further described in the SAP. 
To evaluate efficacy in patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone after disease progression on daratumumab, the response rate 
(ORR and CBR) and time to event (DOR, DOCB, TTR, TTP, TTNT and OS)) will be presented 
descriptively with 95 % confidence interval.  Time to event will be calculated from date of first 
treatment after crossover. 
 
Multiplicity 
. 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. The full procedure will be 
described in the SAP. 


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Analyses of Pharmacokinetic Data 
PK parameters for melphalan will be derived using non-compartmental analysis in Phoenix 
WinNonLin®.Statistical analysis of pharmacokinetic (PK) parameters will be performed of the 
parameters maximum observed concentration, Area under the concentration versus time curve 
from 0 h to infinity and elimination half-life dependent variables. Results will be described using 
descriptive statistics and correlations analyses with patient factors. 
PK parameters for daratumumab will be analyzed descriptively.  
 
Safety Analyses 
Study treatment administration, including duration of exposure, total dose, dose modifications 
and all AE reporting will be summarized for each group separately, and also separately for 
patients in Arm B who crossover to treatment with melflufen, daratumumab and dexamethasone.  
Each reported AE term will be mapped to a preferred term (PT) and a system organ class (SOC) 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  The 
summaries of adverse events (AEs) will be based on TEAEs. TEAEs are defined as AEs that 
start on or after the first day of study treatment is administered and within 30 days of the last 
administration of study treatment or before start of subsequent anticancer treatment (whichever 
occurs first) or that worsen on or after the first day of study treatment.   
The number (%) of patients experiencing TEAEs will be summarized by MedDRA SOC and PT. 
The denominator for the percentage will be based on the number of patients in the Safety 
analysis set. A patient reporting the same AE more than once will be counted only once when 
calculating incidence 1) within a given SOC, and 2) within a given SOC and PT combination. 
For such cases, the maximum CTCAE toxicity grade and strongest causal relationship to study 
treatment for the event will be used in the incidence calculations. Treatment-related AEs, defined 
as AEs with a relationship of possibly or probably related will be summarized in the same way. 
Summaries of TEAEs and treatment-related AEs will be provided according to maximum 
toxicity grade. Grade 3 or higher TEAEs and treatment-related AEs, serious AEs, and TEAEs 
resulting in permanent discontinuation of study treatment will be provided.   
Grade 3 and 4 thrombocytopenia and neutropenia will be evaluated to determine their frequency, 
duration, relationship to treatment 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 5.0. 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 vital sign results, including weight, blood pressure, 
pulse, and temperature, will be summarized at each scheduled visit. Any clinically significant 
values will be reported by the investigator as AEs. 
 


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Other Analyses  
Immunogenicity analyses of daratumumab and rHUPH20 will be described and presented 
separately from the main clinical study report (CSR). 
Biomarker exploratory analyses will be described and presented separately from the main 
clinical study report (CSR). The following subgroups will be analyzed separately: 
• Patients with <3 prior lines of treatment and ≥3 prior lines of treatment respectively 
• Patient double-refractory to an IMiD and PI or not, respectively 
• Patients previously treated with anti-CD38 antibody or not, respectively 
• Patients with extramedullary disease 
 
Handling of dropouts and missing data 
The SAP will describe 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, determination of whether a medication is concomitant or an AE is treatment-
emergent), the date will be imputed. Details of methods of imputation will be provided in the 
SAP. 
9.5. Interim Analyses  
No interim analyses will be performed. 
 
Data Monitoring Committee 
Safety and tolerability will be reviewed regularly during the study. This review will be done by 
an independent Data Monitoring Committee (DMC), and will be based on aggregate data 
summaries where the randomized treatment allocation is disclosed. Access to this data will be 
restricted to the members of DMC. Scope of work, procedures, roles and responsibilities for the 
DMC is described in a separate DMC charter to ensure independence and minimize potential 
bias in the evaluation of unblinded data. The DMC can recommend continuing the study, with or 
without modifications, or stop the study based on benefit/risk concerns. 
 
Independent Review Committee 
All response assessments, including PD will be assessed by an Independent Review Committee 
(IRC) using the IMWG response criteria. The IRC members will be blinded to all treatment data 
(including investigator response) and perform their reviews in closed-meeting sessions. The IRC 
members will be provided with patient-level data summaries where treatment is blinded. Scope 
of work, procedures, roles and responsibilities for the IRC is described in a separate IRC Charter 
to ensure independence.  


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


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The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
All patients must sign an (IRB/IEC/REB)-approved informed consent form within 28 days of 
enrollment and prior to any study related procedures. A copy of the ICF(s) must be provided to 
the patient or the patient’s legally authorized representative.  
A patient who is rescreened is not required to sign another ICF if the rescreening occurs within 
28 days from the previous ICF signature date. 
Patients in Arm B who are eligible to crossover to treatment with melflufen, daratumumab and 
dexamethasone must sign an IRB/IEC/REB approved informed consent before the new treatment 
is started.  
 
Data Protection 
Patient will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
 
Dissemination of Clinical Study Data 
Oncopeptides AB assures that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.  
The 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. 
 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or electronic CRF (eCRF) unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
The data collection tool for the study will be a validated, internet based, electronic data capture 
system (EDC) software system called RAVE.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  


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


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Publication Policy 
• The results of this study will be published and potentially be presented at scientific 
meetings. The Sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publications of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
• The investigators agree to submit any subsequent manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
 
 


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10.2. Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 10-1will be performed.  
• Investigators must document their review of each laboratory report. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5 of the protocol. 
• Please refer to the Laboratory Manual for details on sample collection, processing and 
shipment. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• During the study, blood and bone marrow will be drawn at the study visits. Limited 
volumes will be taken at each single occasion. Approximate, maximum volume per 
sample type and study visit have been listed in Table 10-2. See Section 8.1 for sample 
collection timepoints.  
Table 10-1 
Protocol-Required Laboratory Assessments 
Laboratory Laboratory 
Assessment 
Parameters 
Local 
Laboratory 
Hematology  
• 
Platelet Count  
• 
Red Blood Cell (RBC), Erythrocytes Count 
o 
Hemoglobin 
o 
Hematocrit 
• RBC, Erythrocytes Indices:  
o 
Mean Corpuscular Volume (MCV) 
o 
Mean Corpuscular Hemoglobin (MCH) 
o 
% Reticulocytes 
• White blood Cell (WBC), Leukocytes count with 
Differential: 
o 
Neutrophils 
o 
Lymphocytes 
o 
Monocytes 
o 
Eosinophils 
o 
Basophils 


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Laboratory Laboratory 
Assessment 
Parameters 
 
Clinical Chemistry  
• Alanine Aminotransferase (ALT) also known as Serum 
Glutamic-Pyruvic Transaminase (SGPT) 
• Albumin 
• Alkaline Phosphatase (ALP) 
• Aspartate Aminotransferase (AST), also known as Serum 
Glutamic-Oxaloacetic Transaminase (SGOT) 
• Blood Urea Nitrogen (BUN) or Urea 
• Calcium 
• Chloride 
• Creatinine (in serum) 
• Creatinine Clearance (by Cockcroft-Gault formula) 
• Glucose (fasting at baseline) 
• Lactase Dehydrogenase (LDH) 
• Magnesium 
• Phosphate 
• Potassium 
• Sodium 
• Total Bilirubin 
• Total Protein 
• Uric Acid 
Local 
Laboratory 
Blood type and 
screen  
Interference with cross-
matching 
Prior to daratumumab administration. 
Red Blood Cell 
Antibody screening 
Hepatitis B/C and 
HIV screen  
Hepatitis B surface 
Antigen 
 
Anti - Hepatitis B core 
Antigen 
Anti - Hepatitis B 
surface Antigen  
Anti-HCV antibody 
 
Anti-HIV1/2 
antibody/antigen 
 
Pregnancy test  
Serum or urine human 
Chorionic Gonadotropin 
(hCG) pregnancy test  
 
Coagulation 
• Prothrombin 
Time (PT) 
 


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Laboratory Laboratory 
Assessment 
Parameters 
• International 
Normalized 
Ratio (INR) 
Urinalysis 
Specific gravity 
 
pH 
By dipstick. 
Glucose 
Protein 
Blood 
Ketones 
Microscopic 
examination 
If blood or protein is abnormal. 
Central 
Laboratory 
Other blood tests  
β2-microglobulin 
 
M-protein 
assessment -  
24 hr urine sample  
Urine Protein 
Electrophoresis (UPEP) 
 
Urine Immunofixation 
(U-IFE); 
At screening and if UPEP are not 
detectable and to confirm CR. 
M-protein 
assessment - Serum  
Serum Protein 
Electrophoresis (SPEP) 
 
Serum Immunofixation 
(S-IFE) 
At screening and if SPEP are not 
detectable and to confirm CR. 
Free Light Chain 
(SFLC)  
• Kappa 
• Lambda 
• Ratio 
 
DIRA 
For patients with IgG kappa multiple 
myeloma with an SPEP: 
- ≤0.2 g/dL on 2 or more 
consecutive cycles or 
- No detectable M-protein, but 
persistently positive IFE for 
IgG kappa on 2 or more 
occasions 
Quantitative 
Immunoglobulins 
• IgA 
• IgD 
• IgE 
• IgG 
- To be repeated at Day 1 in all 
cycles for IgA and IgD 
myeloma. 


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Laboratory Laboratory 
Assessment 
Parameters 
• IgM 
 
Bone Marrow tests 
% plasma cells 
 
Cytogenetics 
By karyotyping and interphase 
Fluorescence In-Situ Hybridization 
(iFISH). Mandatory iFISH probes 
include t(4;14), t(14;16), t(14;20), 
del(17/17p), gain(1q). 
 
Morphology 
 
MRD 
By Next Generation Sequencing. 
DNA/RNA Sequencing 
 
Pharmacokinetic 
blood test 
melphalan 
 
For patients in Arm A (not applicable 
after crossover). 
Pharmacokinetic 
blood test 
daratumumab and 
daratumumab 
immunogenicity 
 
For patients in Arm A and Arm B (not 
applicable after crossover). 
rHUPH20 
immunogenicity 
blood test 
 
For patients in Arm A and Arm B (not 
applicable after crossover). 
Immunoprofiling 
samples whole 
blood 
 
For patients in Arm A and Arm B (not 
applicable after crossover). 
Biomarker blood 
test 
Biomarkers for 
myeloma-related bone 
disease  
• TRACP‐5b  
• Total RANK 
• Osteopontin 
• Osteocalcin 
• IL-6/IL-10 
• CTX/bone ALP 
ratio  
• PINP 
 
For patients in Arm A and Arm B (not 
applicable after crossover). 


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Laboratory Laboratory 
Assessment 
Parameters 
DNA/RNA Sequencing  
Circulating tumor cells and/or 
sequencing of the circulating free 
tumor DNA. 
 
 
 


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Table 10-2 
Blood and Bone Marrow Volumes  
Assessment 
Screening 
Days -21 
to -1 
Regimen A and B, All Cycles 
(except where specified) 
End of 
Treatment 
8 weeks after 
last dose of 
daratumumab 
PFS-FU 
OS and PFS2-FU  
Day 1 
Day 4 
Day 8 
Day 15 
Day 22 
Pregnancy test, 
WOCBP only 
X 
X 
 
 
 
 
X 
X 
X 
 
RBC typing and 
antibody screening  
X 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
(X) 
X 
(X) 
X 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
DNA/RNA 
sequencing in blood  
 
X  
 
 
 
 
(X) 
 
(X) 
 
Biomarkers for 
myeloma related 
bone disease in 
blood 
 
X 
 
 
 
 
X 
 
X 
 
Chemistry 
X 
X 
 
 
 
 
X 
 
(X) 
 
Hepatitis B, C and 
HIV screen 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspiration  
X 
(X) 
 
 
 
 
(X) 
 
(X) 
 
M protein 
assessment 
Xa 
X 
 
 
 
 
X 
 
X 
 
Pharmacokinetic 
samples melphalan,  
Arm A only 
 
(X) 
 
 
 
 
 
 
 
 


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Assessment 
Screening 
Days -21 
to -1 
Regimen A and B, All Cycles 
(except where specified) 
End of 
Treatment 
8 weeks after 
last dose of 
daratumumab 
PFS-FU 
OS and PFS2-FU  
Day 1 
Day 4 
Day 8 
Day 15 
Day 22 
Pharmacokinetic 
samples 
daratumumab 
 
(X) 
(X) 
 
 
 
X 
X 
 
 
Immunogenicity 
samples 
daratumumab 
 
(X) 
 
 
 
 
X 
X 
 
 
Immunogenicity 
samples rHUPH20  
 
(X) 
 
 
 
 
X 
X 
 
 
Immunoprofiling 
samples whole 
blood 
 
(X) 
 
 
 
 
X 
 
 
 
Approximate 
Blood Volume per 
visit (mL) 
50 
75 
5 
15 
15 
15 
75 
10 
30 
15 
Approximate Bone 
Marrow Volume 
per visit (mL) 
10 
(10) 
 
 
 
 
(10) 
 
(10) 
 
(X) if indicated 
a) Including β2 Microglobulin 


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10.3. Appendix 3:  Optional crossover for patients in Arm B to treatment 
with melflufen, dexamethasone and daratumumab 
Patients in Arm B who are confirmed to have disease progression while receiving daratumumab 
alone may be eligible to crossover and receive treatment with melflufen, dexamethasone and 
daratumumab, using the daratumumab dosing schedule at the time of disease progression.  
Study Treatment after 
crossover:Melflufen 
30 mg (i.v.) 
 
Daratumumab 1800 mg (s.c.)b, c 
 
Dexamethasone (p.o.)a 
 
All cycles: Day 1 
Dosing Schedule at time of disease 
progression to be continued: 
If Cycle 1 and 2: Days 1, 8, 15 and 22 
If Cycle 3 to 6: Days 1 and 15 
If Cycle 7+: Day 1 
40 mg weekly for patients < 75 
years of age  
20 mg weekly for patients ≥75 
years of age  
a) For additional details on dexamethasone administration see Section 6.1.3.  
b) Premedication should be administered to prevent infusion/administration related reactions (see Section 
6.1.4.1.1). 
c) Post-medication may be administrated to minimize administration related reactions according to Section 
6.1.4.1.2. 
 
Criteria for initiation of treatment following crossover 
Prior to initiation of treatment with melflufen, dexamethasone and daratumumab, patients who 
crossover must continue to meet eligibility criteria and the entry criteria as follows:  
1. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol; 
2. Confirmed progressive disease. There should be a documented PD according to the 
IMWG-URC guidelines (Kumar et al.2016) to be confirmed on two consecutive 
assessments (if PD due to increase in M-protein), and verified by the Medical Monitor 
prior to treatment discontinuation, see Appendix 8. 
3. Adequate organ function with the following laboratory results during initiation 
visit/EOT Arm B (within 28 days) and immediately before study treatment 
administration on Cycle 1 Day 1 following crossover: 
• ANC ≥ 1,000 cells/ mm3 (1.0 x 109/L)  


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• Platelet count ≥ 50,000 cells/ mm3 (50 x 109/L) (without transfusion during the 
previous 5 days to initiation of therapy). Thrombopoietin receptor agonists are 
not permitted, see Section 6.5.3.   
4. For patients who crossover,  treatment with melflufen, dexamethasone and 
daratumumab must be started within 56 days from the last daratumumab dose in Arm 
B.  
5. All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except 
peripheral neuropathy Grade 1 without pain, alopecia and fatigue ≤ Grade 2). 
 
6. a) Male patients: Male patient who agrees to use contraception as detailed in this 
protocol during the treatment period and for at least 3 months after the last dose of 
study treatment and refrain from donating sperm during this period.   
 
b) Female patients: A female patient is eligible to participate if she is not pregnant, 
not breastfeeding, and at least one of the following conditions applies: 
i. 
Not a woman of childbearing potential (WOCBP) or 
ii. 
A WOCBP who agrees to follow the contraceptive guidance in the protocol 
during the treatment period and for at least 3 months after the last dose of study 
treatment. 
 
