Clinical trial NCT03481556
Conditions: Multiple Myeloma
Sponsor: Oncopeptides AB
Start date: 2018-04-12; Completion date: 2022-02-02
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.

Detailed description:

Arms: arm 1: Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with bortezomib at 1.3mg/m² S.Q. on Days 1, 4, 8, 11 and dexamethasone 20 mg (12 mg ≥ 75 years) Days 1, 4, 8, 11 and 40 mg (20 mg ≥ 75 years) on Day 15 and 22 of each 28-day cycle. arm 2: Melflufen 30 mg and 40 mg or 20 mg i.v. Day 1 of each 28-day cycle in combination with daratumumab 16 mg/kg weekly for 8 doses, every other week for 8 doses and then once every 4 weeks. Dexamethasone p.o. 40 mg weekly (20 mg weekly for patients age ≥ 75 years).
Interventions: intervention 1: Melphalan flufenamide (Melflufen) intervention 2: Dexamethasone intervention 3: Bortezomib intervention 4: Daratumumab
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Oral tablets intervention 3: Subcutaneous administration intervention 4: Intravenous infusion

Protocol documents:
Prot_000.pdf: 
Protocol Number:  OP-104 
Official Title:  An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and 
Dexamethasone in Combination with either Bortezomib or Daratumumab in Patients with Relapsed or 
Relapsed-Refractory Multiple Myeloma 
NCT Number: NCT03481556 
Document Date:  05 May 2021 


Confidential 
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Oncopeptides AB 
Protocol No. OP-104 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
Clinical Development Protocol 
OP-104 Anchor Trial 
An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen 
and Dexamethasone in Combination with either Bortezomib or 
Daratumumab in Patients with Relapsed or Relapsed-Refractory 
Multiple Myeloma 
Investigational Product 
Study Sponsor 
Melflufen 
Oncopeptides AB 
Västra Trädgårdsgatan 15 
SE-111 53 Stockholm, Sweden 
Protocol Number 
OP-104 
EudraCT number 
2017-002120-24 
Investigational New Drug Number 
Clinical Research Organization (CRO) 
116362 
Development phase 
Phase 1/2 
Document status 
Version 1.0, June 22, 2017 
Version 2.0, Amendment 1; November 13, 2017 
Version 3.0, Amendment 3: May 17, 2018 
Version 4.0, Amendment 4: November 16, 2018 
Version 5.0, Amendment 5: February 14, 2019 
Version 5.1, Amendment 6: March 18, 2020 
Version 6.1, Amendment 7: April 10, 2020 
Version 6.2, Amendment 8: May 05, 2021 
CONFIDENTIALThis document contains confidential information belonging to Oncopeptides AB. Except as may be otherwise 
agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in confidence and not to 
disclose it to others (except where required by applicable law) nor use it for unauthorized purposes. In the event of actual or 
suspected breach of this obligation, Oncopeptides AB should be promptly notified.


 
 
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Oncopeptides AB 
 
Protocol No. OP-104 
 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
Signature Page 
Protocol Number: OP-104 ANCHOR Trial 
 
Protocol Title: 
An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen 
and Dexamethasone in Combination with either Bortezomib or 
Daratumumab in Patients with Relapsed or Relapsed-Refractory Multiple 
Myeloma 
 
Date of Original Protocol:   Version 1.0, June 22, 2017 
 
 
 
 
 
 
Version 2.0, Amendment 1; November 13, 2017 
 
 
 
 
Version 3.0, Amendment 3; May 17, 2018 
 
 
 
 
Version 4.0, Amendment 4; November 16, 2018 
 
 
 
 
Version 5.0, Amendment 5: February 14, 2019 
 
 
 
 
Version 5.1, Amendment 6: March 18, 2020 
Version 6.1, Amendment 7: April 10, 2020 
Version 6.2, Amendment 8: May 05, 2021 
 
 
 
 
 
Approved By: 
 
 
 
 
________________________________ 
________________________________ 
 
 
 
 
Date 
 
 
 
 
 
 
________________________________ 
________________________________ 
  
 
 
Date 
                                       
 
 
 
 
 
________________________________ 
________________________________ 
 
 
 
 
Date 
 
 
 
07 May 2021 | 01:45 PDT
07 de mayo de 2021 | 01:57 PDT
07 May 2021 | 02:09 PDT


 
 
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Oncopeptides AB 
 
Protocol No. OP-104 
 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
Protocol Acceptance Page 
 
 
Protocol Number:  OP-104: ANCHOR TRIAL 
 
Protocol Title:   
An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen 
and Dexamethasone in Combination with either Bortezomib or 
Daratumumab in Patients with Relapsed or Relapsed-Refractory Multiple 
Myeloma 
 
 
 
Protocol Date:  Version 1.0, June 22, 2017 
 
 
   Version 2.0, Amendment 1; November 13, 2017 
 
 
   Version 3.0, Amendment 3; May 17, 2018 
 
 
   Version 4.0, Amendment 4; November 16, 2018 
 
 
   Version 5.0, Amendment 5: February 14, 2019 
 
 
   Version 5.1, Amendment 6: March 18, 2020 
   Version 6.1, Amendment 7: April 10, 2020 
Version 6.2, Amendment 8: May 05, 2021 
 
 
    
 
By signing this protocol acceptance page, I confirm I have read, understood, and agree to 
conduct the study in accordance with the current protocol.  
 
 
 
__________________________________________ 
Principal Investigator Name (Printed) 
 
__________________________________________ 
____________ 
Principal Investigator Signature 
 
 
 
Date 
 
 
This clinical study was designed and shall be implemented and reported in accordance with 
the International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki. 
 
The study protocol and any amendments are to be reviewed by an Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) before implementation. 
 
Confidential information contained in this document will not be used for any purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent of 
Oncopeptides AB. 


 
 
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Oncopeptides AB 
 
Protocol No. OP-104 
 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
Protocol Amendment Summary of Changes 
 
Overall Rationale for Amendment 8, 05 May 2021: 
Non-substantial amendment due to update of assigned safety CRO. SAE reporting email 
address updated to 
.  
 
Changes Amendment 8 (non-substantial) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Signature Page – 
Sponsor  
Change of Sponsor Clinical 
Operations Director. 
Administrative update. 
Error! Reference 
source not found. 
Assigned safety CRO changed. 
 
SAE reporting email address 
added: 
 
 
Safety CRO changed for the study. 
Error! Reference 
source not found. 
10.3 Pregnancy 
Assigned safety CRO changed. 
 
SAE reporting email address 
added: 
 
 
Safety CRO changed for the study. 
 
 


 
 
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Oncopeptides AB 
 
Protocol No. OP-104 
 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
TABLE OF CONTENTS 
 
List of Figures ............................................................................................................. 9 
List of Tables .............................................................................................................. 9 
Protocol Synopsis ..................................................................................................... 10 
1 
Background ............................................................................................................... 28 
1.1 
Overview of Multiple Myeloma ................................................................... 28 
1.2 
Overview of Melflufen ................................................................................. 28 
1.2.1 
Melflufen Description .................................................................. 28 
1.2.2 
Melflufen Scientific Rationale ..................................................... 29 
1.3 
Clinical Experience ....................................................................................... 30 
1.3.1 
Clinical Experience in RRMM ..................................................... 30 
1.3.2 
Safety Summary ........................................................................... 32 
1.4 
Clinical Efficacy ........................................................................................... 32 
1.4.1 
Clinical Pharmacokinetics ............................................................ 32 
1.5 
Overview of Bortezomib .............................................................................. 33 
1.6 
Overview of Daratumumab .......................................................................... 33 
2 
Rationale ................................................................................................................... 34 
2.1 
Study Rationale ............................................................................................. 34 
2.2 
Rationale for the Selected Patient Population............................................... 35 
2.3 
Rationale for Dose Selection ........................................................................ 35 
3 
Study Objectives ....................................................................................................... 36 
3.1 
Primary Objectives ....................................................................................... 36 
3.1.1 
Phase 1 Primary Objective ........................................................... 36 
3.1.2 
Phase 2a Primary Objective ......................................................... 36 
3.2 
Secondary Objectives ................................................................................... 36 
3.3 
Exploratory Objectives ................................................................................. 37 
4 
Study Design............................................................................................................. 37 
4.1 
Description of Study Design ......................................................................... 37 
5 
Patient Population ..................................................................................................... 39 
5.1 
Patient Screening .......................................................................................... 39 
5.1.1 
Screening Failures ........................................................................ 39 
5.2 
Patient Eligibility .......................................................................................... 39 
5.2.1 
Inclusion Criteria .......................................................................... 39 
5.2.2 
Exclusion Criteria ......................................................................... 41 
5.3 
Patient Enrollment ........................................................................................ 42 
5.3.1 
Enrollment Procedure ................................................................... 42 
5.3.2 
Patient Numbering........................................................................ 43 
5.3.3 
Replacement Policy ...................................................................... 43 


 
 