Criteria Day 1, Subsequent cycles 
• ANC must be ≥ 1,000 cell/mm3 (1.0 x109/L). For administration of growth factors, see 
Section 6.6.1.2. 
• All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except 
peripheral neuropathy Grade 1 without pain, alopecia and fatigue ≤ Grade 2). 
• Absence of daratumumab IRR that require discontinuation (Grade 4 or Grade 3 on three 
occurrences in the previous cycle, see Section 6.6.3.3.1).   
• Platelet count: 
o Platelet count must be ≥ 50,000 cell/mm3 (50.0 x 109/L) (platelet transfusions not 
recommended within ≤ 5 days of dosing (see Section 6.5.2). For patients who 
have discontinued melflufen but remain on daratumumab and dexamethasone the 
platelet count must be ≥ 25,000 cell/mm3 (25.0 x 109/L). 
If these criteria are not met on the scheduled Day 1, the new cycle should be held, and patients 
should be re-evaluated weekly. Refer to Section 6.6.3 for guidelines on dose modification due to 
drug related toxicity.   
The maximum amount of time for which study treatment may be held due to drug related toxicity 
is 28 days from a scheduled Day 1 (Day 57). If study treatment is not administered for more than 
28 days due to drug related toxicity, the patient will be removed from the study treatment and 
enter follow up phase. If the patient was clearly benefiting from treatment, the patient may be 


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able to continue treatment at the Investigator’s discretion and in consultation with the Medical 
Monitor, after resolution of the AE.   
 
Dose Modification and Reduction Steps 
Dose reduction steps for melflufen and dexamethasone are outlined in Section 6.6.2.            
There are no dose reduction steps for daratumumab.                                                                 
Dose modifications for toxicity and management of infusion related reactions are outlined in 
Section 6.6.3.  
 
Study Procedures  
Patients in Arm B with confirmed disease progression may receive melflufen, dexamethasone 
and daratumumab treatment if they are willing and eligible per criteria listed in 10.3.1.  All 
patients who crossover must sign and date an IRB/IEC/REB approved informed consent form 
within 28 days of initiating treatment with melflufen, dexamethasone and daratumumab and 
prior to any study related procedure. After providing written informed consent, the patients will 
be evaluated for eligibility. 
Once a patient is determined to be eligible, treatment with melflufen, dexamethasone and 
daratumumab has to start within 56 days from the last dose of daratumumab in Arm B.   
10.3.4.1. Crossover initiation visit 
The EOT visit after completion of Arm B treatment could be combined with the crossover 
initiation visit and should be performed within 28 days of last dose of daratumumab. The 
following assessments will be performed in addition to those completed during the EOT visit:  
• Sign and date an IRB/IEC/REB approved informed consent form for the crossover.  
• Evaluate criteria per Section 5.1 if patient is eligible for initiation of melflufen and 
dexamethasone treatment in addition to the current daratumumab dosing schedule.  
• β2-microglobulin 
• Concomitant medications review 
• AE monitoring 
10.3.4.2. Procedures Day 1 during crossover  
The following study procedures will be performed during active study treatment at the times 
specified. All study procedures are applicable at all cycles unless otherwise specified.   
• Criteria for initiation of therapy should be fulfilled, see Section 6.6.1.  
• PRO assessments (EORTC QLQ-C30 and EQ-5D-3L), prior to any study visit activities 
(tests, examination or treatment). The questionnaires should be administered even if the 
treatment is not given, see Section 8.12. 
• PRO pain assessments (BPI-SF and NRS for measure of bone pain), prior to study visit 
activities (tests, examination or treatment). BPI-SF should be completed first and if patient 
has experienced pain, the NRS for measure of bone pain should be completed. The 
questionnaires should be administered even if the treatment is not given, see Section 8.12.   


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• Physical examination; including assessment for extramedullary myeloma. Plasmacytomas 
that can be followed by physical examination should also be evaluated each cycle with 
measurements documented in the source documents.  
• Vital signs, including blood pressure, pulse, respiratory rate, temperature, should be assessed 
before melflufen dose as well as before and after daratumumab dosing. Weight should be 
assessed prior to melflufen dose.  
• ECOG performance status   
• Pregnancy test; only for WOCBP   
• Blood tests: 
o Hematology: CBC with differential and platelet count. 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric 
acid, blood urea nitrogen [BUN](or urea), serum creatinine, estimated creatinine 
clearance (by Cockcroft-Gault Formula), glucose (non-fasting), ALT (SGPT), 
AST (SGOT), alkaline phosphatase, total protein, total bilirubin, albumin, and 
lactate dehydrogenase (LDH).  
• Bone marrow aspiration; at the time of CR/VGPR, the below samples should be obtained in 
the following order and sent to the central laboratory for analysis. See Laboratory Manual for 
additional information. 
1. 
% plasma cells and morphology including immunohistochemistry 
2. 
3 mL for MRD assessment  
3. 
DNA/RNA sequencing 
• Concomitant medications review   
• M-protein assessments described in Section 8.2.1 is planned pre-dose Day 1 of each cycle 
(day 29 of prior cycle) and with assessment of myeloma response from Cycle 2. If treatment 
is delayed, an assessment should still be made at day 29 and should be repeated prior to next 
cycle if the delay is 2 weeks or longer, and to confirm any response or PD.  
• Extramedullary myeloma assessment; Known or suspected plasmacytomas should be 
assessed, using the same method as at screening, every 2 cycles up to disease progression. 
• Skeletal X-ray or low-dose CT scan; as clinically indicated. 
• Administration of study treatment; see Section 6.1.  
• Use of health services and hospitalization 
• AE monitoring  
10.3.4.3. Procedures Day 8, 15 and 22 visits 
If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive 
therapy (G-CSF, blood or platelet transfusion) in the two preceding cycles, then Day 8 and Day 
22 will not be required for the respective cycle.  
• Physical examination: symptom directed as needed during treatment.   
• Vital signs; including blood pressure, pulse, respiratory rate, temperature, to be assessed 
before and after each daratumumab infusion (see Section 6.1.4 for daratumumab 
administration schedule).  
• Blood tests: 


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o Hematology: CBC with differential and platelet count. If patient tolerability is 
good, i.e. no dose modifications, dose delays or need of supportive therapy (G-
CSF, blood or platelet transfusion) in the two preceding cycles, then Complete 
Blood Count assessments may be excluded at Day 8 and Day 22. 
• Concomitant medications review 
• Administration of study treatment, see Section 6.1. 
• AE monitoring 
10.3.4.4. Procedures after active study treatment  
Patients will be treated until progressive disease (confirmed PD should be verified by Medical 
Monitor prior to discontinuation of therapy), unacceptable toxicity, consent withdrawal, or if the 
patient/treating physician determines it is not in the patient’s best interest to continue. 
An EOT visit will be scheduled within 30 days of the last dose of study drug. Patients who 
discontinue therapy for reasons other than disease progression will enter PFS follow-up. Patients 
who discontinue therapy for disease progression will enter the OS follow-up. 
Patients with Grade 3 or 4 thrombocytopenia or neutropenia should be followed until resolution 
to ≤ Grade 2 or start of subsequent therapy. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, not expected to resolve or the patient is lost to 
follow-up (as defined in Section 7.3).  
Patients who withdrew consent for treatment will continue to be followed for disease progression 
and/or survival unless they explicitly withdraw consent for these procedures. 
10.3.4.5. Procedures at End of Treatment Visit 
EOT visit should be scheduled 30 days (accepted time window ±3 days) after last dose of study 
treatment or as soon as possible if the decision to remove patient from therapy occurs later than 
30 days after last dose (such as in the case of a prolonged cycle). For patients who are 
randomized but withdraw from study, for any reason, prior administration of any study drug, the 
EOT visit should be completed as soon as possible after decision to remove the patient from 
study (including withdrawal of consent to study treatment) has been made. 
If a new treatment for MM is to be introduced sooner than 30 days after last dose of study drug, 
the EOT visit should occur as close as possible before the first dose of the new drug. 
Patients progressing while on treatment, require 2 consecutive M protein assessments at any time 
(including the same day for SPEP/FLC). The confirmed PD should be verified by the Medical 
Monitor 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). 
• PRO assessments (EORTC QLQ-C30 and EQ-5D-3L), prior to any examination/procedure. 
If the EOT is for a reason other than PD, the assessments should be continued, on any on-site 
visit, each month until PD and/or start of new anti-myeloma treatment. 
• PRO pain assessments (BPI-SF and NRS for measure of bone pain), prior to any 
examination/procedure. BPI-SF should be completed first and if patient has experienced 


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pain, the NRS for measure of bone pain should be completed. If the EOT is for a reason other 
than PD, the assessments should be continued, on any on-site visit, each month until PD 
and/or start of new anti-myeloma treatment. 
• Physical examination; including and assessment for extramedullary myeloma.  
• Vital signs; including weight, blood pressure, pulse, respiratory rate and temperature. 
• ECOG performance status. 
• Pregnancy test; only for WOCBP 
• 12-lead ECG, Q-Tc interval to be assessed by Fridericia formula.   
• Blood tests;   
o Hematology: CBC with differential and platelet count. 
o Chemistry: sodium, chloride, potassium, magnesium, calcium, phosphate, uric 
acid, blood urea nitrogen [BUN](or urea), serum creatinine, estimated creatinine 
clearance) (by Cockcroft-Gault Formula), glucose (non-fasting), ALT (SGPT), 
AST (SGOT), alkaline phosphatase, total protein, total bilirubin, albumin, and 
lactate dehydrogenase (LDH). 
o Blood sample for DNA/RNA sequencing. 
See Laboratory Manual for additional information. 
• M protein and myeloma response assessments, see Section 8.2.1.   
• Bone marrow aspirate (BMA) should be collected to confirm CR/VGPR or if needed to 
document PD 
• Extramedullary myeloma assessment; known or suspected plasmacytomas should be 
assessed until disease progression. 
• Skeletal X-ray or low dose CT scan; as clinically indicated. 
• Concomitant medications review.   
• AE monitoring; Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EOT visit are 
to be followed until resolution (≤ Grade 2) or initiation of subsequent therapy. All SAEs, will 
be followed until resolution, stabilization, the event is otherwise explained, not expected to 
resolve or the patient is lost to follow-up (as defined in Section 7.3). 
• Use of health services and hospitalization. 
 
10.3.4.6. Procedures during Progression Free Survival follow-up in crossover 
During the follow up, the below assessments should be recorded:  
• PRO assessments (EORTC QLQ-C30 and EQ-5D-3L), should be completed monthly on any 
on-site follow-up visit until PD and/or start of new anti-myeloma treatment. If PD and start 
of next treatment occur at the same time, only one assessment is required at that time. If the 
new treatment starts during OS follow-up, an additional assessment must be completed at 
that time. 
• PRO pain assessments (BPI-SF and NRS for measure of bone pain), should be completed 
monthly on any on-site follow-up visit until PD and/or start of new anti-myeloma treatment. 
If PD and start of next treatment occur at the same time, only one assessment is required at 
that time. If the new treatment starts during OS follow-up, an additional assessment must be 
completed at that time. BPI-SF should be completed first and if patient has experienced pain, 


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the NRS for measure of bone pain should be completed.  
• Blood sample for DNA/RNA sequencing should be collected in case of disease progression. 
See Laboratory manual for additional information. 
• Bone marrow aspirate (BMA) should be collected to confirm CR/VGPR or if needed to 
document PD 
• Extramedullary myeloma assessment; Known or suspected plasmacytomas should be 
assessed every 2 months until disease progression. 
• Skeletal X-ray or low dose CT scan; as clinically indicated. 
• M protein and myeloma response assessment;  
o Monthly until confirmed disease progression or initiation of next anti-myeloma 
treatment, for patients who discontinue study treatment for reasons other than disease 
progression. 
o Confirmed disease progression requires 2 consecutive M protein assessments at any 
time (including the same day for SPEP/FLC). The second assessment must be a 
separate serum and urine sample. If the second consecutive M protein sample can only 
be obtained after the start of subsequent therapy, it may be used as confirmation of 
PD. 
o The first assessment should be performed 4 weeks after the EOT visit. Serum calcium, 
albumin (corrected calcium) required if this is the presenting symptom of disease 
progression.  
• Second primary malignancies follow-up. 
• For WOCBP: Collect and record any result of a pregnancy home test performed at 8 and 12 
weeks after last dose of daratumumab on the following PFS-FU if not done separately by 
phone. The 8 and 12-weeks pregnancy test can be taken at home, and site can contact the 
patient for follow-up by phone. 
• Use of health services and hospitalization. 
10.3.4.7. Procedures during Overall Survival follow-up in crossover 
Following PFS, patients will be contacted every 3 months +/- 7 days for OS for 24 months. 
Follow-up may be completed by phone, email, site visit or other method of contact. Death 
information from public sources, e.g. death registry, obituary listing, etc. can also be used when 
it is available and verifiable.   
• Subsequent therapy review; 
 
o Regimen (all individual drugs) 
o Start dates  
o If PD has not been confirmed prior to the initiation of subsequent therapy, the reason for 
the subsequent therapy should be documented.   
OS will be captured every 3 months until a minimum of 24 months. Following 24 months, 
annual follow up of OS might be conducted, and information can then be captured outside the 
eCRF and as an addendum to the study report.   


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Table 10-3 
Schedule of Activities (SoA) Crossover Arm B 
 
Assessment Crossover  
Crossover 
initiation 
visit  
Day  
(-28 to -1  
Regimen Crossover, All Cycles 
(except where specified) 
End of Treatment 
Visit r 
PFS -
FU w  
OS s 
End of 
Study 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±3 days 
±3 days 
±3 days 
±3 days 
±7 
days 
±7 
days 
 
Informed consent a 
X 
 
 
 
 
 
 
 
 
Criteria for initiation of melflufen, 
daratumumab and dexamethasone 
treatmentb 
X 
 
 
 
 
 
 
 
 
Physical examination c  
 
X 
(X) 
(X) 
(X) 
X 
 
 
 
Vital signs d 
 
X 
(X) 
(X) 
(X) 
X 
 
 
 
ECOG performance status 
 
X 
 
 
 
X 
 
 
 
Pregnancy test e 
 
X 
 
 
 
X 
X 
 
 
M protein assessment (and 
myeloma response assessment 
from Cycle 2) f 
 
X 
 
 
 
X 
X 
 
 


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Assessment Crossover  
Crossover 
initiation 
visit  
Day  
(-28 to -1  
Regimen Crossover, All Cycles 
(except where specified) 
End of Treatment 
Visit r 
PFS -
FU w  
OS s 
End of 
Study 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±3 days 
±3 days 
±3 days 
±3 days 
±7 
days 
±7 
days 
 
β2-microglobulin 
X 
 
 
 
 
 
 
 
 
Hematology g 
 
X  
X 
X 
X 
X 
 
 
 
Chemistry h 
 
X  
 
 
 
X 
(X) 
 
 
Blood sample for DNA/RNA 
sequencing t  
 
 
 
 
 
(X) 
(X) 
 
 
Bone marrow aspiration i 
 
(X) 
 
 
 
(X) 
(X) 
 
 
12- lead Electrocardiogram j  
 
 
 
 
 
X 
 
 
 
Extramedullary myeloma 
(plasmacytoma) assessment k 
X (only if 
not done at 
EOT) 
(X) 
 
 
 
(X) 
(X) 
 
 
Lytic bone lesion assessment: 
skeletal X-ray or low-dose CT l 
X (only if 
not done at 
EOT) 
(X) 
 
 
 
(X) 
(X) 
 
 


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Assessment Crossover  
Crossover 
initiation 
visit  
Day  
(-28 to -1  
Regimen Crossover, All Cycles 
(except where specified) 
End of Treatment 
Visit r 
PFS -
FU w  
OS s 
End of 
Study 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±3 days 
±3 days 
±3 days 
±3 days 
±7 
days 
±7 
days 
 
Criteria for initiation of 
therapy/new cycle m 
 
X 
 
 
 
 
 
 
 
PRO assessments (EORTC QLQ-
C30 and EQ-5D-3L) u 
 
X 
 
 
 
X 
X 
 
 
PRO Pain Assessments (BPI-SF, 
NRS) x 
 
X 
 
 
 
X 
X 
 
 
Dexamethasone administration and 
review of patient compliance  
 
X 
X 
X 
X 
 
 
 
 
Melflufen administration 
 
X 
 
 
 
 
 
 
 
Daratumumab administration 
according to treatment schedule  
 
X 
(X) 
(X) 
(X) 
 
 
 
 
Use of health services and 
hospitalization v  
 
X 
 
 
 
X 
X 
 
 


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Assessment Crossover  
Crossover 
initiation 
visit  
Day  
(-28 to -1  
Regimen Crossover, All Cycles 
(except where specified) 
End of Treatment 
Visit r 
PFS -
FU w  
OS s 
End of 
Study 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
 
Visit Window 
 
±3 days 
(except 
Cycle 1) 
±3 days 
±3 days 
±3 days 
±3 days 
±7 
days 
±7 
days 
 
Concomitant medications n 
X 
 
        X 
 
 
 
AE monitoring o 
X 
 
       X 
 
 
 
Subsequent therapy review p 
 
 
 
X 
X 
 
End of study information q 
 
 
 
 
 
X 
 (X)  
Only if indicated (see footnotes and treatment schedule). 
 
a) All patients who crossover must sign an (IRB/IEC/REB)-approved ICF within 28 days of initiation of treatment with melflufen, dexamethasone and 
daratumumab and prior to any study related procedures. 
b) Patients are eligible to crossover if all the criteria specified in section 10.3.1 of Appendix 3 apply. 
c) A physical examination, including assessment for extramedullary myeloma will be conducted at the crossover initiation visit/ End of Treatment (EOT) 
visit. A symptom directed physical examination will be conducted as needed during treatment period. 
d) Vital signs including blood pressure, pulse, respiratory rate, temperature will be assessed at each dosing day before melflufen dose and before and after 
daratumumab dosing and at EOT visit. Weight will be assessed at Day 1 of each cycle and at EOT visit. 
e) All WOCBP must have a negative serum urine pregnancy test prior to the initiation of therapy at each cycle. Pregnancy test also be taken at EOT visit, 8 
weeks after last dose of daratumumab and at 12 weeks after last dose of daratumumab. The 8 and 12-weeks urine test can be taken at home, and site can 
contact the patient for follow-up by phone. 