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Protocol No. OP-104 
 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
6 
Study Treatment ....................................................................................................... 43 
6.1 
Regimen A and B: Dose Level Selection ..................................................... 43 
6.1.1 
Phase 1.......................................................................................... 43 
6.1.2 
Phase 2a ........................................................................................ 43 
6.2 
Regimen A and B:  Initiation of Therapy (Cycle 1 Day 1)........................... 43 
6.3 
Regimen A and B:  dose escalation schema ................................................. 44 
6.4 
Regimen A and B: Dose Levels to be Tested ............................................... 45 
6.4.1 
Regimen A Dose levels ................................................................ 45 
6.4.2 
Regimen B Dose Levels ............................................................... 45 
6.5 
Study Drug Administration ........................................................................... 47 
6.5.1 
Regimen A and B: Melflufen Administration .............................. 47 
6.5.2 
Regimen A and B: Dexamethasone Administration .................... 48 
6.5.3 
Regimen A: Bortezomib Administration ..................................... 49 
6.5.4 
Regimen B: Daratumumab Administration.................................. 49 
6.6 
Phase 1 Dose Limiting Toxicity ................................................................... 51 
6.6.1 
Regimen A: Dose Limiting Toxicity ............................................ 51 
6.6.2 
Regimen B: Dose Limiting Toxicity ............................................ 51 
6.7 
Regimen A and B: Initiation of a new cycle of therapy ............................... 52 
6.8 
Dose Modifications ....................................................................................... 53 
6.8.1 
Dose Reduction Steps................................................................... 53 
6.8.2 
Regimen A: Dose Modification Guidelines Based on Toxicity ... 55 
6.8.3 
Regimen B: Dose Modification Guidelines Based on Toxicity ... 57 
6.8.4 
Regimen A and B: Dose Modifications for Dexamethasone ....... 59 
6.9 
Treatment Duration ....................................................................................... 60 
7 
Concomitant Therapy ............................................................................................... 60 
7.1 
Required Concomitant Therapy .................................................................... 60 
7.2 
Recommended Concomitant Therapy .......................................................... 61 
7.3 
Prohibited Concomitant Therapy .................................................................. 62 
8 
Visit Schedule and Assessments............................................................................... 63 
8.1 
Study Flow and Visit Schedule ..................................................................... 63 
8.2 
Study Assessments ........................................................................................ 69 
8.2.1 
Screening Disease Assessments ................................................... 69 
8.2.2 
Efficacy Assessments ................................................................... 69 
8.2.3 
Safety and Tolerability Assessments............................................ 70 
8.2.4 
Pharmacokinetic Assessments...................................................... 71 
8.2.5 
Assessments if Melflufen is Discontinued ................................... 71 
8.2.6 
End of Treatment .......................................................................... 71 
8.2.7 
Follow Up Assessments ............................................................... 71 
8.2.8 
Criteria for Premature Patient Withdrawal................................... 72 


 
 
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9 
Study Drug Supply and Handling ............................................................................. 73 
9.1 
Melflufen ...................................................................................................... 73 
9.1.1 
Melflufen Packaging and Labeling .............................................. 73 
9.1.2 
Melflufen Storage ......................................................................... 73 
9.1.3 
Melflufen Supply.......................................................................... 73 
9.1.4 
Melflufen Special Handling ......................................................... 73 
9.1.5 
Melflufen Drug Preparation ......................................................... 73 
9.2 
Dexamethasone ............................................................................................. 74 
9.2.1 
Dexamethasone Packaging and Labeling ..................................... 74 
9.2.2 
Dexamethasone Storage ............................................................... 74 
9.2.3 
Dexamethasone Supply ................................................................ 74 
9.3 
Bortezomib.................................................................................................... 74 
9.3.1 
Bortezomib Packaging and Labeling ........................................... 74 
9.3.2 
Bortezomib Storage ...................................................................... 74 
9.3.3 
Bortezomib Supply ....................................................................... 75 
9.3.4 
Bortezomib Special Handling ...................................................... 75 
9.3.5 
Bortezomib Drug Preparation ...................................................... 75 
9.4 
Daratumumab................................................................................................ 75 
9.4.1 
Daratumumab Packaging and Labeling ....................................... 75 
9.4.2 
Daratumumab Storage .................................................................. 75 
9.4.3 
Daratumumab Supply ................................................................... 76 
9.4.4 
Daratumumab Drug Preparation .................................................. 76 
9.5 
Study Drug Compliance and Accountability ................................................ 76 
9.5.1 
Study Drug Compliance ............................................................... 76 
9.5.2 
Study Drug Accountability........................................................... 76 
10 Safety Monitoring and Reporting ............................................................................. 76 
10.1 
Adverse Events ............................................................................................. 76 
10.1.1 
Definitions .................................................................................... 76 
10.1.2 
Grading of Severity ...................................................................... 77 
10.1.3 
Causality ....................................................................................... 77 
10.1.4 
Adverse Event Reporting ............................................................. 77 
10.1.5 
Laboratory Test Abnormalities .................................................... 78 
10.2 
Serious Adverse Events ................................................................................ 79 
10.2.1 
Definitions .................................................................................... 79 
10.2.2 
Serious Adverse Event Reporting ................................................ 80 
10.3 
Pregnancy...................................................................................................... 81 
11 Data Collection and Management ............................................................................ 81 
11.1 
Data Confidentiality ...................................................................................... 81 
11.2 
Site Monitoring ............................................................................................. 82 


 
 
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11.3 
Data Collection ............................................................................................. 82 
11.4 
Database Management and Quality Control ................................................. 83 
12 Statistical Methods and Data Analysis ..................................................................... 83 
12.1 
Study Endpoints ............................................................................................ 83 
12.1.1 
Primary Endpoints ........................................................................ 83 
12.1.2 
Secondary Endpoints .................................................................... 83 
12.1.3 
Exploratory Endpoints.................................................................. 84 
12.2 
Sample Size Calculation ............................................................................... 84 
12.3 
General Considerations for the Statistical Analyses ..................................... 84 
12.3.1 
Analysis Populations .................................................................... 84 
12.4 
Analysis of Primary Endpoints ..................................................................... 85 
12.4.1 
Phase 1.......................................................................................... 85 
12.4.2 
Phase 2a ........................................................................................ 85 
12.5 
Analysis of Secondary Endpoints ................................................................. 85 
12.5.1 
Analysis of efficacy endpoints ..................................................... 85 
12.5.2 
Analysis of Safety Endpoints ....................................................... 87 
12.6 
Analysis of Exploratory Endpoints ............................................................... 88 
12.6.1 
Pharmacokinetic Analysis ............................................................ 88 
12.6.2 
Minimal Residual Disease ............................................................ 89 
12.7 
Handling of Drop-outs and Missing Data ..................................................... 89 
13 Ethical Considerations and Administrative Procedures ........................................... 89 
13.1 
Regulatory and Ethical Compliance ............................................................. 89 
13.2 
Data Safety Monitoring Committee .............................................................. 89 
13.3 
Independent Response ADJUDICATION .................................................... 90 
13.4 
Responsibilities of the Investigator and IRB/IEC/REB ................................ 90 
13.5 
Informed Consent Procedures ....................................................................... 90 
13.6 
Discontinuation of the Study ........................................................................ 90 
13.7 
Publication of Study Protocol and Results ................................................... 90 
13.8 
Study Documentation, Record Keeping and Retention of Documents ........ 91 
13.9 
Confidentiality of Study Documents and Patient Records ........................... 91 
13.10 Audits and Inspections .................................................................................. 92 
13.11 Financial Disclosures .................................................................................... 92 
14 Protocol Adherence .................................................................................................. 92 
14.1 
Amendments to the Protocol......................................................................... 92 
15 References ................................................................................................................ 93 
16 Appendices ............................................................................................................... 96 
Appendix A.  Eastern Cooperative Oncology Group (ECOG) Performance Scale ........ 96 
Appendix B.  National Cancer Institute CTCAE Version 4.03 ....................................... 96 
Appendix C.  IMWG Uniform Response Criteria ........................................................... 97 


 
 
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Appendix D.  Line of Therapy Definition ....................................................................... 99 
Appendix E.  Definition of Relapsed Disease ............................................................... 100 
Appendix F.  Declaration of Helsinki ............................................................................ 100 
Appendix G.  Estimated Creatinine Clearance by Cockcroft- Gault Formula .............. 101 
Appendix H.  Assessment of QTC Interval ................................................................... 101 
Appendix I.    ISS and R-ISS Score ............................................................................... 102 
Appendix J    BSA DuBois Formula ............................................................................. 102 
Appendix K  Products containing boron, mannitol, sodium citrate and polysorbate-
80 ............................................................................................................................ 103 
List of Figures 
Figure 1-1:   Structure of Melflufen 
29 
List of Tables 
Table 1-2 Summary of Melflufen Treatment-Related Grade 3 or 4 AE in ≥5% of 45 
Patients Dosed with 40 mg Melflufen in combination with 
dexamethasone in trial O-12-M1 
31 
Table 4-1 Daratumumab Schedule 
38 
Table 6-1 Dose Levels to be Tested 
45 
Table 6-2 Regimen B Dose Levels 
45 
Table 6-3 Daratumumab Dosing Schedule 
49 
Table 6-4 Infusion Rates for Daratumumab Administration 
50 
Table 6-5 Dose Reduction Steps for Melflufen 
53 
Table 6-6 Dose Reduction Steps for Dexamethasone 
54 
Table 6-7 Dose Reduction Steps for Bortezomib 
54 
Table 6-8 Regimen A: Dose Modification Guidelines for Melflufen and Bortezomib 
Related Toxicity 
55 
Table 6-9 Dose Modification for Bortezomib Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
56 
Table 6-10 Dose Modifications for Melflufen and Daratumumab Drug Related 
Toxicity 
57 
Table 6-11 Dose Modifications for Toxicity Related  to Dexamethasone 
59 
Table 8-1 Schedule of Events 
64 
Table 10-1 Adverse Event Severity 
77 
Table 12-1 Conventions for Censoring for PFS 
86 
 