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f) 
SPEP, UPEP, serum and urine Immunofixation ((IFE) if SPEP or UPEP are not detectable and to confirm a CR), quantitative immunoglobulins (Igs) 
and SFLC assay (only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hours and SPEP is < 0.5 g/dL]) are to be conducted at 
initiation, pre-dose Cycle 1 Day 1 and prior to each cycle even if treatment is delayed. Quantitative Igs need to be repeated for patients with IgA or IgD 
myeloma for all response assessments. In the event treatment is delayed 2 weeks, response assessments are required to be repeated on the day the new 
cycle starts. If treatment is discontinued at or beyond ≥ 6 weeks (Day 43) the response assessments should be repeated on the day of the decision (or as 
soon as possible ≥ 30 days after last dose of study drug) as part of the EOT visit. Daratumumab Interference Reflex Assay (DIRA) test should be 
conducted in patients with IgG kappa MM with SPEP 
o 
≤0.2 g/dl on 2 or more consecutive cycles   
o 
OR 
o 
at zero, but persistently positive IFE for IgG kappa on 2 or more occasions 
g) Hematology: Complete Blood Count (CBC) with differential, and platelet count should be taken at each dosing day of all cycles, prior to initiation of 
therapy, and at the EOT visit. If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive therapy (G-CSF, blood or 
platelet transfusion) in the two preceding cycles, then CBC assessments may be excluded at Day 8 and Day 22. 
h) Chemistry should be taken at Day 1 of all cycles, at the EOT visit, prior to initiation of therapy. During PFS-FU serum calcium and albumin (corrected 
calcium) are required if evidence of PD.  
i) 
Bone marrow aspirate (BMA) should be collected to confirm CR/VGPR or if needed to document PD. See Protocol and Laboratory manual. 
j) 
A 12-lead ECG will be performed at initiation/EOT Arm B and at end of treatment of the crossover. Q-Tc interval to be assessed by Fridericia formula. 
k) Known or suspected extramedullary myeloma (plasmacytomas) are to be assessed, with the same method at EOT of Arm B or at the crossover initiation  
visit if not done at EOT visit, and every 2 cycles up to disease progression. 
l) 
Lytic bone lesion assessment: skeletal X-ray or low-dose CT scan should be performed when clinically indicated. Limited X-rays may be performed to 
confirm PD. 
m) Evaluate if the treatment should be given, delayed, or held. See Protocol Section 6.6.1 and 10.3.2. 
n) Concomitant medications and procedures: All blood products and medications within 21 days prior to first dose in Arm B until the EOT visit (end of 
crossover) should be recorded. 
o) SAEs will be collected from signing of the ICF in the main study until 30 days after last dose of study treatment or initiation of subsequent therapy 
whichever occurs first. AEs will be collected from the start of study treatment until 30 days after the last dose of any study drug (melflufen, 
dexamethasone or daratumumab) or initiation of subsequent therapy whichever occurs first. 
p) Subsequent therapy review including regimen (all individual drugs), start and stop dates. If PD has not been confirmed prior to the initiation of 
subsequent therapy, the reason for the subsequent therapy, best response, and date of disease progression per investigator review. 
q) Patient study end date and primary reason for ending study will be collected. 


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r) 
EOT visit should be scheduled 30 days after last dose of study treatment or as soon as possible if the decision to remove patient from therapy occurs 
later than 30 days after last dose (such as in the case of a prolonged cycle). 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. 
s) 
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 at least 24 months. 
t) 
Blood sample for DNA/RNA sequencing should be collected at the time of disease progression. 
u) EORTC QLQ-C30 and EQ-5D-3L should be completed 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. See Protocol for details. 
v) Use of health services and days of hospitalization will be completed by the patient on Day 1 of each cycle, at time of EOT visit and at follow-up until 
start of new treatment. To be completed prior to any procedures on the day of the visit and prior to being told anything related to health. 
w) Schedule the first PFS assessment 4 weeks after the EOT visit. Patients who discontinue therapy for reasons other than disease progression should 
continue to have monthly disease assessments done until documented disease progression or initiation of subsequent therapy. See Section 10.3.4.6.  
x) BPI-SF and NRS for measure of bone pain. The patient should complete the questionnaires prior to any procedures, and prior to dexamethasone dosing, 
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.  
BPI-SF should be completed first and if patient has experienced pain, the NRS for measure of bone pain should be completed. The questionnaires 
should be submitted to patients at Day 1 of each cycle. The questionnaires should also be submitted at the time of EOT visit, at the time of disease 
progression and at the time of starting a new treatment (day 1 of new treatment). 
 


 
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10.4. Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study patient, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment. 
 
Events Meeting the AE Definition  
• 
Any clinical significant laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.  
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or 
SAE. 


 
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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition. 
• 
The disease/disorder being studied or expected progression.  
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be a SAE even if serious conditions 
are met. 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
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• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the assigned safety CRO, TFS, in lieu of completion of the SAE form and 
AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the assigned safety CRO. In this case, all patient identifiers, with the 
exception of the patient number, will be redacted on the copies of the medical 
records before submission to the assigned safety CRO. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Severity 


 
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The investigator will make an assessment of severity/intensity for each AE and SAE 
reported during the study. Whenever possible, the CTCAE version 5.0 should be used to 
describe the event and for assessing the severity of AEs. Any events representing a 
change in the CTCAE Grade need to be reported on the AE eCRF. This includes any 
abnormal laboratory values that the investigator considers clinically significant see 
Section 8.4.7.  
For AEs not adequately addressed in the CTCAE, the following severity grading should 
be used. 
Severity 
Description 
Grade 1 – Mild 
Transient or mild discomfort; no limitation in activity; no 
medical intervention/therapy required. 
Grade 2 – Moderate 
Mild to moderate limitation in activity some assistance may 
be needed; no or minimal medical intervention/therapy 
required. 
Grade 3 – Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
Grade 4 - Life-threatening 
Extreme limitation in activity, significant assistance 
required; life-threatening (immediate risk of death); 
significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
Grade 5 – Fatal 
Death 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of a SAE, NOT when it is rated as severe.  
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (for melflufen and 
daratumumab) and Product Information/SmPCs (for Dexamethasone), in his/her 
assessment. 


 
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• 
Causality should be assessed using the following categories: 
Causality 
Description 
Unrelated 
Clinical event with an incompatible time 
relationship to investigational agent 
administration, and that could be explained by 
underlying disease or other drugs or chemicals or 
is incontrovertibly not related to the 
investigational agent; 
Possibly related: 
Clinical event with a reasonable time relationship 
to investigational agent administration, and that is 
unlikely to be attributed to concurrent disease or 
other drugs or chemicals; 
Probably related 
Clinical event with plausible time relationship to 
investigational agent administration, and that 
cannot be explained by concurrent disease or 
other drugs or chemicals. 
 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
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 
8.4.7). 
• 
There may be situations in which a SAE has occurred, and the investigator has 
minimal information to include in the initial report to the assigned Safety CRO. 
However, it is very important that the investigator always makes an assessment 
of causality for every event before the initial transmission of the SAE data to the 
assigned Safety CRO. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 


 
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assigned safety CRO to elucidate the nature and/or causality of the AE or SAE as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to the assigned safety CRO 
within 24 hours of receipt of the information. 
 
 
 
SAE Reporting to assigned Safety CRO, TFS; via Paper SAE reporting form 
• 
Facsimile or email transmission of the SAE paper reporting form is the preferred 
method to transmit this information to the assigned Safety CRO via email to 
safety.report@oncopeptides.com or facsimile (local fax numbers are provided in 
the Investigator Site File) 
• In rare circumstances and in the absence of facsimile or email equipment, 
notification of the CRA or Medical Monitor by telephone is acceptable with a 
copy of the SAE data collection tool sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found in SAE report completion instruction in 
the Investigator Site File. 
 
 
COVID-19 reporting 
Positive COVID-19 tests are considered clinically significant and must always be 
reported as a separate AE.  
AE verbatim: ‘COVID-19 Test Positive’ 
Start date: Date the positive COVID-19 test was taken 
Stop date: Date the subsequent negative COVID-19 test was taken. 
COVID-19 related AEs shall be reported like any other non-serious or serious AE, i.e. as 
specific as possible. 


 
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If an AE is due to COVID-19, the verbatim shall start with ‘COVID-19’, e.g. 
“COVID-19 related pneumonia”, “COVID-19 related renal failure”. 
 
Conclusion COVID-19 reporting: 
Symptomatic COVID-19 shall be reported as two separate AEs: 
One AE for the COVID-19 related event 
One AE for the positive COVID-19 test (‘COVID-19 Test Positive’) 
 
Asymptomatic COVID-19 (no clinical signs and symptoms and a positive COVID-19 
test) shall be reported as two separate AEs: 
One AE for the COVID-19 related event (‘Asymptomatic COVID-19 infection’) 
One AE for the positive COVID-19 test (‘COVID-19 Test Positive’) 
 
 
 


 
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10.5. Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  Lack of menses as a result of chemotherapy does not constitute 
menopausal status.    
Contraception Guidance: 
Male patients  
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following from the start of the first dose of study drug until 3 months after 
the last dose of study drug, 
• Are abstinent from penile vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 10-4 when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 
Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration for 
the duration of the treatment and for 3 months after last dose of study drug. 
 


 
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In addition, male patients must refrain from donating sperm for the duration of the treatment and 
for 3 months after last dose of study drug. 
It is not known if melflufen may cause permanent sterility. Therefore, male patients may wish to 
consider cryo-preservation of semen before initiating therapy with melflufen.  
 
Female patients  
Female patients of childbearing potential are eligible to participate if they, from the start of the 
first dose of study drug until 3 months after the last dose of study drug, agree to use a highly 
effective method of contraception consistently and correctly as described in Table 10-4. 
Table 10-4 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the patient.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for patients participating in clinical studies.  


 
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b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, two highly effective methods of contraception should be 
utilized during the treatment period and for at least 3 months after the last dose of study treatment.  
 
Pregnancy Testing: 
• 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
• 
Additional pregnancy testing is required on Day 1 of each cycle during the treatment period 
and at the End of Treatment visit and as required locally. 
• 
Pregnancy testing should also be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• 
Pregnancy testing should be performed at the local laboratory.  
Collection of Pregnancy Information: 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported on the study specific Pregnancy reporting 
form. A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy related SAE, considered reasonably related to the study treatment by 
the investigator, will be reported to the Sponsor or designee as described in Section 8.4.4. While 
the investigator is not obligated to actively seek this information in former study patients , he or 
she may learn of an SAE through spontaneous reporting.  
Male patients with partners who become pregnant  
• 
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is receiving melflufen and for 3 
months after the last dose of study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor or designee within 24 hours from learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and the child will be forwarded to the 
Sponsor or designee. Generally, the follow-up will be no longer than 6 to 8 weeks following 
the estimated delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure.  
Female patients who become pregnant  
• 
The investigator will collect pregnancy information on any female patient who becomes 
pregnant after start of study drug and until 3 months after last dose of study drug. 
Information will be recorded on the appropriate form and submitted to the Sponsor or 


 
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designee within 24 hours from learning of a patient’s pregnancy. The patient will be 
followed to determine the outcome of the pregnancy. The investigator will collect follow-up 
information on the patient and the neonate and the information will be forwarded to the 
Sponsor or designee. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• 
Any female patient who becomes pregnant while on study drug will discontinue study 
treatment. 
 
Pregnancy Reporting to assigned Safety CRO, TFS; via Paper Pregnancy Reporting 
Form 
• 
Facsimile or email transmission of the Pregnancy paper Reporting Form is the 
preferred method to transmit this information to the assigned Safety CRO via 
email to safety.report@oncopeptides.com or facsimile (local fax numbers are 
provided in the Investigator Site File) 
• In rare circumstances and in the absence of facsimile or email equipment, 
notification of the CRA or Medical Monitor by telephone is acceptable with a 
copy of the Pregnancy data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Pregnancy CRF pages within the designated reporting time 
frames. 
• Contacts for Pregnancy reporting can be found in Pregnancy report completion 
instruction available in the Investigator Site File. 


 
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10.6. Appendix 6: Eastern Cooperative Oncology Group (ECOG) 
Performance Scale 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 


 
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10.7. Appendix 7: NCI CTCAE Version 5.0 
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute 
(NCI) v5.0. Publish Date: (v5.0: Nov 27, 2017)  
• https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/ 
• https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf  
 
 


 
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10.8. Appendix 8: IMWG Uniform Response Criteria 
Response 
IMWG criteria (Kumar et al., 2016) 
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 hours.   
• 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 hours. 
• If the serum and urine M-protein are unmeasurable, a > 50% decrease in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria. 
• If serum and urine M-protein are not measurable, and serum free light 
assay is also not measurable, > 50% reduction in plasma cells is required 
in place of M-protein, provided baseline bone marrow plasma cell 
percentage was > 30%. 
• In addition to the above listed criteria, if present at baseline, a > 50% 
reduction in the size of soft tissue plasmacytomas is also required. 
Minimal 
Response  
(MR) 
• ≥25% but < 49% reduction of serum M protein and reduction in 24-hour 
urine M protein by 50 – 89%, which still exceeds 200 mg/24 hours. 
• In addition to above; if present at baseline, 25-49% reduction in the size of 
soft tissue plasmacytomas is also required. 


 
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EBMT 
Criteria 
• No increase in size or number of lytic bone lesions (development of 
compression fractures does not exclude response). 
Stable Disease 
(SD) 
• Not meeting criteria for CR, VGPR, PR, MR or progressive disease. 
Progressive 
Disease 
(PD) 
- Increase of > 25% from lowest response value in any one of the 
following: Serum M-protein (the absolute increase must be > 0.5 
g/dL) and/or  
- Urine M-protein (the absolute increase must be > 200 mg/24 hours) 
and/or  
• Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL. 
• Only in patients without measurable serum and urine M-protein and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute % must be ≥ 10%).  
• Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas. 
• Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder. 
 
All response categories require two consecutive assessments made at any time before the 
institution of any new therapy; all response categories also require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. VGPR and CR 
categories require serum and urine studies regardless of whether disease at baseline was 
measurable in serum, urine both or either. Radiographic studies are not required to satisfy these 
response requirements. Bone marrow assessments need not to be confirmed. For progressive 
disease, serum M-protein increases of ≥ 1 g/dL are sufficient to define relapse if starting M-
protein is ≥ 5 g/dL. 
IMWG clarification for coding PD: The 25% increase refers to M-protein, FLC, and bone 
marrow results and does not refer to bone lesions, soft tissue plasmacytomas or hypercalcemia. 
Note the lowest response value does not need to be a confirmed value. 
Daratumumab interference with determination of complete response 
Daratumumab is a human IgG kappa mAb that can be detected on both, the serum protein 
electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of 
endogenous M-protein. This interference can impact the determination of complete response and 
of disease progression in some patients with IgG kappa myeloma protein. As daratumumab is a 


 
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monoclonal IgG kappa antibody, the SPEP and IFE can be positive for daratumumab. For 
patients with IgG kappa multiple myeloma with an SPEP at or below 0.2 g/dL on 2 or more 
consecutive cycles, or zero, but persistently positive IFE for IgG kappa on 2 or more occasions, 
the DIRA test must be completed. 
 
 


 
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10.9. Appendix 9: Line of Therapy Definition 
According to the IMWG Consensus panel 1 on uniform reporting criteria in clinical trials 
(Rajkumar, 2011, Rajkumar 2015), a line of therapy consists of at least 1 or more cycles of a 
planned treatment regimen. This may consist of single-agent or combination therapy or a 
sequence of treatments administered in a planned manner.  For example, a planned induction, 
followed by ASCT followed by maintenance is considered one line of therapy. A new line of 
therapy starts when a planned course is modified to include other treatment agents as a result of 
disease progression, relapse or toxicity or when a planned period of observation is interrupted by 
the need for additional treatment of the disease.    
Modification of drug doses or resuming therapy after holding will not be considered a new line 
of therapy provided that there was no evidence of progression of disease as defined in the 
IMWG-URC guidelines. The definition is further clarified by Rajkumar et al, 2015. 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens (e.g., 
3-6 cycles of initial therapy with bortezomib-dexamethasone [VD] followed by stem cell 
transplantation [SCT], consolidation, and lenalidomide maintenance is considered as 1 line of 
therapy). 
• New line of therapy 
• A treatment is considered a new line of therapy if any 1 of the following 3 
conditions are met:  
• Start of a new line of treatment after discontinuation of a previous line: If a 
treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. A regimen is considered to 
have been discontinued if all the drugs in that given regimen have been stopped. 
A regimen is not considered to have been discontinued if some of the drugs of the 
regimen, but not all, have been discontinued. 
• The unplanned addition or substitution of 1 or more drugs in an existing regimen: 
Unplanned addition of a new drug or switching to a different drug (or 
combination of drugs) due to any reason is considered a new line of therapy. 
• SCT: In patients undergoing >1 SCT, except in the case of a planned tandem SCT 
with a predefined interval (such as 3 months), each SCT (autologous or 
allogeneic) should be considered a new line of therapy regardless of whether the 
conditioning regimen used is the same or different. We recommend that data on 
type of SCT also to be captured. 
 
 


 
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10.10. 
Appendix 10: ISS and R-ISS Score 
 
Standard Risk Factors for MM and the Revised -ISS (R-ISS)   
Prognostic Factor 
Criteria 
ISS Stage 
Stage I 
Serum B2-microglobulin < 3.5 mg/L, serum 
albumin ≥ 3.5 g/dL 
Stage II 
Not ISS stage I or III 
Stage III 
Serum B2-microglobulin ≥ 5.5 mg/L 
Chromosomal abnormalities (CA) by interphase florescent in situ hybridization (iFISH) 
High Risk  
Presence of del(17p) and/or translocation of 
t(4:14) and/or translocation of t(14:16) 
Standard Risk 
No high risk CA 
LDH 
Normal  
Serum LDH < upper limit of normal 
High 
Serum LDH > upper limit of normal 
A new model for risk stratification of MM R-ISS 
Stage I  
ISS stage I and standard risk CA by iFISH 
and normal LDH 
Stage II 
Not R-ISS stage I or III 
Stage III 
ISS stage III and either high risk CA by 
iFISH or high LDH 
(Palumbo et al. 2015) 


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


 
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10.12. 
Appendix 12: Assessment of Q-Tc interval 
Q-Tc Fridericia Formula: 
 
10.13. 
Appendix 13: Estimated Creatinine Clearance by 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 and Gault 1976 
 


 
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10.14. 
Appendix 14:  EQ-5D-3L 
https://euroqol.org/wp-content/uploads/2019/10/Sample_UK__English__EQ-5D-
3L_Paper_Self_complete.pdf 
 
10.15. 
Appendix 15:  EORTC QLQ-C30 
https://www.eortc.org/app/uploads/sites/2/2018/08/Specimen-QLQ-C30-English.pdf 
 
10.16. 
Appendix 16:  BPI-SF 
http://www.npcrc.org/files/news/briefpain_short.pdf 
 
 
 


 
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10.17. 
Appendix 17:  NRS for measure of bone pain 
 


 
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10.18. 
Appendix 18:  Use of health services and hospitalization 
 
 
 
 
 


 
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10.19. 
Appendix 19: Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
ADP 
Adenosine diphosphate 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase/Alanine aminotransferase, also known as glutamic 
pyruvic transaminase (SGPT) 
ANC 
Absolute Neutrophil Count 
Anti-HBc- 
Anti-hepatitis B core antibody negative 
Anti-HBs- 
Anti-hepatitis B surface antibody negative 
Anti-HBc+ 
Anti-hepatitis B core antibody positive 
Anti-HBs+ 
Anti-hepatitis B surface antibody positive 
ASCT 
Autologous Stem-Cell Transplantation 
AST 
Aspartate transaminase/Aspartate aminotransferase, also known as glutamic 
oxaloacetic transaminase (SGOT) 
BMA 
Bone Marrow Aspirate 
BUN 
Blood Urea Nitrogen 
CA 
Chromosomal Abnormalities 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus disease 
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 


 
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DIRA 
Daratumumab Interference Reflex Assay 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOCB 
Duration of Clinical Benefit 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
H2 
Histamine 2 receptor 
HBV 
Hepatitis B virus 
HBsAg+ 
Hepatitis B surface antigen positive 
HBsAg- 
Hepatitis B surface antigen negative 
IB 
Investigator’s Brochure 
ICF 
Informed Consent From 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
iFISH 
interphase Fluorescence In Situ Hybridization 
IFE 
Immunofixation  
Ig 
Immunoglobulin 
IL 
Interleukin 
IMiD 
Immunomodulatory Drug 


 
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IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
IND 
Investigational New Drug 
IRC 
Independent Review Committee 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reaction 
ISS 
International Staging System 
IUD 
Intra Uterine Device 
i.v. 
Intravenously 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
mAb 
monoclonal Antibody 
MDSC 
myeloid derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines & Healthcare products Regulatory Agency 
MM 
Multiple Myeloma 
MR 
Minimal Response 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NRS 
Numeric Rating Scale 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PFS-2 
Progression Free Survival on next line of therapy 


 
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PI 
Proteasome Inhibitor 
PICC 
Peripherally Inserted Central Catheter 
PK 
Pharmacokinetics 
p.o. 
Per oral 
POEMS 
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein 
PPIs 
Proton Pump Inhibitors 
PR 
Partial Response 
q.d. 
Quaque die/ one a day 
rHuPH20 
Recombinant human hyaluronidase PH20 
RBC 
Red Blood Cell 
REB 
Regional Ethics Board 
R-ISS 
Revised International Staging System 
RRMM 
Relapsed Refractory Multiple Myeloma 
SGOT 
Serum Glutamic Oxaloacetic Transaminase, also known as AST 
SGPT 
Serum Glutamic Pyruvic Transaminase, also known as ALP 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent Complete Response 
s.c. 
Subcutaneous 
SD 
Stable Disease 
SFLC 
Serum Free Light Chain 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SoC 
Standard of Care 
SOC 
System Organ Class 
SPEP 
Serum Protein Electrophoresis 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 


 
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TTNT 
Time to Next Treatment 
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 
WOCBP 
Woman of Child Bearing Potential 


 
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SAP_001.pdf: 
Statistical Analysis Plan 
Version 1.1, 11 May 2022 
 
Protocol OP-108 
 
Protocol Title: A Randomized, Controlled, Open-Label Phase 3 Study of 
Melflufen in combination with Daratumumab Compared with Daratumumab in 
Patients with Relapsed or Relapsed-Refractory Multiple Myeloma 
 
 
National Clinical Trial number: NCT04649060 


CONFIDENTAL 
Page 1 of 51 
 
Oncopeptides AB 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL OP-108 
 
A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in combination with 
Daratumumab Compared with Daratumumab in Patients with Relapsed or Relapsed-
Refractory Multiple Myeloma 
 
Protocol code:  
OP-108 
SAP Version:  
Final 1.1 
SAP Date:  
11 May 2022 
Author:  
 
 
 
 


CONFIDENTAL 
Page 2 of 51 
 
DOCUMENT HISTORY 
VERSION HISTORY 
Version # 
Version Date 
Final 1.0 
13 January 2021 
Final 1.1 
11 May 2022 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
1.0 
N/A 
Initial release 
N/A 
1.1 
1 
Clarification of impact on 
statistical analysis due to the 
early termination of the study 
Early termination of study 
 
 
 
 


Statistical Analysis Plan: OP-108 
Review Status: Final 
 
Version: 1.1 
 
Version Date: 11 May 2022 
 
 
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APPROVAL SIGNATURES 
STUDY TITLE: A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in 
combination with Daratumumab Compared with Daratumumab in Patients with Relapsed or 
Relapsed-Refractory Multiple Myeloma 
 
PROTOCOL NUMBER: Version 2.1: Amendment 2, November 25, 2020 
SAP Final 1.1, 11 May 2022 
 
PSI 
Author: 
 Senior Statistician 
Signature: 
...Not applicable.................................................... 
Date: ...................... 
 
Peer-reviewer Statistician: 
 Senior Group Leader Biostatistics 
Signature: 
...... Not applicable..... .................................................... 
Date: ...................... 
 
Project Manager: 
 Project Director 
Signature: 
....... Not applicable......................................................... 
Date: ...................... 
 
Medical Writer: 
 Associate Medical Writer 
Signature: 
...... Not applicable......................................................... 
Date: ...................... 
 
Oncopeptides AB 
Study Statistician: 
 Senior Study Statistician 
 
 
 
Signature: 
................................................................ 
Date: ...................... 
 
Study Physician: 
 
 
 
 
 
Signature: 
................................................................ 
Date: ...................... 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................. ERROR! BOOKMARK NOT DEFINED. 
2. 
STUDY OBJECTIVES ...................................................................................................................................... 9 
2.1 
Primary Objectives ....................................................................................................................................... 9 
2.2 
Secondary Objectives ................................................................................................................................ 10 
2.2.1 
Key Secondary Objectives ....................................................................................................................... 10 
2.2.2 
Other Secondary Objectives .................................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................................................ 10 
3. 
STUDY DESCRIPTION .................................................................................................................................. 12 
3.1 
Study Design ............................................................................................................................................. 12 
3.2 
Study Treatment ........................................................................................................................................ 12 
3.3 
Treatment duration ..................................................................................................................................... 14 
3.4 
Independent Review Committee (IRC) ......................................................................................................... 15 
3.5 
Data Monitoring Committee (DMC) .............................................................................................................. 15 
3.6 
Dose Modifications ..................................................................................................................................... 15 
4. 
SAMPLE SIZE AND POWER CALCULATION .................................................................................................. 16 
5. 
ANALYSIS ENDPOINTS ................................................................................................................................ 17 
5.1 
Primary Endpoints ...................................................................................................................................... 17 
5.2 
Secondary Endpoints ................................................................................................................................. 17 
5.2.1 
Key Secondary Endpoints ........................................................................................................................ 17 
5.2.2 
Other Secondary Endpoints ..................................................................................................................... 17 
5.3 
Exploratory Endpoints ................................................................................................................................ 18 
6. 
ANALYSIS POPULATIONS ............................................................................................................................ 19 
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS ........................................................................................ 21 
7.1 
General Conventions and Statistical Considerations ..................................................................................... 21 
7.2 
Definition of Baseline, Study Visits, and Visit Windows ................................................................................. 22 
7.3 
Handling of Missing Data ............................................................................................................................ 22 
7.4 
Patient Disposition ..................................................................................................................................... 24 
7.5 
Protocol Deviations .................................................................................................................................... 24 
7.6 
Patient Characteristics ................................................................................................................................ 25 
7.6.1 
Baseline and Demographic Characteristics ............................................................................................. 25 
7.6.2 
Medical History and Current Medical Conditions ..................................................................................... 25 
7.6.3 
Multiple Myeloma Disease History ........................................................................................................... 26 
7.6.4 
Prior MM Therapies .................................................................................................................................. 29 
7.6.5 
Prior and Concomitant Medication ........................................................................................................... 30 
7.7 
Efficacy Endpoints and Analysis .................................................................................................................. 31 
7.7.1 
Primary Endpoint ...................................................................................................................................... 32 
7.7.2 
Key Secondary Efficacy Endpoints .......................................................................................................... 34 
7.7.3 
Other Secondary Efficacy Endpoints ....................................................................................................... 36 
7.7.4 
Exploratory Efficacy Endpoints ................................................................................................................ 39 
7.7.5 
Multiplicity ................................................................................................................................................. 40 
7.7.6 
Other Efficacy Assessments .................................................................................................................... 41 
7.8 
Safety Endpoints and Analysis .................................................................................................................... 41 
7.8.1 
Exposure to Study Treatment................................................................................................................... 41 
7.8.2 
Adverse Events ........................................................................................................................................ 43 
7.8.3 
Laboratory Data ........................................................................................................................................ 47 
7.8.4 
Vital Signs ................................................................................................................................................ 48 
7.8.5 
Physical Examination ............................................................................................................................... 49 
7.8.6 
12-lead Electrocardiogram (ECG) ............................................................................................................ 49 
7.9 
Exploratory Endpoints and Analysis ............................................................................................................ 49 
7.9.1 
Patient Reported Outcome (PRO) ........................................................................................................... 49 
7.9.2 
Pharmacokinetics ..................................................................................................................................... 49 
7.9.3 
ECOG ....................................................................................................................................................... 50 
7.9.4 
Biomarkers ............................................................................................................................................... 50 


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7.9.5 
Immunogenecity ....................................................................................................................................... 50 
8. 
INTERIM ANALYSES .................................................................................................................................... 50 
9. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE PROTOCOL .............................................................. 50 
10. 
PROGRAMMING SPECIFICATIONS ............................................................................................................... 51 
11. 
REFERENCES .............................................................................................................................................. 51 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase  
ATC 
anatomical therapeutic chemical 
BPI  
brief pain inventory 
BPI-SF 
brief pain inventory - short form 
BR 
best response 
CA 
chromosomal abnormalities 
CBR 
clinical benefit rate 
CI 
confidence interval 
cm 
centimeters 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CSR 
clinical study report 
CT 
computerized tomography 
CTCAE 
common terminology criteria for adverse events 
CTX 
c-terminal telopeptide 
DOR 
duration of response 
DOCB 
duration of clinical benefit 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMD 
extramedullary disease 
eCRF 
electronic case report form 
EOT 
end of treatment 
FAS 
full analysis set 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 
F-U 
follow-up 
ICH 
International Council of Harmonisation 
IFE 
immunofixation  
Ig 
immunoglobulin 
IMiD 
immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
INR  
international normalized ratio 
IRC 
independent review committee 
ISS 
international staging system 
i.v.  
intravenously  


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K-M 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
mAb 
monoclonal antibodies 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MR 
minimal response 
MRD 
minimal residual disease 
MDSC 
myeloid derived suppressor cell 
NCA 
non-compartmental analysis 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NK 
natural killer 
NRS 
numeric rating scale 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
PFS-FU 
progression free survival follow-up 
PI 
proteasome inhibitor 
PINP 
procollagen I N - terminal propeptide 
PK 
pharmacokinetics 
p.o. 
per os/by mouth/orally 
PPAS 
per protocol analysis set 
PR 
partial response 
PRO 
patient reported outcome 
PT 
preferred term 
PVC 
peripheral venous catheter 
q.d. 
Quaque die/ one a day 
QoL 
quality of life 
rHuPH20 
recombinant human hyaluronidase PH20 
R-ISS 
revised international staging system 
RANK 
receptor activator of nuclear factor-kappa B 
RNA 
ribonucleic acid 
RRMM 
relapsed refractory multiple myeloma 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneous 
sCR 
stringent complete response 
S-Cr 
serum creatinine 
SD 
standard deviation; stable disease (depending on context)  
SDG 
standardized drug groupings 
SDTM 
study data tabulation model 


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SF 
short form 
SFLC 
serum free light chain 
SMQ 
Standardized MedDRA Query 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
TEAE 
treatment-emergent adverse event 
TRACP-5b 
tartrate-resistant acid phosphatase 5b 
TTR 
time to response 
TTP 
time to progression 
TTNT 
time to new therapy 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 
US 
United States 
VGPR 
very good partial response 
WHO 
World Health Organization 
WBC 
white blood cells 
 


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1. 
EARLY TERMINATION OF STUDY 
 
The study was prematurely terminated by the Sponsor 7 Feb 2022. As a consequence, no formal 
statistical analyses will be performed, and most activities as described in the SAP will no longer 
be performed.  
An abbreviated CSR will be produced based on updated outputs from DMC, where the details 
are described in the DMC charter and not necessarily according to the details in this SAP.  
No efficacy endpoints will be derived.  
 