 
 


 
 
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Protocol No. OP-104 
 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
Protocol Synopsis 
Compound Name 
Melflufen 
Protocol Name 
OP-104 ANCHOR Trial 
Chemical Name 
4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine 
ethyl ester hydrochloride   
Study Protocol Title 
An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen 
and Dexamethasone in Combination with either Bortezomib or 
Daratumumab in Patients with Relapsed or Relapsed-Refractory Multiple 
Myeloma 
Study Sponsor 
Oncopeptides AB 
 
 
Site(s)  
Approximately 17 sites in Europe and US. 
Study Period  
Enrollment from April 2018 – December 2021 
Background and 
Rationale 
Melflufen is a peptidase-potentiated alkylator. Melflufen is lipophilic and 
can thereby traverse the cell membrane passively and relatively freely.  
Once inside the cell, melflufen is cleaved by peptidases, which are over-
represented in the cancer cells.  Due to its lipophilicity and peptidase-
dependent distribution profile, a strong increase of alkylator is achieved in 
cancer cells, without a corresponding increase in other cells (which 
determines the side effect profile (Gullbo et al. 2003c, Wickström et al. 
2010).  Consequently, melflufen has a different bio distribution and 
bioavailability profile compared to other alkylators.  Melphalan is the most 
potent existing alkylator for the treatment of multiple myeloma. Cancer 
cells receive around 50 times higher exposure of alkylators after exposure 
to melflufen compared to melphalan.  Via studies in animals and later 
clinical studies it has been established that this increase in exposure after 
treatment with melflufen does not lead to an increased number, or different 
types of, adverse effects.  However, the cytotoxic effect on cancer cells 
increases and new efficacy qualities arise, such as increased effect on 
multi-resistant cancer cells and substantial anti-angiogenic effects (Gullbo 
et al. 2004, Wickström et al. 2007, Chauhan et al. 2013). 
An assessment of data from clinical trial O-12-M1 in relapsed-refractory 
multiple myeloma (RRMM) was performed after the data base lock 
November 09, 2017. Of the 45 patients treated with at least 1 dose of 40 
mg melflufen in combination with weekly dexamethasone, 21 patients 
(47%) have reported a best response of minimal response (MR) or better 
and 14 patients (31%) have reported partial response (PR) or better.  These 
45 patients had a median of 4 prior lines of therapy, including 
immunomodulatory drugs (IMiD)s, proteasome inhibitors (PI)s and 
alkylators.   The median progression free survival (PFS) was 5.7 months 
at the time of data-cut based on 41 events in 45 patients with ≥ 1 cycle.  
Median number of cycles completed was 5.0 (1 – 14).  The safety profile 
of melflufen suggested by preclinical studies is supported by clinical data 
from 45 patients with solid tumors and from a total of 75 patients with 
RRMM in the completed Phase 1/2a clinical trial O-12-M1 (58 patients 
dosed at the MTD of 40 mg of melflufen and 17 patients dosed at other 
doses in Phase 1 part of the trial).  Taken together, clinical and preclinical 
data support that melflufen provides peptidase potentiated alkylating 
metabolites to tumor cells such as MM and thereby exerts a higher anti-


 
 
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Protocol No. OP-104 
 
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tumor activity compared with equimolar administration of melphalan but 
with a similar safety profile.  
In non-clinical in vitro studies, the combination of melflufen with 
bortezomib or dexamethasone triggered synergistic anti–multiple 
myeloma activity, evidenced by a significant decrease in viability of 
MM.1S cells. Importantly, a similar synergism was observed between 
melflufen and bortezomib or dexamethasone in melphalan-resistant LR5 
multiple myeloma cells. Although definitive evidence of decreased 
toxicity of combination therapy awaits results of clinical trials, the synergy 
observed in vitro may allow for use of lower doses and decreased toxicity 
(Chauhan et al. 2013). 
A pharmacokinetic drug-drug interaction between melflufen and 
bortezomib is unlikely to occur.  Melflufen is very rapidly distributed out 
of systemic circulation and metabolized to melphalan by peptidases and 
esterases. Hence, renal and hepatic elimination of melflufen and binding 
to drug metabolic enzymes is likely to be negligible. For melphalan the 
package insert states: Co-administration of melphalan-prednisone 
increased the exposure of bortezomib by 17% in 21 patients.  However, 
this increase is unlikely to be clinically relevant. 
The combination of melphalan, bortezomib and prednisone (VMP) is an 
established combination treatment in MM, and is part of the IMWG 
recommendations (Palumbo et al. 2014) for newly diagnosed patients who 
are not eligible for high dose therapy and stem cell transplant, as well as 
for patients with relapsed disease. 
A Phase 3 trial, with bortezomib-melphalan-prednisone-thalidomide 
followed by maintenance treatment with bortezomib-thalidomide 
evaluated a once weekly bortezomib dosing schedule and found no 
difference in efficacy, reduced peripheral neuropathy and reduced 
discontinuation due to this adverse event (Bringhen et al. 2010).  
Daratumumab is a ﬁrst-in-class, human immunoglobulin G1 kappa 
(IgG1k) mAb that binds malignant cells expressing CD38 with high 
afﬁnity and induces tumor cell death through several immune-mediated 
mechanisms. Daratumumab was initially studied in monotherapy setting 
in study GEN501 (Lokhorst et al. 2014, Usmani et al. 2016) and in the 
SIRIUS study (Lonial et al. 2016, Usmani et al. 2016). The combined 
results showed an overall response rate of 31% of daratumumab 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 month). Daratumumab has also 
been studied in combination with lenalidomide and dexamethasone 
(Dimopoulos et al, 2016), or bortezomib and dexamethasone (Palumbo 
2016), for the treatment of patients with multiple myeloma who have 
received at least one prior therapy. These studies resulted in approval for 
daratumumab in these combinations. These studies reported that the 
addition of daratumumab to these therapies improved response rates but 
did not increase the toxicity of the backbone therapy other than 
daratumumab related infusion reactions, including when combined with 
the alkylating agent melphalan. Study MMY3007/Alcyone study is 
presently ongoing comparing daratumumab+VMP vs VMP. 
Although the incorporation of novel agents such as PIs and IMiDs, 


 
 
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Protocol No. OP-104 
 
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including retreatment, sequential and combination therapy approaches, has 
significantly improved outcomes in addition to autologous stem cell 
transplant (ASCT) (for those that are eligible), myeloma is not yet curable 
and additional treatment options are needed. Given the promising efficacy 
and unique mechanism, melflufen represents a reasonable option for 
evaluation in triple drug combinations.  
Study Design 
This is an open-label, Phase 1/2a, multicenter study which will enroll 
patients with relapsed or relapsed-refractory MM to combination regimens 
of melflufen with currently approved agents. The currently planned 
combinations include: 
 
Regimen A:  Melflufen plus bortezomib and dexamethasone  
 
Regimen B:  Melflufen plus daratumumab and dexamethasone 
 
Each combination will begin with a Phase 1 component which will follow 
the standard 3 + 3 Phase 1 design with 3 to 6 patients at each dose level, 
depending on dose limiting toxicity (DLT) observed in the first cycle of 
each patient. Patients who discontinue treatment during Cycle 1 due to 
reasons other than study drug related toxicity, and/or who are considered 
non-evaluable for DLT assessment, may be replaced at the discretion of 
the Data Safety Monitoring Committee (DSMC). Patient recruitment will 
continue until a full cohort of safety evaluable patients has been achieved. 
A DSMC will evaluate all treated patients in each cohort prior to dose level 
adjustment decisions.  
Regimen A: Melflufen Plus Bortezomib and Dexamethasone 
Up to 3 dose levels of melflufen will be tested; i.v. melflufen at 30 mg and 
40 mg or 20 mg given on Day 1 of every 28-day cycle, in combination 
with subcutaneous (SQ) bortezomib at 1.3 mg/m2 twice weekly on Days 
1, 4, 8 and 11 of each 28-day cycle and a fixed dose of dexamethasone 20 
mg orally (p.o.) (12 mg for patients ≥ 75 years of age) on Days 1, 4, 8, 11 
and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Day 
15 and 22, of each 28-day cycle. Alternate dose levels or schedules of 
melflufen, bortezomib or dexamethasone may be explored based on 
tolerability following review and recommendation of the DSMC. 
Regimen B: Melflufen Plus Daratumumab and Dexamethasone 
Up to 3 dose levels of melflufen will be tested; i.v. melflufen at 30 mg and 
40 mg or 20 mg given on Day 1 of every 28-day cycle, in combination 
with daratumumab 16 mg/kg according to the following daratumumab 
schedule: 
Daratumumab Schedule 
Cycle  
Days 
1  
2*, 8, 15 and 22 
2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7+ 
1 
*Due to prolonged infusion time of the first dose of daratumumab, the 