2. 
INTRODUCTION 
 
 
This statistical analysis plan (SAP) describes the statistical analysis and reporting for the study 
protocol Version 2.1: Amendment 2, November 25, 2020 entitled; a randomized, controlled, 
open-label phase 3 study of melflufen in combination with daratumumab compared with 
daratumumab in patients with relapsed or relapsed-refractory multiple myeloma.  
The purpose of the plan is to outline the types of analyses and data presentations that will address 
the study objectives outlined in the protocol, and to explain in detail how the data will be handled 
and analyzed, adhering to commonly accepted standards and practices of biostatistical analysis in 
the pharmaceutical industry. If the protocol is amended, this SAP will be revised as required.  
The statistical principles applied in the design and planned analyses of this study are consistent 
with International Council of Harmonisation (ICH) guidelines E9 (Statistical Principles for 
Clinical Trials). 
This SAP does not include the description of immunogenicity, PRO, PK and biomarkers 
analyses. 
 
3. 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES 
 
• To show superiority of progression free-survival (PFS) in patients treated with melflufen 
and dexamethasone in combination with daratumumab compared to daratumumab alone. 
 


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3.2 
SECONDARY OBJECTIVES  
3.2.1 KEY SECONDARY OBJECTIVES 
 
• To evaluate and compare Overall Response Rate (ORR) in patients treated with melflufen 
and dexamethasone in combination with daratumumab compared to daratumumab alone. 
• To evaluate and compare Duration of Response (DOR) in patients treated with melflufen 
and dexamethasone in combination with daratumumab compared to daratumumab alone. 
• To assess the safety and tolerability of melflufen and dexamethasone in combination with 
daratumumab compared to daratumumab alone. 
3.2.2 OTHER SECONDARY OBJECTIVES 
 
• To evaluate and compare efficacy endpoints in patients treated with melflufen and 
dexamethasone in combination with daratumumab compared to daratumumab alone: 
- Best response during the study 
- Clinical benefit rate (CBR) 
- Duration of Clinical Benefit (DOCB) 
- Time to response (TTR) 
- Time to progression (TTP) 
- Time to next treatment (TTNT) 
- Overall survival (OS) 
 
3.3 
EXPLORATORY OBJECTIVES 
 
• To assess minimal residual disease (MRD) in patients achieving a complete response 
(CR) or very good partial response (VGPR) in patients treated with melflufen and 
dexamethasone in combination with daratumumab compared to daratumumab alone. 
• To evaluate the Progression Free Survival following next line of treatment (PFS-2) in 
patients treated with melflufen and dexamethasone in combination with daratumumab 
compared to daratumumab alone. 
• To assess and compare the changes in pain in patients treated with melflufen and 
dexamethasone in combination with daratumumab compared to daratumumab alone. 


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• To assess and compare responses in patients with extramedullary myeloma 
(plasmacytomas). 
• To assess and compare use of health services and number and duration of hospitalizations 
in patients treated with melflufen and dexamethasone in combination with daratumumab 
compared to daratumumab alone, and in patients who crossover and receive treatment 
with melflufen, daratumumab and dexamethasone. 
• 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 PK and immunogenicity of subcutaneous daratumumab. 
• To evaluate the immunogenicity of recombinant human hyaluronidase PH20 (rHuPH20) 
following subcutaneous daratumumab administration. 
• To assess translational biomarkers that might predict response/non-response to the 
treatment, aid in monitoring of disease progression as well as improve understanding of 
mechanism of action. 
• To assess and compare functional status and wellbeing based on patient reported outcome 
(PRO) assessments for patients treated with melflufen and dexamethasone in combination 
with daratumumab compared to daratumumab alone. 
• To evaluate efficacy in patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone after progression on daratumumab: 
- Overall response rate (ORR) 
- Duration of response (DOR) 
- Best response during the study 
- Clinical benefit rate (CBR) 
- Duration of Clinical Benefit (DOCB) 
- Time to response (TTR) 
- Time to progression (TTP) 
- Time to next treatment (TTNT) 
- Overall Survival (OS) 
- Progression free-survival (PFS) 


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• To assess and compare the changes in pain for patients in Arm B who crossover to 
treatment with melflufen, dexamethasone and daratumumab. 
• To assess and compare functional status and wellbeing based on patient reported outcome 
(PRO) assessments for patients in Arm B who crossover to treatment with melflufen, 
dexamethasone and daratumumab. 
• To assess the safety and tolerability of melflufen, dexamethasone and daratumumab 
treatment for patients in Arm B who crossover. 
 
Additional exploratory analyses of endpoints related to pharmacokinetics and HRQoL will be 
described separately. 
 
4. 
STUDY DESCRIPTION 
4.1 
STUDY DESIGN 
 
This is an open-label, randomized, international, multicenter Phase 3 trial which will enroll 
patients with relapsed or relapsed-refractory multiple myeloma (MM) who are either double 
refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI), given alone or 
in combination or had at least 3 prior lines of therapy including being exposed to both an IMiD 
and a PI.  The patients will be randomized in a 1:1 fashion into either one of two treatment arms, 
Arm A or Arm B. Patients who receive daratumumab in Arm B and have a confirmed disease 
progression will have the option to crossover and receive treatment with melflufen, 
daratumumab and dexamethasone. 
 
4.2 
STUDY TREATMENT 
 
Arm A: 
 
In Arm A melflufen i.v. 30 mg will be administered on Day 1 in every 28-day cycle in 
combination with daratumumab s.c. 1800 mg according to the schedule in Table 1-1.  
 
 


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Table 1-1 
Daratumumab Schedule, Arm A 
Cycles  
Days 
1 and 2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7 + 
1 
 
Dexamethasone 40 mg p.o. (20 mg p.o. for patients ≥ 75 years) will be given weekly (see Table 
1-2). 
 
 
Table 1-2  
Dexamethasone dosing schedule 
Dexamethasone dosing on days when melflufen and daratumumab are given  
All Cycles Day 1  
patients < 75 years of 
age 
40 mg prior to melflufen 
administration  
patients ≥ 75 years of 
age 
20 mg prior to melflufen 
administration 
Dexamethasone dosing on days when only daratumumab is givena 
Cycle 1 and 2: Days 8, 15 
and 22 
Cycle 3 to 6: Day 15 
patients < 75 years of 
age 
40 mg prior to daratumumab 
administration 
 
patients ≥ 75 years of 
age 
20 mg prior to daratumumab 
administration 
Dexamethasone dosing on weeks when no other drug is given 
Cycle 3 to 6: Days 8 and 22 
Cycle 7+ Days 8, 15 and 22 
patients < 75 years of 
age 
40 mg weekly 
patients ≥ 75 years of 
age 
20 mg weekly 
a) Prior to daratumumab administration in Cycle 1, oral dexamethasone may be substituted with i.v. dexamethasone 
during Cycle 1, at the investigator’s discretion, if this is the standard of care of the study center.  
 
 
Arm B: 
 
In Arm B daratumumab will be given at the dose of 1800 mg s.c. according to the schedule in 
Table 2-1.   
 
 


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Table 2-1 
Daratumumab Schedule, Arm B 
Cycles  
Days 
1 and 2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7 + 
1 
 
 
Patients in Arm B who are confirmed to have disease progression while receiving daratumumab 
alone may be eligible to crossover and receive treatment with melflufen, dexamethasone and 
daratumumab, using the daratumumab dosing schedule at the time of disease progression. 
Once a patient is determined to be eligible, treatment with melflufen, dexamethasone and 
daratumumab has to start within 56 days from the last dose of daratumumab in Arm B. 
 
 
4.3 
TREATMENT DURATION 
 
Patients in both treatment arms will receive treatment until there is documented PD (Progressive 
Disease) according to the IMWG-URC (International Myeloma Working Group Uniform 
Response Criteria) guidelines (Kumar et al. 2016), unacceptable toxicity, the patient/treating 
physician determines it is not in the patient’s best interest to continue, or patient’s withdrawal of 
consent. Confirmed PD (on two consecutive assessments if based on M-protein assessments) 
should be verified by the Medical Monitor prior to treatment discontinuation. Patients in Arm B 
with documented PD verified by the Medical Monitor may crossover and receive treatment with 
melflufen, dexamethasone and daratumumab (using the daratumumab dosing schedule 
corresponding to the cycle when disease progression occurred). Patients receiving therapy after 
crossing over will receive treatment until there is documented PD, unacceptable toxicity, the 
patient/treating physician determines it is not in the patient’s best interest to continue, or 
patient’s withdrawal of consent. Confirmed PD should be verified by the Medical Monitor prior 
to treatment discontinuation. 
 
 


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4.4 
INDEPENDENT REVIEW COMMITTEE (IRC) 
 
All response assessments, including PD, will be assessed by an Independent Review Committee 
(IRC) using the International Myeloma Working Group (IMWG) response criteria. The IRC 
members will be blinded to all treatment data (including investigator response) and perform their 
reviews in closed-meeting sessions. 
 
4.5 
DATA MONITORING COMMITTEE (DMC) 
 
An independent Data Monitoring Committee (DMC) will perform surveillance of efficacy/safety 
balance at regular intervals during the study, using unblinded treatment-aggregated data. The 
scope of work, procedures, roles and responsibilities for the DMC are described in a separate 
DMC charter. The DMC can recommend continuing the study, with or without modifications, or 
stop the study based on benefit/risk concerns. 
 
4.6 
DOSE MODIFICATIONS 
 
There are no dose reductions for daratumumab. For the other drugs, dose modifications will be 
implemented for individual patient tolerability according to dose modification guidelines 
described in Section 6.6 of the protocol. Patients unable to tolerate therapy following 
implementation of the guidelines will be permanently discontinued, unless in the opinion of the 
investigator and approved by the Medical Monitor, it is in the patient's best interest to continue 
therapy. In addition, patients discontinuing either melflufen or daratumumab in Arm A (or 
patients in Arm B who crossover to treatment with melflufen, dexamethasone and 
daratumumab), may continue with the remaining 2 study drugs according to the protocol, if in 
the best interest of the patient and approved by the Medical Monitor.  
 
 
 
 


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5. 
SAMPLE SIZE AND POWER CALCULATION 
 
The sample size of 200 patients was calculated based on achieving 90% power to observe a 
statistically significant result for comparing the treatment arms in terms of PFS, using a log-rank 
test for 2 survival curves and the parameter assumptions presented in Table 3-1. Assuming a 
dropout rate of approximately 15%, it is anticipated to randomize 120 patients in each treatment 
arm, to a total number of 240 patients. 
 
The randomization will be stratified by number of previous lines of treatment (<3 prior lines of 
treatment versus ≥3 prior lines of treatment) and previous treatment with daratumumab or 
another anti-CD38 antibody (no previous treatment versus previous treatment). 
 
The final analysis will take place when 160 patients have experienced a PFS event. 
 
Table 3-1 
Sample Size Determination 
Parameter 
Assumption 
Power 
90% 
Significance level 
5%, two-sided 
Hazard Ratio (Arm A / Arm B) 
0.60 
Distribution of survival curves 
Exponential 
Method  
Lakatos normal approximation 
Accrual time 
24 months 
Follow up time 
6 months after last patient randomized 
Total study time 
18 months 
Median PFS for Arm A 
6.7 months 
Median PFS for Arm B 
4.0 months 
 
The assumptions for this sample size estimation are based on preliminary data from an ongoing 
phase 1/2 study (ANCHOR OP-104) and a pooled analysis of two open-label Phase 1/2 studies 
of daratumumab monotherapy (IB for melflufen, Usmani et al. 2016).  
 


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6. 
ANALYSIS ENDPOINTS 
6.1 
PRIMARY ENDPOINTS 
 
• PFS (time from the date of randomization to the date of first documentation of confirmed 
PD or death due to any cause). 
 
6.2 
SECONDARY ENDPOINTS  
6.2.1 KEY SECONDARY ENDPOINTS 
 
• ORR (proportion of patients who achieve a best confirmed response of stringent 
Complete Response (sCR), CR, VGPR or Partial Response (PR)). 
• DOR (time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to 
first confirmed disease progression, or death due to any cause). DOR is defined only for 
patients with a confirmed PR or better. 
• Frequency and Grade of treatment emergent adverse events (TEAE) 
6.2.2 OTHER SECONDARY ENDPOINTS 
 
• Best Response (proportion of patients with sCR, CR, VGPR, PR, Minimal Response 
(MR), Stable Disease (SD), PD or non-evaluable). 
• CBR (the proportion of patients who achieve a best confirmed response of sCR, CR, 
VGPR, PR or MR). 
• DOCB (time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or 
MR to first confirmed disease progression, or to death due to any cause).  DOCB is 
defined only for patients with a confirmed MR or better. 
• TTR (time from randomization to the date of the first documented confirmed response in 
a patient who has responded with ≥PR). 
• TTP (time from the date of randomization to the date of the first documented confirmed 
PD). 
• TTNT (time from randomization to the date of next anti-myeloma treatment or until 
death) 
• OS (time from date of randomization to death due to any cause). 
 


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6.3 
EXPLORATORY ENDPOINTS 
 
• Assessment of MRD status by Next Generation sequencing (NGS) in patients who 
achieve a CR or VGPR. 
• PFS-2 (defined as time from randomization to progression on next line of treatment or 
death from any cause, whichever occurs first). 
• Value and changes in pain in Brief Pain Inventory – SF (BPI-SF) and Numeric Rating 
Scale (NRS) for measure of bone pain. 
• Response rate (CR and PR) according to IMWG consensus criteria of extramedullary 
myeloma (plasmacytomas). 
• Number of health services. 
• Number and days of hospitalization. 
• PK parameters of melphalan in selected treatment cycles. 
• Serum daratumumab concentrations. 
• Incidence of antibodies to daratumumab. 
• Incidence of antibodies to rHuPH20. 
• DNA/RNA-based drug response biomarkers including but not limited to aminopeptidases 
and esterases. 
• Serum levels of bone reabsorption related proteins including but not limited to TRACP‐
5b (Tartrate-resistant acid phosphatase 5b), PINP (Procollagen I N-terminal Propeptide), 
Total RANK, Osteopontin, Osteocalcin, CTX (C-Terminal telopeptide), bone ALP 
(Alkaline phosphatase). 
• Serum levels of cytokines IL-6, IL-10. 
• Immune profiling in peripheral blood including but not limited to T Reg. (Regulatory T), 
MDSC (Myeloid-derived suppressor cell) and NK (Natural killer) cells. 
• Value and changes from baseline in EORTC QLQ-C30 summary score, each scale of the 
EORTC QLQ-C30, EQ-5D utility index, each dimension of the EQ-5D-3L, and the 
Visual Analogue Scale (VAS) of the EQ-5D-3L. 
• ORR (proportion of patients who achieve a best confirmed response of sCR, CR, VGPR 
or PR after crossover). 


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• DOR (time from the first evidence of confirmed assessment (after crossover) of sCR, CR, 
VGPR or PR to first confirmed disease progression, or death due to any cause). DOR is 
defined only for patients with a confirmed PR or better after crossover. 
• Best Response (proportion of patients with sCR, CR, VGPR, PR, Minimal Response 
(MR), Stable Disease (SD), PD or non-evaluable) after crossover. 
• CBR (the proportion of patients who achieve a best confirmed response of sCR, CR, 
VGPR, PR or MR) after crossover. 
• DOCB (time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or 
MR after crossover to first confirmed disease progression, or to death due to any cause).  
DOCB is defined only for patients with a confirmed MR or better after crossover. 
• TTR (time from crossover to the date of the first documented confirmed response in a 
patient who has responded with ≥PR after crossover). 
• TTP (time from crossover to the date of the first documented confirmed PD after 
crossover). 
• TTNT (time from crossover to the date of next anti-myeloma treatment or until death 
after crossover). 
• OS (time from crossover until death of any cause after crossover). 
• Value and changes from crossover in pain, in BPI-SF and NRS for measure of bone pain. 
• Value and changes from crossover in EORTC QLQ-C30 summary score, each scale of 
the EORTC QLQ-C30, EQ-5D utility index, each dimension of the EQ-5D-3L, and the 
Visual Analogue Scale (VAS) of the EQ-5D-3L after crossover. 
• Frequency and Grade of treatment emergent adverse events (TEAE) after crossover. 
 