 
 
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Cycle 1 infusion of daratumumab will be given on Day 2 of Cycle 1.  
Dexamethasone 40 mg p.o. (20 mg p.o. for patients ≥ 75 years of age) will 
be given weekly.  Due to the need for steroids to prevent infusion reactions 
with daratumumab, dexamethasone dosing may be split prior to 
daratumumab, and on the day after daratumumab on weeks when 
daratumumab is given.  Refer to the dose and schedule of dexamethasone 
below in section Study Treatment, Regimen B of the synopsis and in 
Section 6.4.2,  Table 6-2.    
Alternate dose levels or schedules of melflufen, daratumumab and 
dexamethasone may be explored based on tolerability following review 
and recommendation of the DSMC. 
All Dosing Regimens 
The primary objective is to determine the optimal dose of melflufen, up to 
40 mg, in combination with partner drugs (drugs defined in a Regimen) in 
triple combinations. Once the optimal dose of melflufen in combination 
with the partner therapy is determined, alternate doses and/or schedules 
may be explored following review and recommendation of the DSMC.  
The objective of all dose adjustments is to find the best benefit/risk 
balance. Dose modifications may be made for individual patients based on 
toxicity during therapy.  
Once the optimal dose, up to 40 mg of melflufen has been determined to 
be safe for a given Regimen in Phase 1, approximately additional 20 
efficacy evaluable patients will be enrolled in that Regimen and treated in 
a Phase 2a part of the study at the dose established in Phase 1. 
Patients will be assessed for response after each cycle according to the 
International Myeloma Working Group - uniform response criteria 
(IMWG-URC) (Rajkumar et al. 2011). Patients who have benefit from the 
therapy may continue treatment until disease progression or unacceptable 
toxicity. Dose modifications may be implemented to manage toxicity 
according to the protocol guidelines. Patients who discontinue treatment 
with one of the drugs in the Regimen (excluding dexamethasone) may 
continue on the other, at the investigator’s discretion if in the best interest 
of the patient. Patients who discontinue melflufen and continue to be 
treated with the other drug in the Regimen will be followed for response, 
PFS and OS follow-up. 
Regimen Selection 
All patients meeting the required eligibility criteria may be eligible for one 
or both of the defined Regimens.  For patients that are eligible for both 
Regimens, the Regimen selection may be determined by the investigator, 
given cohort availability for the selected Regimen at the time of screening. 
Only one cohort per patient will be reserved at a given time. If the patient 
fails screening for the reserved Regimen cohort, enrollment in a non-
reserved Regimen cohort will be based on availability.  Patients may be re-
screened if appropriate. Both Regimens may enroll simultaneously to an 
available cohort.   
During Phase 2a, enrollment based on number of prior therapies and/or 
refractory status may be further explored to optimize the benefit/risk 
balance as recommended by the DSMC.  


 
 
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Objectives 
Primary Objective(s) 
Phase 1 
To determine the optimal dose of melflufen, up to a maximum of 40 mg, 
given every 28 days, in triple drug combination therapy in patients with 
relapsed or relapsed-refractory MM. Each treatment regimen and dose will 
be evaluated separately. 
Phase 2a 
To evaluate the overall response rate (≥ PR) of melflufen, in each 
combination Regimen, at the dose levels and schedules determined in 
Phase 1 in efficacy evaluable patients as well as in all treated patients. Each 
treatment regimen and dose will be evaluated separately. 
Secondary Objectives 
 
To evaluate the best response including the complete 
response/stringent complete response (CR/sCR), very good partial 
response (VGPR), partial response (PR) and clinical benefit rate 
(CBR: proportion of patients with ≥ minimal response (MR)), , 
time to response (TTR), duration of response (DOR; PR or better), 
duration of clinical benefit (CB), , progression free survival (PFS) 
and overall survival (OS) up to a minimum of 2 years in efficacy 
evaluable patients as well as in all treated patients.   IMWG-URC 
guidelines will be used. Each treatment regimen and dose will be 
evaluated separately.To further explore the safety and tolerability 
of the combination regimens. Each treatment regimen and dose 
will be evaluated separately. 
Exploratory Objectives 
Pharmacokinetics will be evaluated in patients enrolled at selected sites 
only. 
To evaluate minimal residual disease (MRD) in patients achieving a CR. 
Inclusion Criteria 
Patients will be considered eligible for inclusion in this study if they meet 
all of the following criteria: 
1. Male or female, age 18 years or older;  
2. A prior diagnosis of multiple myeloma with documented disease 
progression in need of treatment at time of screening; 
3. One to four prior lines of therapy (Appendix D); 
4. Measurable disease defined as any of the following: 
 Serum monoclonal protein ≥ 0.5g/dL by serum protein 
electrophoresis (SPEP)  
  ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-
hour electrophoresis (UPEP)  
 Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal 
serum kappa to lambda free light chain (FLC) ratio 
5. Life expectancy of ≥ 6 months; 
6. ECOG performance status ≤ 2 (patients with lower performance 
status based solely on bone pain secondary to multiple myeloma may 
be eligible following consultation and approval of the medical 
monitor); 


 
 
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7. Patient is a female of childbearing potential (FCBP)* with a negative 
serum or urine pregnancy test prior to initiation of therapy and agrees 
to practice appropriate methods of birth control, or is a female not of 
childbearing potential, or the patient is a male and agrees to practice 
appropriate methods of birth control (refer to Section 7.1);  
8. Ability to understand the purpose and risks of the study and provide 
signed and dated informed consent;  
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by 
Fridericia Formula (QTcF) interval of ≤ 470 msec (Appendix H);  
10. Adequate organ function with the following laboratory results during 
screening (within 21 days) and immediately before study drug 
administration on Cycle 1 Day 1: 
 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 
109/L) (Growth factors cannot be used within 10 days (14 days 
for pegfilgrastim) prior to initiation of therapy) 
 Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without 
required transfusions during the 10 days prior to initiation of 
therapy) 
 Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted) 
 Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or 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 of ≥ 45 mL/min and serum creatinine ≤ 2.0 
mg/dL (Appendix G); 
11. Must have, or be willing to have an acceptable central catheter (port 
a cath, peripherally inserted central catheter [PICC] line, or central 
venous catheter). 
 
Regimen Specific Inclusion criteria: 
 
Regimen A – Melflufen + Bortezomib and Dexamethasone 
A1   Must be intolerant or refractory to a prior IMiD; refractory defined 
as failure to respond (MR or better) or progression while on therapy 
or within 60 days of last dose. 
 
Regimen B – Melflufen + Daratumumab and Dexamethasone 
B1   Must have had a prior IMiD and a proteasome inhibitor (PI); alone 
or in combination and must be refractory or intolerant to an IMiD, 
PI or both. 
 
*(FCBP) is any sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (not having menstrual cycles due to cancer therapy does 
not rule out childbearing potential) for at least 24 consecutive months. 


 
 
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Exclusion Criteria 
Patients will be ineligible for this study if they meet any one of the 
following criteria: 
1. Primary refractory disease (i.e. never responded with ≥ MR to any 
prior therapy);  
2. Evidence of mucosal or internal bleeding and/or platelet transfusion 
refractory (i.e. platelet count fails to increase by > 10,000 cells/mm3 
after transfusion of an appropriate dose of platelets);  
3. Any medical conditions that, in the Investigator’s opinion, would 
impose excessive risk to the patient or would adversely affect his/her 
participating in this study.  Examples of such conditions are: a 
significant history of cardiovascular disease (e.g., myocardial 
infarction, significant cardiac conduction system abnormalities, 
uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the 
last 6 months); 
4. Known active infection requiring parenteral or oral anti-infective 
treatment within 14 days of initiation of therapy;  
5. Other malignancy diagnosed or requiring treatment within the past 
3 years with the exception of adequately treated basal cell carcinoma, 
squamous cell skin cancer, carcinoma in-situ of the cervix or breast 
or very low and low risk prostate cancer in active surveillance;  
6. Pregnant or breast-feeding females; 
7. Serious psychiatric illness, active alcoholism, or drug addiction that 
may hinder or confuse compliance or follow-up evaluation; 
8. Known human immunodeficiency virus or active hepatitis B or C 
viral infection (see criterion B5 for additional requirements for 
Regimen B); 
9. Concurrent symptomatic amyloidosis or plasma cell leukemia; 
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, 
organomegaly, endocrinopathy, monoclonal protein and skin 
changes); 
11. Previous cytotoxic therapies, including cytotoxic investigational 
agents, for 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 antibodies (mAb) within 4 
weeks of initiation of therapy. Prednisone up to but no more than 10 
mg orally once daily (q.d.) or its equivalent for symptom 
management of comorbid conditions is permitted but dose should be 
stable for at least 7 days prior to initiation of therapy;  
12. Residual side effects to previous therapy > Grade 1 prior to initiation 
of therapy (alopecia any grade and/or neuropathy Grade 1 without 
pain are permitted);  
13. Prior peripheral stem cell transplant within 12 weeks of initiation of 
therapy; 
14. Prior allogeneic stem cell transplantation with active graft-versus-