• PFS (time from crossover to the date of first documentation of confirmed PD or death 
due to any cause after crossover). 
 
7. 
ANALYSIS POPULATIONS 
 
Analysis Population 
Description 
Enrolled Population Set 
Includes all screened patients, i.e. patients having completed 
assessments and procedures during screening as outlined in 
Section 8.1.1 of the protocol. The Enrolled Population Set will 


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include randomized patients and non- randomized patients 
(defined as screening failures) and will be used for summaries 
of disposition. 
Full Analysis Set (FAS) 
Includes all patients who are randomized. Analyses will be 
performed according to the treatment assigned at 
randomization. The primary endpoint and all secondary 
efficacy endpoints will be based on FAS. 
Safety Analysis Set 
Includes all patients in the FAS with at least one exposure to 
any study drug. Analyses will be performed according to the 
treatment actually received. 
Pharmacokinetic Analysis Set Includes all patients in FAS who received at least 1 dose of 
daratumumab or for melflufen includes all patients in FAS 
who received at least 1 dose of melflufen and have 3 samples 
with measurable concentrations in at least one treatment cycle. 
Analyses will be performed according to the treatment 
actually received. 
Per Protocol Analysis Set 
 
The Per Protocol Analysis Set includes all patients in the FAS 
who have received at least 1 dose of study medication. 
Patients who have important protocol deviations, related to 
critical eligibility criteria, the assessment of efficacy or the 
safety of the patient who could significantly impact the 
interpretation of study result, will be excluded from the PPAS. 
These major protocol deviations include: 
• Eligibility criteria not fulfilled 
• Patient received incorrect study drug 
• Absence of post-baseline MM response assessments 
 
The final list of major deviations will be made during the 
blinded data review meeting prior to final database lock. 
The PPAS will be used for sensitivity analyses of selected 
efficacy variables. 
Analyses will be performed according to the treatment 
actually received. 
QoL Analysis Set 
All patients who received at least 1 dose of melflufen or 
Daratumumab, respectively, and have evaluable changes in 
QoL parameters. Analyses will be performed according to the 
treatment actually received. 
 
 


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8. 
ANALYTICAL PLAN AND STATISTICAL METHODS 
8.1 
GENERAL CONVENTIONS AND STATISTICAL CONSIDERATIONS 
 
All analyses will be performed using SAS (statistical analysis software) version 9.4 or higher. 
Descriptive statistics for continuous variables will include the number of patients with non-
missing data (n), arithmetic mean, standard deviation (SD), median, minimum and maximum. 
Summary statistics for categorical variables will contain count and percentage based on the 
number of patients in the selected analysis population. Percentages will be presented to one 
decimal, except for zero and one hundred percent, which will be presented as 0% and 100%.  
For descriptive statistics of continuous variables, the accuracy of the minimum and maximum 
should match the original data; for the mean and median one more decimal point in addition to 
the original data will be presented, and for SD two more decimal points in addition to the 
original data will be presented. For the derived variables (e.g., time since diagnosis) minimum 
and maximum will be presented with one decimal after point; mean, median and SD decimals 
will be applied following the rule above. 
Presented decimal places should however not be greater than 4. 
Denominators for percentages will be based on the number of patients with non-missing data in 
the population used in each column, for the summaries presented by time points the denominator 
will be the number of patients with non-missing data at each time-point. A “missing” category 
will be included for any variables for which information is missing, without a percentage. 
By default the data collected in the electronic case report form (eCRF) and by external vendors 
will be used for analysis unless it is specified that additional derivation is required. 
 
Demographics and efficacy analyses will be repeated for the following subgroups: 
• Patients with <3 prior lines of treatment and ≥3 prior lines of treatment, respectively 
• Patient double-refractory to an IMiD and PI or not, respectively 
• Patients previously treated with anti-CD38 antibody or not, respectively 
• Patients with extramedullary disease 
In case of mis-stratification the actual value from the CRF, and not the IWRS value, will be used 
for statistical analyses (e.g., for subgroup analysis, Cox models, Cochran-Mantel-Haenszel 
(CMH) test, etc.) 


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8.2 
DEFINITION OF BASELINE, STUDY VISITS, AND VISIT WINDOWS 
 
Where assessments are made on the day of first treatment that are per protocol scheduled to take 
place prior to treatment, it will be assumed that the assessment is pre-dose, and is a valid baseline 
assessment. Where assessments are not performed on the first treatment day, screening or last 
available observation prior to the first dose of study drug will be considered as baseline. Refer to 
the protocol for the study visits-schedule.  
Note that for this study there is no study Day 0, so the day immediately prior to study Day 1 is 
study Day - 1. For any events occurring on or after the first dose of study drug, the study day is 
calculated as: event date – date of first administration of study treatment + 1. As such, the first 
dose date was study Day 1.  
For any events before the first dose date, study day is calculated as: event date – date of first 
administration of study treatment. As such, one day before first dose date was study Day - 1.  
Because unscheduled assessments are not associated with any scheduled time point, they will be 
excluded from all summaries by time point. Unscheduled assessments will be considered when 
deriving myeloma response parameters as described in Section 7.7 and for analysis of laboratory 
parameters by worst toxicity grade as specified in Section 7.8.3 of this SAP. All unscheduled 
assessments will be presented in the respective listings. 
The data will be analyzed according to the visits recorded in the eCRF, and no analysis windows 
will be applied. 
 
8.3 
HANDLING OF MISSING DATA 
 
Missing data will not be estimated or carried forward for any of the other summaries or analyses 
not mentioned in this section. 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 adverse event (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 


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(i.e., 1) with the following exception: if the partial date falls in the same month and year 
as the date being used in the calculation (e.g., first dose date, informed consent date), then 
the partial date will be imputed to equal the date being used for the calculation, unless 
there is a complete end date which is earlier. 
• For missing start day and month: Day and month will be imputed as the first day of the 
year (i.e., 1 January) with the following exception: if the partial date falls in the same 
year as the date being used in the calculation (e.g., first dose date, informed consent date), 
then the partial date will be imputed to equal the date being used for the calculation, 
unless there is a complete end date which is earlier. 
• Stop dates (e.g., AE resolution date or stop date of medication). For missing stop day 
only: Day will be imputed as the last day of the month (i.e., 28, 29, 30, or 31). 
 
• For missing stop day and month: Day and month will be imputed as the last day of the 
year (i.e., 31 December). 
 
Any partial dates will be displayed in data listings without imputation of missing days and/or 
months (e.g., MAR2011, 2009).  
 
In case of incomplete date of relapse, for the purpose of calculation of the time since most recent 
relapse the rules mentioned above for the partial start date will be used. However, for the purpose 
of calculation of time since frontline transplant to relapse and derivation of refractory status the 
simplified approach of assigning first day of a month in case of missing day and 1 January in 
case of missing month and day will be used. 
If time is not available but is required for a calculation (e.g., timing of AE vs study drug 
administration) the most conservative approach should be used, i.e., assuming that the time of 
AE was after study drug administration or that the time of concomitant medication was after AE. 
Adverse events with a missing relationship will be considered related for purposes of summaries. 
In case of multiple cases the information regarding the number of imputed relationships will be 
provided in the footnote of the respective summaries. 
Adverse events with a missing severity will be considered severe (grade 3) for purposes of 
summaries.  Imputed relationship and severity will not be included in the listings. 


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The handling of dropouts and missing disease status assessments for the efficacy variables is 
described in their definitions in the relevant sections.   
 
8.4 
PATIENT DISPOSITION 
 
Disposition summary will be based on the Enrolled Population Set and presented by treatment 
arms and overall. Disposition data for patients in Arm B who crossover to treatment with 
melflufen, daratumumab and dexamethasone will be summarized separately, where applicable. 
 
The disposition of patients includes: 
• Number (%) of patients randomized  
• Number (%) of treated patients  
• Number (%) of patients in the FAS, PPAS, Safety, PK and QoL Analysis Sets 
• Number (%) of patients permanently discontinued from the treatment along with the 
primary reasons for permanent treatment discontinuation 
• Number (%) of patients in PFS follow-up (F-U), PFS-2 F-U and OS F-U 
• Number (%) of patients discontinued from the study and reasons for study 
discontinuation  
Treatment discontinuations due to AEs specific to COVID-19 will also be presented separately. 
All patient disposition information will be presented in the respective listings.  
 
8.5 
 PROTOCOL DEVIATIONS 
 
Major protocol deviations will be summarized by deviation type for the FAS and presented by 
treatment arms and overall. Protocol deviations data for patients in Arm B who crossover to 
treatment with melflufen, daratumumab and dexamethasone will be summarized separately. 
All protocol deviations will also be provided in a listing. 
 


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8.6 
PATIENT CHARACTERISTICS 
8.6.1 BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
 
The following demographic and baseline characteristics will be summarized descriptively for the 
FAS and presented by treatment arms and overall: 
• Age (years) 
• Age categories (<65,  ≥ 65 - ≤75,  >75) 
• Sex 
• Race 
• Ethnicity 
• Baseline fertility status 
• Baseline height (cm) 
• Baseline weight (kg) 
• Baseline Eastern Cooperative Oncology Group (ECOG) performance status 
• Hepatitis and HIV screening, including: hepatitis B surface antigen (HBsAg), anti-
hepatitis B core antibody (Anti-HBc), anti-hepatitis B surface antibody (Anti-HBs), anti-
HCV antibody, anti-HIV1/2 antibody/antigen 
Baseline and demographics characteristics will also be repeated by subgroups: 
• Patients with <3 prior lines of treatment and ≥3 prior lines of treatment, respectively 
• Patient double-refractory to an IMiD and PI or not, respectively 
• Patients previously treated with anti-CD38 antibody or not, respectively 
• Patients with extramedullary disease 
Data for patients in Arm B who crossover to treatment with melflufen, daratumumab and 
dexamethasone will be summarized separately.  
A listing will be provided for patient’s demographic and baseline characteristics. 
Separate listings will be provided for hepatitis and HIV screening, patient childbearing potential 
and ECOG results.  
 
8.6.2 MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
 
Medical history will be summarized by Medical Dictionary of Regulatory Activities (MedDRA) 


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(version 23.0 or higher), System Organ Class (SOC) and preferred term (PT) using number (n) 
and percentage (%) of patients having at least one occurrence of a disease for the FAS by 
treatment arms and overall. Medical history data for patients in Arm B who crossover to 
treatment with melflufen, daratumumab and dexamethasone will be summarized separately. A 
listing will be provided for patient medical history. 
 
8.6.3 MULTIPLE MYELOMA DISEASE HISTORY 
 
The following disease characteristics at diagnosis will be summarized descriptively for the FAS 
by treatment arms and overall: 
• Stage of disease (international staging system (ISS) and revised international staging 
system (R-ISS)) 
• Heavy chain and light chain subtypes 
• Evidence of lytic bone lesions 
• Evidence of extramedullary disease (EMD) 
 
The following disease characteristics at screening will be summarized descriptively for the FAS: 
• Stage of disease (ISS and R-ISS) 
• Heavy chain and light chain subtypes 
• Evidence of lytic bone lesions 
• Evidence of EMD 
• EMD subtype split 
• Disease status (relapsed/relapsed-refractory) 
• Time since diagnosis in years (calculated as [date of first dose of study drug – date of 
diagnosis+1]/365.25). Partial dates will be imputed according to the Section 7.3 of this 
SAP 
• Time since most recent relapse/progression in months (calculated as [date of first dose of 
study drug– date of most recent relapse/progression+1]/30.4375) 
• Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), 
kappa/lambda values 
• Bone marrow plasma cells (%) as values and by categories (<30%, 30 - <60%, ≥60%) 
• Laboratory assessments 
o β2 microglobulin (mg/L) as values and categories (< 3.5, 3.5 – 5.5 and > 5.5) 


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o Platelet count (10^9/L) as values and categories (<25, 25 - <50,  50 - <75,  75 -  
<LLN) 
o Absolute neutrophil count (ANC) (10^9/L) as values and categories (<0.5, 0.5-<1.0, 
1.0 – 1.5, and >1.5) 
o Hemoglobin (g/L) as values and categories (<65, 65 - <80, 80 – 100, >100) 
o Lactate dehydrogenase (LDH) (u/L) as values and categories (<1.5xULN and 
≥1.5xULN) 
o Albumin (g/L) as values and categories (<35,  ≥35) 
o Creatinine 
o Creatinine clearance (ml/min) as values and categories ( <45,  ≥45 - <60,  ≥60 - <90, 
≥90) 
o Corrected calcium 
 
In addition to the above ISS Stage and Revised ISS (R-ISS) Stage will be derived [Palumbo, 
2015], see Table 4. 
ISS will be derived from screening serum β2 microglobulin and albumin levels. This derived ISS 
will in turn be used with screening serum LDH level and high-risk cytogenetics at study entry (as 
defined by the R-ISS guidelines) to derive the R-ISS. Derived ISS and R-ISS will be referred as 
“Derived ISS” and “Derived R-ISS” respectively. 
Data for patients in Arm B who crossover to treatment with melflufen, daratumumab and 
dexamethasone will be summarized separately. 
 


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Table 4: 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 high LDH  
 
A separate summary dedicated to fluorescence in situ hybridization (FISH) cytogenetics 
investigations at diagnosis and screening will be presented, including the number and percentage 
of patients having particular types of cytogenetic abnormalities. Cytogenetics abnormalities will 
also be pooled by risk level (high-risk, standard-risk and unknown).  
• High-risk is defined in case the following abnormalities were found: deletion (17p), gain 
1q (+1q), gain (1q21), t (4;14), t(4;14) (p16;q32), t (14;16), t (14;16) (q32;q 23), t(14,20), 
t(14,20)(q32,q11). 
• Not high-risk consists of patients who have a genetic subtype recorded but none of the 
genetic subtypes categorized as high-risk. 
• Unknown consists of patients for whom the FISH procedure was not done or 
unevaluable. 
The same analysis as for FISH will also be presented for cytogenetics investigations performed 
by karyotyping. 
Bone lesion assessments at screening will be analyzed descriptively with the number and 
percentage of patients. The following information will be presented: number and percentage of 
patients for whom skeletal survey or low dose CT scan was performed, method of skeletal 


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survey, result of exam, and bone lesion locations. The same information will be presented for the 
other imaging procedures. 
Listings will be provided for patient MM history. 
 
8.6.4 PRIOR MM THERAPIES 
 
The following information related to prior MM therapies will be summarized for the FAS by 
treatment arms and overall: 
• Number and percentage of patients who had a frontline transplant (transplant as a 
component of the first line of therapy). This can be a single or tandem transplant. Planned 
tandem autologous or tandem autologous-allogeneic transplants are considered as one 
line of therapy. 
• Number of patients who had a salvage transplant (defined as any transplant where the 
patient has already had 1 or more transplants in earlier lines). Planned tandem autologous 
or tandem autologous-allogeneic transplants are considered as one line of therapy. 
• Frontline transplant type (allogeneic or autologous)  
• Number and percentage of patients with the tandem transplant 
• Number and percentage of patients with at least one prior autologous transplant, and 
number and percentage of patients with at least two prior autologous transplants 
• Number of prior autologous transplants 
• Time from frontline transplant to relapse in years (as continuous variable as well as per 
categories < 1 year, ≥1 year – <1.5 years, ≥1.5 years – ≤2 years, >2 years)  
• Number of prior systemic therapy lines 
• Best response to the last prior line of therapy 
• Refractory status to last prior line of therapy 
• Number and percentage of patients with any prior therapy lines (as well as during the last 
therapy) including: immunomodulatory drugs (IMiD’s), proteasome inhibitors (PI’s), 
alkylators, anti-CD38 monoclonal antibodies (mAb), other mAb and others 
• The number and percentage of patients refractory to at least one prior line of therapy (as 
well as to last prior therapy line) mentioned in the point above  
• Number and percentage of patients who received an IMiD and PI (double-class)   


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• Number and percentage of patients who received an IMiD, PI, and anti-CD38 mAb 
(triple-class) 
• Number and percentage of patients that are double class refractory to at least one prior 
line (refractory to at least one PI and one IMiD)  
• Number and percentage of patients with prior radiotherapy 
The following lists of drugs are associated with each drug class: 
• IMiD is defined as WHO DD Standardized Drug Groupings (SDG) “Antineoplastic 
thalidomide analogues”  
• PI is defined as SDG “Antineoplastic proteasome inhibitors” 
• Alkylators is defined as SDG “Antineoplastic alkylating drugs” 
• Anti-CD38 mAb is defined as SDG “Antineoplastic CD38 antigen inhibitors” 
• Other mAb is defined as SDG “Monoclonal antibodies – antineoplastics” excluding SDG 
“Antineoplastic CD38 antigen inhibitors” 
• Other antineoplastic drugs for the treatment of multiple myeloma will be referred to as 
‘Other. These will be identified by manual review of the drugs not included into the 
categories above. 
Refractory is defined as non-response disease (achieving SD or PD as the best response) while 
on therapy, or reason for termination was PD, or relapse/progression within 60 days after stop 
date of treatment.  
All patient details of prior MM therapies will be presented in the respective listings. 
 