 
 
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host-disease); 
15. Prior major surgical procedure or radiation therapy within 4 weeks 
of initiation of therapy (this does not include limited course of 
radiation used for management of bone pain within 7 days of 
initiation of therapy); 
16. Known intolerance to the required dose and schedule of steroid 
therapy, as determined by the investigator. 
17. Prior treatment with melflufen. 
Regimen specific exclusion criteria 
Regimen A – Melflufen + Bortezomib and Dexamethasone 
A1    Refractory to a PI in the last line of therapy prior to enrollment in 
this trial; refractory defined as failure to respond (MR or better) 
or progression while on therapy or within 60 days of last dose; 
A2 History of allergic reaction/hypersensitivity attributed to 
compounds containing boron, mannitol, polysorbate 80 or 
sodium citrate dihydrate (See Appendix K). 
Regimen B – Melflufen + Daratumumab and Dexamethasone 
B1 Prior exposure to an antiCD-38 mAb; 
B2 Chronic obstructive pulmonary disease (COPD) with a Forced 
Expiratory Volume in 1 second (FEV1) less than 50% of 
predicted normal; 
B3 Moderate or severe persistent asthma within the past 2 years, or 
currently has uncontrolled asthma of any classification; 
B4 ≥ Grade 3 conduction system abnormalities unless patient has a 
pacemaker. 
B5 Active hepatitis B (defined as HBsAg+) or those at risk for 
reactivation (HBsAg-, Anti-HBs+, Anti-HBc+).  
 
Patients with prior hepatitis B vaccine are permitted (defined 
as HBsAg-, Anti-HBs+, Anti-HBc-).  
 
Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) 
may only be enrolled following approval by the sponsor after 
consideration of risk of reactivation (additional screening and 
monitoring for reactivation of hepatitis B and consultation 
with a liver disease specialist may be required) (see Table 8-
1, footnote u).   
Study Treatment(s) 
For each Regimen, treatment may be given in an outpatient treatment 
setting in cycles.  Each cycle is 28 days.   
Dose levels to be tested: 
Regimen A: Melflufen Plus Bortezomib and Dexamethasone 
Phase 1 
 
Dose 
Level 
Melflufen 
dose (i.v.) 
Bortezomib dose 
(SQ)* 
Dexamethasone dose ## 
(p.o.) 
Cycle = 
28 days 
Day 1 
Days 1, 4, 8, 11 
Days 1,  4,  8,  11,  15 and 22#  


 
 
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Level-1 
20 mg 
1.3 mg/m2 
20 mg** 
Level 1 
30 mg 
1.3 mg/m2 
20 mg** 
Level 2 
40 mg 
1.3 mg/m2 
20 mg** 
*i.v. administration of bortezomib is acceptable only if SQ procedure is 
not tolerated.  **12 mg for patients ≥ 75 years of age. #Day 15 and 22 
dexamethasone 40 mg (20 mg for patients ≥ 75 years of age). 
##Dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) may be 
continued weekly during cycle delays.   
 
Regimen B: Melflufen Plus Daratumumab and Dexamethasone 
Phase 1 
:Dose 
Level 
Melflufen 
dose (i.v.) 
Daratumumab 
dose (i.v.) 
Dexamethasone dose# 
(p.o.)* 
Cycle = 
28 days 
Day 1 
Cycle 1 - Days 
2**, 8, 15 and 22 
Cycle 2 - Days 1, 
8, 15, 22 
Cycle 3 to 6 
-  Days 1 and 15 
Cycle 7+ - Day 1 
On days when melflufen and 
daratumumab are given in 
combination (Day 1)**: 
Patients < 75 years old - Pre 
melflufen and daratumumab and 
the day after daratumumab 
Patients ≥ 75 years old -  Pre 
melflufen and daratumumab 
All other daratumumab dosing 
days (see daratumumab 
schedule):  
Patients < 75 years old -  Pre 
daratumumab and the day after 
daratumumab  
Patients ≥ 75 years old -  Pre 
daratumumab 
On weeks when daratumumab is 
not given (not scheduled or dose 
held) on Days 8, 15, 22 (see 
daratumumab schedule) 
Level-1 
20 mg 
16 mg/kg 
 
Melflufen and daratumumab in 
combination:  
Patients < 75 years old - 20 mg 
Day 1** and 2 
Patients ≥ 75 years old – 20 mg 
Day 1** 
All other daratumumab dosing 
days:  
Patients < 75 years old - 20 mg 
pre, and the day after 
daratumumab 
Patients ≥ 75 years old – 20 mg 
pre daratumumab 
During cycles when 
daratumumab is not given (not 
scheduled or dose held) on Days 
8, 15 or 22:   


 
 
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Patients < 75 years old - 40 mg 
p.o.  
Patients ≥ 75 years old – 20 mg 
p.o. 
Level 1 
30 mg 
16 mg/kg 
Melflufen and daratumumab in 
combination:  
Patients < 75 years old - 20 mg 
Day 1** and 2 
Patients ≥ 75 years old – 20 mg 
Day 1** 
All other daratumumab dosing 
days:  
Patients < 75 years old - 20 mg 
pre, and the day after 
daratumumab 
Patients ≥ 75 years old – 20 mg 
pre daratumumab 
During cycles when 
daratumumab is not given (not 
scheduled or dose held) on Days 
8, 15 or 22:   
Patients < 75 years old - 40 mg 
p.o.  
Patients ≥ 75 years old – 20 mg 
p.o. 
Level 2 
40 mg 
16 mg/kg 
Melflufen and daratumumab in 
combination:  
Patients < 75 years old - 20 mg 
Day 1** and 2 
Patients ≥ 75 years old – 20 mg 
Day 1** 
 
All other daratumumab dosing 
days:  
Patients < 75 years old - 20 mg 
pre, and the day after 
daratumumab 
Patients ≥ 75 years old – 20 mg 
pre daratumumab 
During cycles when 
daratumumab is not given (not 
scheduled or dose held) on Days 
8, 15 or 22:   
Patients < 75 years old - 40 mg 
p.o.  
Patients ≥ 75 years old – 20 mg 
p.o. 
*Oral dexamethasone may be substituted with i.v. dexamethasone at the 
investigator’s discretion, prior to daratumumab infusion only, if this is the 
standard of care of the site.   
**Due to prolonged infusion time of the first dose of daratumumab, the 
Cycle 1 infusion of daratumumab will be given on Day 2 of Cycle 1. 
Therefore, the dexamethasone dose of 20 mg will be given on Day 1 prior 
to melflufen and on Day 2 prior to the daratumumab administration in 


 
 
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Cycle 1 for patients < 75 years of age.  For patients ≥ 75 years of age, the 
Cycle 1, Day 1 dexamethasone 20 mg dose may be split between Day 1 
and Day 2 at the investigator’s discretion (e.g. dexamethasone 12 mg p.o. 
on Day 1 prior to melflufen and 8 mg p.o. on Day 2 prior to daratumumab) 
or dexamethasone may also be given i.v. with a split dose (e.g. 
dexamethasone 10 mg i.v. on Day 1 prior to melflufen and 10 mg i.v. on 
Day 2 prior to daratumumab).  No dexamethasone is required the day 
following daratumumab in Cycle 1.  However, additional steroids may be 
given as needed to prevent or treat hypersensitivity reactions at the 
investigator’s discretion and as per the SoC for the site.    
Phase 2 All Regimens 
Patients will be treated with the dose level of the combination regimen 
determined in Phase 1 for a given Regimen with the same schedule.  All 
patients will follow the same procedures for drug administration as in 
Phase 1. 
Dose Escalation 
Criteria 
All Regimens 
The first cohort of patients enrolled in the Phase 1 portion of each Regimen 
will receive dose level 1 (melflufen 30 mg).  A full safety evaluation will 
be conducted by a DSMC when the planned number of melflufen safety 
evaluable patients have completed the first cycle of combination therapy 
with DLT assessment. The optimal dose of melflufen in combination 
therapy will be defined as the highest of 20, 30 or 40 mg of melflufen that 
results in ≤ 1/6 patient with DLT during the first cycle of therapy. The 
minimum dose of melflufen is 20 mg. 
 
 
If no DLT is reported in the first three patients at a dose level, that 
dose level will be considered safe and three patients will be enrolled 
at the next dose level. 
 
If 1/3 patients in a cohort at a dose level has a DLT, the dose level will 
be expanded to obtain six evaluable patients. 
 
If 2/3 patients in a cohort at a dose level has a DLT, that dose level 
will not be considered safe and no further dose escalation will take 
place.   
 
If there are < 2 patients with a DLT among the expanded cohort of six 
evaluable patients a cohort of three patients will be enrolled in the 
next higher dose level. 
 
If there are 2 or more patients with a DLT among the expanded cohort 
of six evaluable patients, that dose level will not be considered safe 
and no further dose escalation will take place.   
 
If less than 6 patients have been treated in the next lower dose level, 
additional patients will be entered into this dose level until there are 6 
patients treated.  If ≤ 1 of these 6 patients encountered DLT, then this 
dose level will be taken forward to Phase 2a.  If 2 or more of the 6 
patients encounter DLT, a lower dose will be considered.   
NOTE: If a patient discontinues treatment during Cycle 1 for reasons other 
than study drug related toxicity and is considered non-evaluable for DLT 
assessment, the patient may be replaced at the discretion of the DSMC.   
Patients who discontinue treatment with any drug in the Regimen 
(excluding dexamethasone) may continue treatment with the other drug in 


 
 
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the Regimen at the investigator’s discretion if in the patient’s best interest.  
Patients who discontinue melflufen and continue to be treated with the 
other drug in the Regimen will be followed for response, PFS and OS 
follow-up. Further details are provided in section 6.7 and 6.8 of the 
protocol.   
Definition of DLT 
The following criteria will apply to all treatment Regimens.  Additional 
Regimen specific criteria are detailed in the protocol Section 6.6.1 and 
6.6.2.  
 
Grade 3 non-hematologic toxicity preventing the administration of > 
1 dose of the partner therapy* (excluding dexamethasone) during the 
1st cycle  
 
Grade 4 or greater non-hematologic toxicity  
 
Grade 4 thrombocytopenia (platelet count < 25,000 cells/mm3) 
preventing the administration of > 1 dose of the partner therapy* 
(excluding dexamethasone) or with clinically significant bleeding 
during the 1st cycle 
 
Grade 4 neutropenia (ANC < 500 cells/mm3), lasting more than 7 
days during the 1st cycle. 
Greater than 14 days’ delay to meet the criteria for the start of a new cycle 
(Cycle 2) due to toxicity. *Partner therapy includes the drugs defined in a 
Regimen excluding dexamethasone. 
Toxicity will be graded according to the National Cancer Institute – 
Common Terminology Criteria for Adverse Events (AE) Version 4.03 
(CTCAE 4.03) Appendix B.  
Duration of Treatment 
Phase 1 and Phase 2a 
Treatment will be administered in cycles of 28 days.  Treatment may 
continue until progressive disease, unacceptable toxicity or if the 
patient/treating physician determines it is not in the patient’s best interest 
to continue. Response will be evaluated every cycle according to the 
IMWG-URC guidelines.   
Concomitant 
Drug/Therapy 
All blood products and concomitant medications received from screening 
until the end of study treatment visit should be recorded.  Refer to Section 
7.0 for complete details on concomitant therapy. 
 
Prophylactic treatment with anti-emetic(s) just prior to study 
treatment administration is recommended 
 
Patients should receive full supportive care while on this study at the 
investigator’s discretion, including red blood cell transfusions, 
antibiotics, anti-diarrheals, analgesics etc., and treatment of other 
concurrent medical conditions. 
 
i.v. or p.o. bisphosphonate therapy, if indicated, is permitted. 
 
Hematopoietic growth factors and platelet transfusions are allowed 
if neutropenia and/or thrombocytopenia occur but should not be used 
prophylactically during Cycle 1 of Phase 1.  Also see Section 7.2 for 
additional limitations on use of growth factors and platelet 


 
 
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transfusions. 
 
No anticancer agents, other than the study medications administered 
as part of this study protocol, are permitted 
 
Regimen specific required pre- and post-medication(s) are detailed 
in the protocol Section 6.5. 
Number of Patients 
All Regimens 
A maximum of 6 DLT evaluable patients will be enrolled in each dose 
level, melflufen 30 mg and 40 mg or 20 mg.  For each Regimen tested, it 
is anticipated that up to 12 DLT evaluable patients will be enrolled in Phase 
1. 
The 6 patients treated at the optimal dose of each Regimen in Phase 1, will 
be included in the Phase 2a assessment for each Regimen.  Approximately  
20 efficacy evaluable patients in each Regimen will be enrolled in the 
Phase 2a portion of the respective Regimen for a total of 26 efficacy 
evaluable patients at the optimal dose for each Regimen.  
Patients in Phase 1 who are not fully evaluable for assessment of DLT may 
be replaced and patients in Phase 2a who are not efficacy evaluable 
(received at least 2 doses of melflufen and ≥ 50% of the partner therapy 
(excluding dexamethasone) during Cycles 1 and 2 with appropriate 
assessments) may be replaced. 
Assessments 
All required study procedures are detailed in Table 8-1 Schedule of Events. 
Screening Disease Assessments 
 
M-protein determination using the following procedures: 
o 
Serum protein electrophoresis (SPEP) and serum protein 
immunofixation (IFE) with quantitative immunoglobulins (lg); 
and  
o 
Urine protein electrophoresis (UPEP) and urine protein IFE (all 
using the same 24-hour urine collection); and 
o 
Serum free light chains (SFLC) and SFLC ratio. 
 
Bone marrow to quantify percent myeloma cell involvement and 
morphology, cytogenetics by Fluorescence In-Situ Hybridization 
(FISH) and a sample stored for possible MRD assessment. If 
cytogenetics by karyotype has been done according to institutional 
guidelines it should be recorded in the CRF. 
 
Extramedullary plasmacytoma evaluation (by physical examination 
[PE] or imaging technique) 
 
Skeletal survey and/or low dose computerized tomography (CT) 
scan 
 
Beta2 microglobulin 
 
Lactate dehydrogenase (LDH)  
 
International staging system (ISS) Staging Score and Revised ISS 
(R-ISS) 
Efficacy Assessments 
 
M-protein determination using the following procedures: 


 
 
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o 
SPEP and IFE with quantitative immunoglobulins (Ig) 
(quantitative Ig required only for patients with IgA or IgD 
myeloma);  
o 
As daratumumab is a monoclonal IgG kappa antibody, the 
SPEP and IFE can be positive due to 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 Daratumumab Interference Reflex Assay 
(DIRA) test must be completed.  
o 
UPEP and urine protein immunofixation (all using the same 24-
hour urine collection); and 
o 
SFLC and SFLC ratio 
 
Bone marrow aspirate to quantify percent myeloma cell 
involvement and minimal residual disease (MRD) in patients 
achieving CR. 
 
Extramedullary plasmacytoma evaluation (by PE or imaging 
technique) 
 
Skeletal X-rays and/or low dose CT scan (same technique used at 
screening and each evaluation) 
 
Serum calcium 
Safety Assessments 
 
Assessment and grading of AEs 
 
Physical examinations with vital signs, neurologic assessment and 
assessment of performance status 
 
Routine safety laboratory tests, (complete blood count [CBC] with 
differential and platelets; clinical chemistry, coagulation tests and 
urinalysis) with calculation of glomerular filtration rate by the 
Cockcroft-Gault formula (Appendix G) 
 
Pregnancy testing 
 
Electrocardiograms 
 
Chest X-ray 
 
Additional Regimen specific evaluations are detailed in Table 8-1: 
Schedule of events 
AEs, including clinical laboratory and vital sign abnormalities, will be 
graded using the National Cancer Institute (NCI)’s Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 (Appendix B). 
Pharmacokinetic Assessments 
 The PK samples will be collected only at selected sites. Three plasma 
samples for determination of melphalan concentrations will be drawn in 
each of the first two melflufen treatment cycles, 10–15 minutes after the 
end of infusion, 1 hour after the end of infusion and the third sample 2 to 4 
hours after the end of infusion (as late as possible within the time frame). 
For Regimen B, the third sample should be taken after the daratumumab 
infusion in cycle 2. 
 
Statistical Methods 
Study Endpoints 


 
 
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Primary Endpoint 
Phase 1 
The primary endpoint of Phase 1 is to analyze the frequency and grade of 
AE occurring during Cycle 1 at each dose level to be tested.  Each regimen 
and dose will be evaluated separately.  
Phase 2a 
The primary endpoint of Phase 2a is the overall response rate (CR, sCR, 
VGPR, PR) observed in patients treated at the optimal dose of melflufen 
in combination therapy according to IMWG -URC. Each treatment 
regimen and dose will be evaluated separately. 
Secondary Endpoints 
 Best response during the study (sCR, CR, VGPR, PR, MR, stable 
disease [SD], PD or non-evaluable)  
 CBR (≥ MR) 
 DOR 
 PFS 
 OS 
 Frequency and grade of AE’s  
 TTR 
 TTP 
 TTNT 
 Duration of clinical benefit 
 
Exploratory Endpoint 
 
 PK parameters of melphalan at selected time points. 
 Assessment of MRD status in patients that achieve a CR.  
 