 
8.6.5 PRIOR AND CONCOMITANT MEDICATION 
 
All concomitant medications will be coded using the WHO Drug Dictionary (WHODD) dated 
01 March 2020 or higher.   
A medication is considered prior if stopped before the date of the first study drug (Melflufen, 
Daratumumab or Dexamethasone) dose. Concomitant medications are defined as medications 
with a start date or end date on or after the date of first study drug dose and start date before the 
date of the last study drug dose + 30 days or are ongoing at the time of first dose.   
The number and percentage of patients with at least one concomitant medication will be 
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preferred name. Summaries will be presented by FAS by treatment arms and overall. 
Concomitant medication data for patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone will be summarized separately. The definition of concomitant 
medications stays the same as for the main part of the study but with first and last study drug 
doses referring to the first and last study doses during crossover part of the study.  
Patients may have more than one medication per ATC class and preferred name.  At each level 
of patient summarization, a patient is counted once if he/she reported one or more medications at 
that level.  The summaries will be ordered by descending frequency of ATC class and preferred 
name within each ATC class in the total group. Prior medications will be presented separately in 
the same way.  
Separate summaries will be provided for the number and percentage of patients with the 
following medication categories: “Haemapoetic growth factors” (WHO DD SDG “Colony 
stimulating factors”) and “Transfusions” (including the following PTs: “Platelets”, 
“Erythrocytes”, “Red blood cells”). 
A listing of prior and concomitant medications will be provided. 
 
8.7 
EFFICACY ENDPOINTS AND ANALYSIS 
 
All efficacy analyses will be produced for the FAS by treatment arms and overall. Efficacy data 
for patients in Arm B who crossover to treatment with melflufen, daratumumab and 
dexamethasone will be summarized separately. The primary efficacy endpoint will also be 
presented for the PPAS as sensitivity analysis. 
All tumor response and progression-depended objectives will be assessed by investigators 
according to the International Myeloma Working Group Uniform Response Criteria (IMWG-
URC) (Kumar et al.2016). 
All the efficacy analyses will be repeated for the following subgroups: 
• Patients with <3 prior lines of treatment and ≥3 prior lines of treatment, respectively 
• Patient double-refractory to an IMiD and PI or not, respectively 
• Refractory to an alkylator (yes, no) 
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• Patients with extramedullary disease at baseline (yes, no) as a whole group and separated 
per paraskeletal vs soft tissue EMD 
• Age  
o <65, ≥65 years  
o <75, ≥75 years 
• Sex (male, female) 
• ISS at baseline (I, II or III) 
• R-ISS at baseline (R-I, R-II or R-III) 
• 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) 
 
The respective subgroup variables will be excluded from the Cox models and CMH tests. 
 
8.7.1 PRIMARY ENDPOINT 
 
The primary endpoint PFS is defined as the duration in months from the date of randomization 
until first documentation of confirmed disease progression as assessed by IRC or death due to 
any cause, whichever occurs first. PFS time, in months, is calculated as (PFS date – date of 
randomization +1)/30.4375. 
 
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 conventions adapted from the 
FDA Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics and the FDA Guidance for Industry, Clinical Trial Endpoints for the Approval of Non-
Small Cell Lung Cancer Drugs and Biologics. 


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PFS will be right-censored for patients who meet one of the following conventions (the ones 
with Outcome=Censored) described in Table 5 below: 
 
       Table 5. Conventions for PFS Date Derivation and Censoring 
Situation 
Date of Progression or Censoring 
Outcome 
No post-baseline disease 
assessments, except in the case of 
death 
Date of randomization 
Censored 
New anticancer therapy started 
before documentation of PD or 
death 
Date of last disease assessment 
prior to start of new anticancer 
therapy 
Censored 
Death or PD immediately after 
more than 1 consecutively missed 
disease assessment visit* 
Date of last disease assessment 
visit without documentation of PD 
that is before the first missed visit 
Censored 
Unconfirmed PD as the final 
response assessment 
Date of latest PD assessment 
Progressed 
Alive and without PD 
documentation  
Date of last disease assessment 
Censored 
Death or PD between planned 
disease assessments 
Date of death or first disease 
assessment showing PD, 
whichever occurs first 
Progressed 
Death before first disease 
assessment 
Date of death 
Progressed 
*unless there was an unscheduled visit showing absence of PD between the last scheduled missing response   
assessment and date of PD identification 
 
The primary statistical analysis of PFS will be performed using a Log-rank test stratified by the 
randomization stratification factors. The Cox proportional hazard will be used to estimate the 
hazard ratio for melflufen+dexamethasone+daratumumab versus daratumumab and its 95% 
confidence interval (CI). Ties will be handled using the Efron methodology.  
The distribution of PFS will be summarized using Kaplan-Meier method. The median PFS will 
be estimated for each treatment arm as the 50th percentile of the corresponding Kaplan- 
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log(-log(survival)) distribution.  
 
Superiority will be demonstrated if the p-value from the statistical test is lower than 0.05 (i.e., the 
upper limit of the 95 % confidence interval for the hazard ratio is <1). All statistical tests will be 
two-sided, and have a null hypothesis of no difference between treatment arms for the applicable 
endpoint. See Section 7.7.5 for a description of multiplicity adjustments.  
 
The following sensitivity analyses for PFS have been added:  
• PFS as assessed by investigators  
• Unstratified log-rank test and unstratified Cox model 
• New anticancer therapy treated as an event 
• New anticancer therapy not treated as an event or a censoring event 
• Death or PD immediately after more than one consecutively missed disease assessment 
visit will be treated as an event 
• Analysis based on scheduled assessment dates instead of actual assessment dates (i.e. 
progression dates recorded between scheduled visit dates will be assigned the next 
scheduled tumor assessment date as the date of progression) 
 
8.7.2 KEY SECONDARY EFFICACY ENDPOINTS 
 
There are two key secondary efficacy endpoints: 
• ORR  
• DOR  
The analysis of the key secondary efficacy endpoints will be performed using statistical methods 
with multiplicity control described in Section 7.7.5. 
 
8.7.2.1 
RESPONSE RATES 
 
ORR 
 
The ORR will be estimated as the proportion of patients who achieve a confirmed response of 
sCR, CR, VGPR, or PR as their best response, as assessed by the IRC.  
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on the Clopper-Pearson method. The treatment groups will be compared using the Cochran-
Mantel-Haenszel test stratified by the randomization stratification factor. 
 
Confirmed response: Two consecutive assessments with the same response result made at any 
time. If the second consecutive assessment (made at any time) the response is higher than the 
previous one, then the confirmed response (linked to the first assessment visit) will be the first 
one (e.g., PR – VGPR consecutive pair will lead to a PR confirmed response at the first visit). If 
the second consecutive response is lower than the first one, then the confirmed response (linked 
to the first assessment visit) will be the second one (e.g., CR – VGPR consecutive pair will lead 
to a VGPR confirmed response at the first visit). This rule for confirmed response is only 
applicable to sCR-SD responses; confirmed PD is treated separately. 
All the details of myeloma response assessment will be presented in a listing. 
 
8.7.2.2 
TIME TO EVENT PARAMETERS 
 
DOR 
DOR is defined as the time in months from the first evidence of confirmed assessment of sCR, 
CR, VGPR, or PR (as assessed by IRC) to first confirmed disease progression according to the 
IMWG-URC (as assessed by IRC) or to death due to any cause.  DOR is defined only for 
patients with a confirmed PR or better. DOR is to be censored using the same rules as for PFS. 
DOR will be derived as (DOR date – date of first documented confirmed response (≥PR) + 
1)/30.4375.   
 
DOR analysis will be performed using Kaplan-Meier method. The median time to event will be 
estimated for each treatment arm from the 50th percentile of the corresponding Kaplan-Meier 
estimates. 95% confidence intervals will be based on the log(-log(survival)) distribution. 
 
The stratified log-rank test and the Cox model will be applied in the same way as for the primary 
PFS analysis. 
 


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8.7.3 OTHER SECONDARY EFFICACY ENDPOINTS 
8.7.3.1 
RESPONSE RATES 
 
Response rates (Best response and CBR) and other dichotomous parameters will be presented 
together with 95% exact binomial confidence intervals based on the Clopper-Pearson method. 
The treatment groups will be compared using the Cochran-Mantel-Haenszel test stratified by the 
randomization stratification factor. 
 
Best Overall Confirmed Response  
The best overall confirmed response during the study, including PFS-FU response assessments, 
(sCR, CR, VGPR, PR, MR, SD, PD, or non-evaluable) as assessed by the IRC according to 
IMWG-URC, will be summarized descriptively. 
 
Best Unconfirmed Response 
The best IRC assessed response achieved on study, including PFS-FU response assessments. 
This response may not be confirmed by a consecutive assessment.  
 
CBR 
CBR is the proportion of patients who achieve a confirmed minimal response or better (sCR, CR, 
VGPR, PR and MR) as their best response, as assessed by the IRC.  CBR will be summarized 
using the same method as for ORR. 
 
All the details of myeloma response assessment will be presented in a listing. 
 
Concordance analysis 
The concordance between the IRC assessment and the investigator’s assessment of progression 
will be summarized descriptively with frequency tables displaying best overall confirmed 
response, cross-classified by rater.  
 
Sensitivity analyses have been added for the key secondary endpoints (ORR and DOR) as 
assessed by investigators. 


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8.7.3.2 
TIME TO EVENT PARAMETERS 
 
Time-to-event analyses (DOCB, TTP, TTNT and OS) will be performed using Kaplan- 
Meier method. The median time to event will be estimated for each treatment arm from the 50th 
percentile of the corresponding Kaplan-Meier estimates. 95% confidence intervals will be based 
on the log(-log(survival)) distribution. 
 
The stratified log-rank test and the Cox model will be applied in the same way as for the primary 
PFS analysis. 
 
DOCB 
DOCB will be calculated as time in months from the first evidence of confirmed IRC 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. DOCB is to be 
censored using the same rules as for PFS. 
DOCB will be derived as (DOCB date – date of first documented confirmed response (≥MR) + 
1)/30.4375. 
 
TTP 
TTP is defined as time in months from randomization to the date of the first documented 
confirmed progression as assessed by IRC. TTP will be derived as (TTP date – randomization 
date +1)/30.4375. 
TTP will be right-censored for patients who meet one of the following conventions described in 
Table 6 below: 
 
 
 
 
 
 


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        Table 6. Conventions for TTP Date Derivation and Censoring 
Situation 
Date of Progression or Censoring 
Outcome 
No post-baseline disease 
assessments, except in the case of 
death 
Date of randomization 
Censored 
New anticancer therapy started 
before documentation of PD  
Date of last disease assessment 
prior to start of new anticancer 
therapy 
Censored 
PD immediately after more than 
1 consecutively missed disease 
assessment visit* 
Date of last disease assessment 
visit without documentation of PD 
that is before the first missed visit 
Censored 
Unconfirmed PD as the final 
response assessment 
Date of latest PD assessment 
Progressed 
No PD documentation  
Date of last disease assessment 
Censored 
PD between planned 
disease assessments 
first disease assessment 
showing PD 
Progressed 
*unless there was an unscheduled visit showing absence of PD between the last scheduled missing response   
assessment and date of PD identification 
 
TTNT 
Time to next treatment (TTNT) in months will be calculated from the date of randomization to 
the start of the next line of therapy (excluding radiotherapy) or death. Patients who have no post 
study myeloma therapy and do not have a date of death will be censored at the date of last 
contact. 
TTNT will be derived as (TTNT date – randomization date +1)/30.4375. 
 
An alternative definition will also be used: 
TTNT in months will be calculated as time in months from the date of randomization to the start 
of the next line of therapy (excluding radiotherapy). Patients who have no post study myeloma 
therapy will be censored at the earlier of date of death and date of last contact. 
TTNT will be derived as (TTNT date – randomization date +1)/30.4375. 
 
 


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OS 
OS is defined as time in months from date of randomization to death due to any cause.  Patients 
still alive at the end of the study, or lost to follow-up, will be censored at last day known alive. 
OS will be derived as (OS date – randomization date +1)/30.4375. 
 
TTR 
TTR will be calculated as time in months from randomization to first documented confirmed 
response as assessed by IRC in a patient that has responded with PR or better.  TTR will be 
presented descriptively for patients with a response. TTR will be derived as (date of first 
documented confirmed response (≥PR) – randomization date +1)/30.4375. 
 
8.7.4 EXPLORATORY EFFICACY ENDPOINTS 
 
PFS-2 
PFS-2 is defined as time from randomization to progression as assessed by IRC on the next line 
of treatment or death from any cause, whichever occurs first. Patients with no progression or 
death will be censored on the date of last disease assessment after the next line of treatment 
started.  
PFS-2 time, in months, will be calculated as (PFS-2 date – date of randomization +1)/30.4375. 
PFS-2 will be presented and analyzed similarly to PFS. 
 
PFS-2 will be performed using Kaplan-Meier method. The median time to event will be 
estimated for each treatment arm from the 50th percentile of the corresponding Kaplan-Meier 
estimates. 95% confidence intervals will be based on the log(-log(survival)) distribution. The 
stratified log-rank test and the Cox model will be applied for PFS-2 the same way as for the 
primary PFS analysis. 
 
MRD Status 
The number and percentage of patients with particular MRD status will be summarized for 
patients achieving CR or VGPR response (as their best response as assessed by IRC) by 
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is non-evaluable; negative; positive, where positive is worst). 
 
The number and percentage of patients with MRD or not in patients achieving CR or VGPR will 
be presented. 
 
Response Rate in Patients with Extramedullary Myeloma 
The response rate in patients with extramedullary myeloma (present at screening) will be 
estimated as the proportion of patients who achieve a confirmed response of CR and PR as their 
best response, as assessed by the IRC, and have extramedullary myeloma present at screening.  
 
Crossover Analyses 
To evaluate efficacy in patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone after disease progression on daratumumab, the response rate 
(ORR, Best Response (BR) and CBR) and time to event (DOR, DOCB, TTR, TTP, TTNT and 
OS) will be presented descriptively with 95% confidence intervals. Time to event will be 
calculated from date of first treatment after crossover. 
 
 
8.7.5 MULTIPLICITY 
 
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 of 0.05. If this comparison is not 
statistically significant, then the comparison of key secondary efficacy endpoints will be 
considered nominal, descriptive and exploratory. 
 
First, the superiority of PFS in patients treated with melflufen and dexamethasone in 
combination with daratumumab compared to daratumumab alone will be tested at an alpha level 
of 0.05.  If the primary endpoint is statistically significant, the following key secondary endpoint 
will be tested in this fixed order at an alpha level of 0.05: 
 
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combination with daratumumab compared to daratumumab alone.  
 
If this key secondary endpoint above is statistically significant then the following key secondary 
endpoint will be tested at an alpha level of 0.05: 
 
• Duration of Response (DOR) in patients treated with melflufen and dexamethasone in 
combination with daratumumab compared to daratumumab alone. 
 
 
8.7.6 OTHER EFFICACY ASSESSMENTS 
 
Myeloma specific laboratory tests results, including SPEP, UPEP, serum and urine 
immunofixation (IFE), and serum free light chain (SFLC) will be summarized descriptively by 
assessment visit.  
 
All the myeloma specific laboratory tests results and other efficacy assessments (i.e. 
extramedullary plasmacytoma assessment) will be presented in the listings. A separate listing for 
bone marrow aspirate will be presented. 
 
8.8 
SAFETY ENDPOINTS AND ANALYSIS 
 
All analyses of safety will be based on the Safety Analysis Set and presented by treatment arms 
and overall, unless otherwise specified for specific analysis. Safety data for patients in Arm B 
who crossover to treatment with melflufen, daratumumab and dexamethasone will be 
summarized separately. 
 