*All tumor response and progression-dependent endpoints are as assessed 
by the investigator according to the IMWG-URC (Rajkumar et al. 2011, 
Appendix C). Oncopeptides will implement an independent review of the 
response and progression assessments performed by the investigator. The 
investigator will be notified of any discrepancies in the form of a data 
query. 
Each regimen and dose will be evaluated separately. 
Analysis Sets 
Safety Analysis Set 
All patients that have initiated treatment (at least one dose or partial dose 
of any drug in the Regimen) will be considered evaluable for safety 
analysis.  The maximum grade for each type of adverse event will be 
recorded for each patient, and frequency tables will be reviewed to 
determine patterns.  Additionally, the relationship of the adverse event(s) 
to the study treatment will be taken into consideration. 
 
DLT Analysis Set 
All patients in Phase 1 that complete one cycle of therapy or discontinue 
due to study drug related toxicity (other than exclusions as defined in the 
Regimen specific DLT criteria). Patients that have been replaced in the 
original assigned cohort will not be included in the DLT analysis set.   


 
 
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Efficacy Analysis Set 
The efficacy population will be comprised of all patients who receive at 
least 2 doses of melflufen and ≥ 50% of the partner therapy (excluding 
dexamethasone) during Cycles 1 and 2, had a baseline disease assessment, 
and had at least 1 post-baseline disease assessment (≥ 28 days after first 
dose).   
ICH and Ethics 
This clinical study was designed and shall be implemented and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European 
Directive 2001/20/EC and US Code of Federal Regulations Title 21), and 
with the ethical principles laid down in the Declaration of Helsinki.  The 
study protocol will be reviewed and approved by local ethics committees 
or IRBs and patients will sign Informed Consent Forms before enrolling 
to the trial.   
 
 
 
 
 
List of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine transaminase/Alanine aminotransferase/glutamic pyruvic 
transaminase(SGPT) 
ANC 
Absolute neutrophil count 
Anti-HBc- 
Anti-hepatitis core antibody negative 
Anti-HBs- 
Anti-hepatitis surface antibody negative 
Anti-HBc+ 
Anti-hepatitis core antibody positive 
Anti-HBs+ 
Anti-hepatitis surface antibody positive 
ASCT 
Autologous stem-cell transplantation 
AST 
Aspartate transaminase/Aspartate aminotransferase/glutamic 
oxaloacetic transaminase(SGOT) 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CA 
Chromosomal abnormalities 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CMV 
Cytomegalovirus 
CRF/eCRF 
Case Report Form/electronic Case Report Form 
CRO 
Contract Research Organization 
CR 
Complete Response 
CT 
Computerized tomography 
CTCAE 
Common terminology criteria for adverse events 
DIRA 
Daratumumab interference reflex assay 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 


 
 
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DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EoT 
End of Treatment 
FCBP 
Female of child bearing potential 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HBsAg+ 
Hepatitis B surface antigen positive 
HBsAg- 
Hepatitis B surface antigen negative 
IB 
Investigator’s brochure 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
IFE 
Immunofixation  
Ig 
Immunoglobulin 
IMiD 
Immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
ISS 
International Staging System 
i.v. 
Intravenously 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Myeloma 
MR 
Minimal response 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
OS-FU 
Overall survival follow-up 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PI 
Proteasome Inhibitor 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetics 
p.o. 
Per os/by mouth/orally 
POEMS 
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein 
PR 
Partial response 
q.d. 
Quaque die/ one a day 


 
 
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RBC 
Red blood cell 
R-ISS 
Revised international staging system 
RRMM 
Relapsed Refractory Multiple Myeloma 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SFLC 
Serum free light chain 
SmPC 
Summary of product characteristics 
SoC 
Standard of Care 
SOC 
System organ class 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TTNT 
Time to next treatment 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
VGPR 
Very good partial response 
VMP 
Melphalan, bortezomib and prednisone 
 
 
 


 
 
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1 
BACKGROUND 
1.1 
OVERVIEW OF MULTIPLE MYELOMA 
Multiple myeloma (MM) is a malignancy of the differentiated plasma cells that affects the 
older patient with a median age at onset of 65 to 70 years and a slight male predominance.  
MM is the second most common hematologic malignancy and nearly 30,330 patients with 
myeloma are diagnosed in the United States in 2015 (SEER 2016).  
The disease is characterized by clonal proliferation of plasma cells in the bone marrow and the 
production of excessive amounts of a monoclonal immunoglobulin (usually of the IgG or IgA 
type or free urinary light chain [paraprotein, M-protein or M-component]).  Patients with MM 
may experience significant decrement to quality of life, including bone pain, bone fractures, 
fatigue, anemia, infections, hypercalcemia, hyperviscosity of the blood and renal function 
compromise (including renal failure).  The disease course for MM varies with the disease stage 
at diagnosis, cytogenetic profile, as well as age and patient comorbidities.  The median survival 
is approximately 5 to 7 years with some significant variation in survival depending on host 
factors, tumor burden, biology and response to treatment (Kumar et al. 2008).  However, the 
disease remains ultimately fatal.   
There are currently 6 classes of approved drugs available for the treatment of MM, including 
steroids (prednisone and dexamethasone), immunomodulatory drugs (IMiDs) (thalidomide, 
lenalidomide and pomalidomide), proteasome inhibitors (PIs) (bortezomib, carfilzomib and 
ixazomib), histone deacetylase inhibitors (panobinostat), conventional chemotherapy 
(melphalan, cyclophosphamide, doxorubicin), including high dose melphalan with autologous 
stem-cell transplantation (ASCT) and the most recent addition of monoclonal antibodies 
(elotuzumab and daratumumab). The selection of treatment in relapsed/refractory multiple 
myeloma (RRMM) is challenging.  The National Comprehensive Cancer Network (NCCN) 
guidelines (NCCN 2017) and a recent overview published in the Mayo Clinic Proceedings 
(Kumar et al. 2016) detail an array of single agent, doublet and triplet combination regimens 
that can be considered.  Patients for whom stem cells were cryopreserved early in the disease 
course, and who are transplant candidates, may benefit from ASCT as salvage therapy (Cavo 
et al. 2011).  In general, MM patients will receive an average of 4 to 8 different treatment 
regimens during their lifespan.   
Recent improvements in therapies have significantly increased the expected life span for these 
patients.  However, despite the availability of effective therapies, the optimal combinations 
and sequencing of these agents with other therapies and with one another is still unclear.  Only 
20 to 30% of the relapsed-refractory MM patients typically respond to any particular treatment 
and ultimately patients relapse from all available options.  Given the inevitable relapses seen 
in these patients, new approaches to therapy are clearly still needed.   
1.2 
OVERVIEW OF MELFLUFEN 
1.2.1 
Melflufen Description 
The chemical name for melflufen is 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-
L-phenylalanine ethyl ester hydrochloride and the chemical structure is provided in Figure 1-
1.  The molecular weight 498.4 as free base and 534.9 as the HCl salt.   


 
 
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Figure 1-1:   Structure of Melflufen 
1.2.2 
Melflufen Scientific Rationale 
Melflufen is a peptidase-potentiated therapy designed for targeted delivery of alkylating 
moieties to tumor cells. In contrast to other alkylating agents that are hydrophilic, the 
lipophilicity of melflufen leads to rapid and extensive distribution into tissues and cells. Inside 
cells, melflufen may directly bind deoxyribonucleic acid (DNA) or is readily metabolized by 
intracellular peptidases into the well-known antitumor compound melphalan or by esterases 
into des-ethylmelflufen, which also has alkylating properties.  Due to the high activity of 
peptidases and esterases in human tumor cells, the formation of melflufen’s metabolites is 
rapid in these cells with continued inflow of more melflufen (Gullbo et al. 2003c, Wickström 
et al. 2010).  Since des-ethylmelflufen and melphalan are relatively hydrophilic, there is a 
possibility for intracellular trapping of these alkylators.  This can be explained by a more 
efficient transport of melflufen into these cells, an efficient conversion into other alkylating 
molecules (i.e. melphalan and des-ethylmelflufen) inside the cells and a less rapid 
disappearance of these molecules from the cells. 
The properties of melflufen are supported by clinical pharmacokinetic data.  Melflufen has a 
relatively low rate of hydrolysis in plasma according to in vitro studies.  After intravenous 
infusion, melflufen shows a very rapid disappearance from plasma with no signs of 
redistribution back to the plasma, indicating that a complete metabolism occurs predominantly 
outside the plasma compartment.  Following administration of melflufen, melphalan is found 
in plasma with a peak concentration at 5 to 10 minutes after the end of melflufen infusion 
(pharmacokinetics [PK] data from clinical trial O-12-M1).  The total melphalan plasma 
exposure assessed as Area Under the Curve (AUC) after melflufen administration is similar to 
historical data on exposure after melphalan administration (Nath et al. 2010).  However, the 
intracellular concentration in tumor cells could be considerably higher as discussed above.  The 
metabolite des-ethylmelflufen reaches only very low concentrations in plasma with peak 
concentrations coinciding with end of melflufen infusion followed by a short elimination half-
life.  
The addition of melflufen to panels of primary cultures of human tumor cells, including MM, 
results in 50- to 100-fold higher efficacy to that of melphalan (Wickström et al. 2008), which 
is explained by the 50-fold higher intracellular exposure as AUC of alkylating agents compared 
to that observed after an equimolar dose of melphalan (Chauhan et al. 2013).  