8.8.1 EXPOSURE TO STUDY TREATMENT 
 
Exposure analysis will be based on the Safety Analysis Set and presented by treatment arms. 
Study treatment administration, including duration of exposure, total dose, dose modifications 
will be summarized for each group separately. 
 
Duration of melflufen treatment in weeks is defined as (date of last dose – date of first dose + 29 
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If a patient discontinued from treatment and the end of treatment (EOT) visit happened prior to 
29 days after last dose, then the duration of meflufen is defined as (date of EOT – date of first 
dose +1) divided by 7. 
If a patient died prior to 29 days after last dose, then the duration of meflufen is defined as (date 
of death – date of first dose +1) divided by 7. 
Duration of dexamethasone treatment in weeks is defined as (date of last dose – date of first 
dose + 1) divided by 7. 
Duration of daratumumab treatment in weeks is defined as (date of last dose – date of first 
dose + 1) divided by 7. 
For treatment Arm A, overall duration of treatment with study drug in weeks is defined as the 
longest duration of dexamethasone, daratumumab and melflufen treatment. 
 
The duration of study treatment exposure will be summarized descriptively and presented for 
overall treatment duration (Arm A only) and also separately for melflufen, dexamethasone and 
daratumumab and will include the following: treatment duration in weeks, number of cycles 
received (and also number of doses for dexamethasone and daratumumab), cumulative dose (in 
mg) of study drug received per patient, average dose of study drug (mg/week for melflufen, 
dexamethasone and daratumumab), and the total number and percentage of patients receiving a 
dose per cycle (for overall treatment (Arm A only) and melflufen). Patients who received only a 
partial dose of melflufen for a given cycle will be considered as having received treatment for 
that cycle. 
Average dose of melflufen in mg/week is defined as the cumulative dose divided by the duration 
of melflufen treatment. The same derivation holds for dexamethasone and daratumumab.  
 
Dose modification information will be summarized descriptively for any drug and then also 
separately for melflufen, dexamethasone and daratumumab. The number of patients with drug 
modifications due to AEs will be presented based on the AE eCRF page, number of patients with 
each action by frequency will be presented based on the melflufen, dexamethasone and 
daratumumab administration eCRF pages. The number of patients with any drug modification 
will also be presented by cycle. 
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following a preceding dose of melflufen (day at the moment of melflufen administration is 
defined as the difference between Cycle X Day 1 (CXD1) date and C(X-1)D1 date +1). Dose 
delays will be categorized as delays in weeks as 1 (day 33 to 39), 2 (day 40 to 46), 3 (day 47 to 
53), 4 (day 54 to 60), and >4 weeks (day 61 or later) for each cycle.  
A separate table will present the number and percentage of patients with delayed completed 
cycles (those with day 33 and later at the moment of melflufen administration following a 
preceding dose of melflufen) as well as the number of delayed cycles by delay categories (1 
week, 2 weeks, 3 weeks, 4 weeks and >4 weeks). 
 
Number of patients with a dose delay due to COVID-19 pandemic will be summarized. 
 
All melflufen, dexamethasone and daratumumab administration details will be presented in the 
respective listings.  
 
8.8.2 ADVERSE EVENTS 
 
All AE summaries will be presented based on the Safety Analysis Set and presented by treatment 
arms and overall. AE data for patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone will be summarized separately. 
 
All AEs will be coded using the MedDRA (version 23.0 or higher), for toxicity assessment the 
National Cancer Institute Common Toxicity Criteria (NCI CTCAE) version 5.0 AE will be used.  
The summaries of AEs will be based on TEAEs (Treatment Emergent Adverse Events).  
TEAEs are defined as AEs that start on or after the first day study treatment (melflufen, 
daratumumab, or dexamethasone) is administered and within 30 days of the last administration 
of study treatment or before the start of a subsequent anticancer treatment (whichever occurs 
first) or that worsen on or after the first day of study treatment. The definition of TEAEs used for 
the crossover part of the study stays the same as for the main part of the study but with first and 
last study drug doses referring to the first and last study drug doses during crossover part of the 
study. 
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patients (as well as total event count) with at least one TEAE; patients with at least one grade 3, 
grade 4 and grade 3/4 TEAE; patients with at least one serious TEAE; patients with TEAEs 
leading to discontinuation; and patients with TEAEs leading to death. 
The overall summary will include the treatment related TEAEs analyzed separately in four ways: 
treatment related TEAEs (melflufen and/or dexamethasone and/or daratumumab-related – 
presented for Arm A and daratumumab-related - presented for Arm B), melflufen related 
TEAEs, dexamethasone-related TEAEs, and daratumumab-related TEAEs. It will include the 
number and percentage of patients (as well as total event count) with related TEAEs; patients 
with related grade 3, grade 4 and grade 3/4 TEAEs; patients with related serious TEAEs; and 
patients with related TEAEs leading to death. In addition the number and percentage of patients 
with TEAEs leading to dose reduction, dose held and dose discontinuation will be presented 
separately for overall treatment (meflufen and/or dexamethasone and/or daratumumab – 
presented for Arm A and daratumumab-related – presented for Arm B) and melflufen.  
 
The number and percentage of patients experiencing TEAEs, as well as total event count (except 
for summaries by toxicity grade), will be summarized by MedDRA SOC and PT for:  
• TEAEs 
• Treatment related (related to melflufen and/or dexamethasone and/or daratumumab 
presented for Arm A and daratumumab-related presented for Arm B) AEs 
• Melflufen related TEAEs 
• Dexamethasone related TEAEs 
• Daratumumab related TEAEs 
• Serious TEAEs 
• Non-Serious TEAEs 
• Treatment related serious TEAEs 
• Melflufen related serious TEAEs 
• Dexamethasone related serious TEAEs 
• Daratumumab related serious TEAEs 
• TEAEs by CTCAE toxicity grade 
• Treatment related TEAEs by CTCAE toxicity grade 


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• Melflufen related TEAEs by CTCAE toxicity grade 
• Dexamethasone related TEAEs by CTCAE toxicity grade 
• Daratumumab related TEAEs by CTCAE toxicity grade 
• Serious TEAEs by CTCAE toxicity grade 
• Treatment related serious TEAEs by CTCAE toxicity grade 
• Melflufen related serious TEAEs by CTCAE toxicity grade 
• Dexamethasone related serious TEAEs by CTCAE toxicity grade 
• Daratumumab related serious TEAEs by CTCAE toxicity grade 
• TEAEs resulting in any treatment modification (hold, reduction, delay, interruption and 
discontinuation) for each study drug and separately for each modification  
 
The number and percentage of patients with grouped AEs – TEAEs defined as follows: 
• Thrombocytopenia (PTs: “Thrombocytopenia”, “Platelet count decreased”) 
• Treatment related thrombocytopenia 
• Melflufen related thrombocytopenia  
• Dexamethasone related thrombocytopenia  
• Daratumumab related thrombocytopenia  
• Neutropenia (PTs: “Neutropenia”, “Neutrophil count decreased”) 
• Treatment related neutropenia 
• Melflufen related neutropenia 
• Dexamethasone related neutropenia 
• Daratumumab related neutropenia 
• Anemia (SMQ “Haematopoietic erythropenia” (BROAD)) 
• Treatment related anemia 
• Melflufen related anemia 
• Dexamethasone related anemia 
• Daratumumab related anemia 
• Febrile neutropenia (PT “Febrile neutropenia”) 
• Infections (SOC “Infections and infestations”) 
• Hemorrhage (SMQ “Haemorrhage terms, excluding laboratory terms”) 


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• Thrombocytopenia concomitant to hemorrhage: Hemorrhage with an onset date within ± 
7 days of the onset and/or resolution date of a grade 3 or 4 thrombocytopenia. Grade 3/4 
thrombocytopenia resolution date is to be identified based on the laboratory data as a first 
day when thrombocytopenia assessment is grade 2 or lower (grade ≤ 2 for toxicity 
“Platelet count decreased”). 
• Neutropenia concomitant to infection: Infection with an onset date within ± 7 days of the 
onset and/or resolution date of a grade 3 or 4 neutropenia. Grade 3/4 neutropenia 
resolution date is to be identified based on the laboratory data as a first day when 
neutropenia assessment is grade 2 or lower (grade ≤ 2 for toxicity “Neutrophil count 
decreased”). 
The groups above will be summarized as separate summaries for all by SOC, PT and all by SOC, 
PT, CTCAE toxicity grade analyses.  
A patient reporting the same TEAE more than once will only be counted once when calculating 
the incidence:  
1) within a given SOC 
2) within a given SOC and PT combination or MedDRA SMQ 
The maximum CTCAE toxicity grade and strongest causal relationship to study treatment for the 
event will be used in the incidence calculations.   
TEAEs reported with a causality assessment of “Probably Related” or “Possibly Related” are to 
be considered as “Related” for analysis purposes. AEs having both onset and end dates missing 
will be considered TEAEs; in cases with a missing start date and a complete end date, the AE 
will be considered a TEAE unless the end date is prior to the date of the first dose of study drug. 
A separate summary will present the number and percentage of patients who died during the 
study treatment period (from the first dose of melflufen (daratumumab for Arm B) up to 30 days 
after last dose of melflufen (daratumumab for Arm B)) and during follow-up (more than 30 days 
after last melflufen dose (daratumumab for arm B)) along with the reasons for the deaths, as well 
as the number of patients who died within 60 days after the first melflufen dose (daratumumab 
for Arm B). Deaths of patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone will be summarized separately. 
 
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and events with fatal outcome. 
 
8.8.3 LABORATORY DATA 
 
Laboratory data will be summarized for the Safety Analysis Set and presented by treatment arms 
and overall. Laboratory data for patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone will be summarized separately. 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units on Study Data Tabulation Model (SDTM) level. Hematology, 
chemistry and coagulation parameters will be summarized descriptively and changes from 
baseline to post-baseline visits for each parameter will be presented. Urinalysis results will only 
be listed.  
All the data from both scheduled and unscheduled time points will be included in the CTCAE 
grade shift tables. 
Shift tables and plots for the change in CTCAE grade (with separate parts for decreased and 
increased grades) will be constructed for hematology and chemistry laboratory parameters, 
which have corresponding CTCAE grades to tabulate changes in NCI CTCAE (version 5.0) from 
baseline to worst post-baseline on study (up to and including EOT visit) CTCAE grade. Number 
of patients with grade 3 or higher toxicity will be summarized as counts and percentages by 
cycle. A separate listing of all laboratory results corresponding to grade 3 or 4 will be provided.   
The following is a list of parameters that will be presented in the toxicity grades laboratory 
tables: 
•  Hematology 
o Hemoglobin (increase, decrease) 
o Platelets (decrease) 
o White blood cells (WBC) (increase, decrease) 
o Absolute neutrophil count (ANC) (decrease) 
o Lymphocyte count (increase, decrease) 
• Serum Chemistry 
o Alanine aminotrasferase (ALT) (increase) 


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o Aspartate aminotrasnferase (AST) (increase) 
o Alkaline phosphatase (increase) 
o Total bilirubin (increase) 
o Creatinine (increase) 
o Corrected Calcium (increase, decrease) 
o Glucose (increase, decrease) 
o Albumin (decrease) 
o Uric acid/urate (increase) 
o Magnesium (increase, decrease) 
o Phosphorus/phosphate (increase, decrease) 
o Potassium (increase, decrease) 
o Sodium (increase, decrease) 
• Coagulation 
o International normalized ratio (INR) 
 
For hemoglobin, ANC and platelet counts, CTCAE grade shift tables will also be presented by 
cycles. Time from the date of the melflufen dose and time from the date of the daratumumab 
dose in a particular cycle until the date of grade 3, grade 4 and grade 3/4 onset/offset will be 
presented for each cycle for ANC and platelets. Time to onset and time to offset (resolved to 
grade 2 or below) of grade 3, grade 4 and grade 3/4 for ANC and platelets will also be presented 
overall (duration in days from the treatment start until the date of grade 3, grade 4 and grade 3/4, 
respectively). 
For laboratory results reported with a prefix, for example "<" or ">", the value derived from the 
reported results without a prefix will be analyzed. 
All laboratory data will be listed, including toxicity grades and normal ranges. A listing will be 
provided for urine pregnancy tests as well. 
 
8.8.4 VITAL SIGNS  
 
Vital signs will be summarized for the Safety Analysis Set and presented by treatment arms and 
overall. Vital signs data for patients in Arm B who crossover to treatment with melflufen, 


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daratumumab and dexamethasone will be summarized separately. 
Results and change from baseline to post-baseline time-points for weight, blood pressure, pulse, 
respiratory rate and temperature will be presented. 
 
8.8.5 
PHYSICAL EXAMINATION 
 
Physical examination results will only be listed without a summary. 
 
 
 
ECG data will be summarized for the Safety Analysis Set and presented by treatment arms and 
overall. ECG data for patients in Arm B who crossover to treatment with melflufen, 
daratumumab and dexamethasone will be summarized separately. 
ECG data (heart rate, PR interval, QRS interval, QT interval, QTc-Fridericia (QTcF) interval, 
RR interval) will be summarized using descriptive statistics. Changes from baseline to EOT visit 
will also be evaluated.  
Shift tables from baseline (normal / abnormal-clinically significant / abnormal – not clinically 
significant) to each visit (excluding the EOT crossover visit) will be summarized for ECG 
interpretation data.   
All ECG data collected will be presented in the listing. 
 
8.9 
EXPLORATORY ENDPOINTS AND ANALYSIS   
 
8.9.1 
PATIENT REPORTED OUTCOME (PRO) 
 
 
PRO analyses will be described in a separate analysis plan. 
 
8.9.2 PHARMACOKINETICS 
 
PK analysis will be described in a separate analysis plan. 
 
 
8.8.6 
12-LEAD ELECTROCARDIOGRAM (ECG)


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8.9.3 ECOG 
 
ECOG performance status will be summarized as counts and percentages using shift tables of 
baseline versus worst performance status during study by treatment arm and overall.  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. 
 
8.9.4 BIOMARKERS 
 
Biomarker exploratory analyses will be described and presented separately from the main 
clinical study report (CSR) and will be managed by the sponsor. 
 
8.9.5 IMMUNOGENECITY 
 
Immunogenicity analyses of daratumumab and rHUPH20 will be described and presented 
separately from the main clinical study report (CSR) and will be managed by the sponsor. 
 
 
9. 
INTERIM ANALYSES 
 
No interim analyses will be performed. 
 
10. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE 
PROTOCOL 
Response assessments by the IRC will be used for the primary analyses while the investigator 
assessments of response will be used for the sensitivity analysis. The study protocol, Version 2.1, 
Amendment 2 (November 25, 2020) states that the IRC will evaluate response assessments as 
sensitivity analysis. 
PFS has been explicitly added as an exploratory objective with a corresponding endpoint for 
patients in Arm B who crossover. It was missed in the objectives section of the protocol but was 
included elsewhere in the protocol. 
TTR will be analyzed descriptively instead of with the Kaplan-Meier method. 


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11. PROGRAMMING SPECIFICATIONS 
 
All outputs will be produced using SAS version 9.4 or higher. 
The margins should be at least 1.50 inches for the binding edge and 1.0 inches for all others.  
In the top left portion of each table/listing, the protocol number will be presented. On the next 
line a table/listing number followed by the title of the table/listing and population information 
will be displayed. Horizontal lines will appear after the column heading of the table/listing. 
Footnotes will be put under the main body of text at the bottom of the page. The source listing 
number will be displayed for all tables. The SAS program name will appear in the bottom left 
corner in a string and the page number will appear on the bottom right corner of each 
table/listing. The date and time of creation of the table/listing will appear bottom left corner 
under to the SAS program name line.  
Courier New 8-point bold font will be used for all tables and listings. Usually, a landscape layout 
is suggested for both tables and listings, but it is not mandatory. Any date information in the 
listing will use the date9. format, for example, 07MAY2002. 
The list of tables, listings and figures (TFLs), and the shells for unique tables and listings are 
provided in a separate Mock-Up TFLs document. 
 
12. 
REFERENCES 
Lonial S, Weiss B, Usmani S, et al. Daratumumab Monotherapy in Patients with Treatment-
Refractory Multiple Myeloma (SIRIUS): An Open-Label, Randomised, Phase 2 Trial. The 
Lancet 2016; 387 (10027): 1551–1560. 
Kumar S, Paiva B, Andersson K et al. International Myeloma Working Group consensus criteria 
for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 
17; e328-46 
Usmani SZ Weiss BM., Plesner T., et al. Clinical Efficacy of Daratumumab Monotherapy in 
Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Blood, 2016; 
128(1):38-44