 
 
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Mechanistically-oriented studies have shown that melflufen-induced apoptosis is associated 
with (i) activation of caspases and poly ADP ribose polymerase cleavage; (ii) reactive oxygen 
species generation; (iii) mitochondrial dysfunction and release of cytochrome c; and (iv) 
induction of DNA damage (Chauhan et al. 2013, Ray et al. 2016).  Moreover, melflufen 
inhibits MM cell migration, tumor-associated angiogenesis and DNA repair.  Importantly, 
in vitro studies in MM cell lines resistant to dexamethasone, bortezomib and melphalan have 
shown cytotoxic activities of melflufen at concentrations similar to those observed in the 
parental, non-resistant cell lines.  Potent cytotoxic activity has also been demonstrated in 
primary MM cells from patients including those relapsing after multiple prior therapies with 
bortezomib, lenalidomide, and dexamethasone.  These results suggest a different resistance 
mechanism for melflufen than for other agents used in MM.  In efficacy studies conducted in 
mice and rats carrying different human tumors, including MM, superior antitumor activity of 
melflufen over equimolar dosage of melphalan was observed at seemingly comparable toxicity 
(Gullbo et al. 2004, Wickström et al. 2007, Chauhan et al. 2013). 
The safety profile of melflufen suggested by preclinical studies is supported by clinical data 
from 45 patients with solid tumors (trial O-05-001) and from a total of 75 patients with RRMM 
in a Phase 1/2a clinical trial O-12-M1 (58 patients dosed at the maximum tolerated dose [MTD] 
of 40 mg of melflufen and 17 patients dosed at other doses in Phase 1 of the trial).  Taken 
together, clinical and preclinical data support that melflufen provides peptidase-potentiated 
delivery of alkylating moieties to tumor cells (such as MM cells) and thereby exerts a higher 
anti-tumor activity compared with equimolar administration of melphalan but with a seemingly 
similar safety profile.  The efficacy seems to be consistent across MM populations including 
patients who are double-refractory to IMiDs and PIs and refractory to alkylators. 
Please see the Investigator’s Brochure (IB) for additional information. 
1.3 
CLINICAL EXPERIENCE 
1.3.1 
Clinical Experience in RRMM 
Melflufen was evaluated in combination with low dose dexamethasone, and as single agent, in 
a Phase 1/2a clinical trial O-12-M1 in RRMM.  Adult patients with documented RRMM with 
at least 2 prior lines of therapy, including an IMiD and a PI, and who demonstrated disease 
progression on or within 60 days of last therapy, Eastern Cooperative Oncology Group 
(ECOG) performance status ≤ 2, life expectancy of ≥ 6 months and preserved organ function 
were eligible to enter the study. Phase 1 followed the standard 3 + 3 Phase 1 design with 3 to 
6 patients per dose cohort, depending on dose limiting toxicity observed, at each dose level 
that was tested.  
The Phase 1 part of the clinical trial was completed in September 2014 
(Paba-Prada et al. 2014).  Based on data from 23 patients in four dose groups (15 mg, 25 mg, 
40 mg and 55 mg), a MTD was established as 40 mg of melflufen in combination with 40 mg 
dexamethasone weekly.  Following identification of the MTD, the Phase 2a part of the trial 
was initiated and all subsequently treated patients received a starting dose of 40 mg of 
melflufen.  The Phase 2 part of the clinical trial was completed in November 2017 including 
data from 45 patients treated with melflufen in combination with dexamethasone and 13 
patients treated with single agent melflufen.  
 


 
 
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1.3.1.1 
Clinical Safety 
As of November 9 , 2017, 58 patients had received 280 doses of melflufen 40 mg.  The median 
number of completed cycles was 5.0 (Range 1 – 14). 
The most common treatment emergent adverse events (TEAE) in trial O-12-M1 were 
hematological events, such as thrombocytopenia, neutropenia and anemia.  This is not 
unexpected since hematological events are both common as a consequence of the disease of 
MM and of treatment with alkylators.  These events were assessed to be dose-related, 
reversible, monitorable and mechanism-driven. 
Treatment related Grade 3 and 4 AE’s were reported in 37 patients out of 45 patients (82%).  
Those related to melflufen and occurring in ≥ 5% of the patients are presented in Table 1-2. 
Table 1-1 Summary of Melflufen Treatment-Related Grade 3 or 4 AE in ≥5% of 45 
Patients Dosed with 40 mg Melflufen in combination with dexamethasone 
in 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) 
 
Continuous review of safety data in the Phase 2a part of the study led and the DSMC to include 
an additional week to the cycle length (i.e. to 28 days) to allow further recovery of platelet and 
neutrophil count and potentially allow the patients to stay on treatment longer and achieve 
more benefit. 
Even though neutropenia and thrombocytopenia have been common in connection to melflufen 
treatment, few cases have been reported as serious adverse events (SAE)s as febrile 
neutropenia or bleeding (please see IB for details). 
Since both the disease of MM as well as treatment with alkylators may cause neutropenia and 
neutropenia may be connected with both pneumonia, sepsis or other infections, it is important 
to follow institutional or NCCN guidelines (NCCN 2017) for antimicrobial prophylaxis for 
multiple myeloma patients. 
Please refer to the current IB for further safety data on melflufen. 
1.3.1.2 
Evaluation of QTcF Intervals from Holter Recordings 
Continuous 12-lead Holter recordings from before start of infusion to 120 minutes after start 
of the 30-minute infusion have been obtained on Day 1 of treatment cycles in a subset of 
patients in Study O-12 M1 for general screening purposes. No patient in the study has 
developed absolute QTcF values that are associated with a meaningful increased risk of 
arrhythmias.  Please see IB for details. 


 
 
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1.3.2 
Safety Summary 
The clinical trials results, to date, indicate that the safety profile for melflufen is similar to that 
for other alkylators, where thrombocytopenia, neutropenia and anemia are the most common 
treatment-related AEs. The incidences of Grade 3 and 4 neutropenia and thrombocytopenia 
after 40 mg doses of melflufen are comparable to the incidences observed in studies with low 
dose melphalan regimens in combination with high dose steroids (Richardson et al. 2010). 
Even though neutropenia and thrombocytopenia have been common in connection to melflufen 
treatment, few cases have been reported as SAEs as febrile neutropenia or bleeding (please see 
current IB for details).  There have been no reports of syncope, seizures, ventricular 
arrhythmias, ventricular tachycardia, ventricular fibrillation, flutter, torsade de pointes, or 
sudden deaths in the clinical trials.  The safety profile for melflufen is thus similar to that of 
other alkylators.  
Since both the disease of MM as well as treatment with alkylators may cause neutropenia and 
neutropenia may be connected with both pneumonia, sepsis or other infections, it is important 
to follow institutional or NCCN guidelines (NCCN 2017) for antimicrobial prophylaxis for 
multiple myeloma patients. 
1.4 
CLINICAL EFFICACY 
 The Phase 2 part of the clinical trial was completed in November 2017 including data from 45 
patients treated with melflufen in combination with dexamethasone and 13 patients treated 
with single agent melflufen. ORR among the 45 patients treated with 40 mg melflufen and 
dexamethasone was 31.1%, median DOR was 8.4 months based on 13 events in 14 patients 
(95% CI: 4.6-9.6), median PFS was 5.7 months based on 41 events in 45 patients (95% CI: 
3.7-9.2) and median OS was 20.7 months based on 23 events in 45 patients (95% CI: 11.8-∞).  
Please refer to the current IB for further details on clinical data on melflufen.  
1.4.1 
Clinical Pharmacokinetics 
In humans, melflufen is metabolized to des-ethyl-melflufen, melphalan and the non-alkylating 
para-fluoro-phenylalanin ethyl ester.  PK data for melflufen and melphalan are available from 
the completed clinical trial O-05-001 in patients with solid tumors and from 10 MM patients 
in the ongoing clinical trial O-12-M1.   
In clinical trial O-12-M1 in MM patients, PK data from 12 patients covering the dose range 
15 mg to 55 mg were available as of 30 November 2017.  In all patients, melflufen plasma 
concentration reached a peak before end of infusion and was eliminated with a half-life of 
1 to 5 minutes as measured from end of infusion.  Melphalan PK parameters were similar to 
those observed in clinical trial O-05-001.  Des-ethyl-melflufen reached only very low 
concentrations in plasma and was eliminated with a half-life of approximately 15 minutes.  
The combined results from the two clinical trials demonstrate that the PK of melflufen is 
characterized by low plasma concentrations and a very rapid disappearance from plasma after 
end of the intravenous infusion. The PK of melphalan after administration of melflufen is 
characterized by a rapid formation where plasma concentrations exceed those of melflufen 
within 15 minutes after start of melflufen infusion, and where peak plasma concentrations are 
lower and AUC similar compared with equimolar infusions of melphalan at a similar rate 
(Mougenot et al. 2004, Nath et al. 2010).  Peak plasma concentrations of melphalan appear 
with a delay by up to 10 minutes after the end of melflufen infusion.  The elimination phase of 
melphalan is similar after melflufen and melphalan infusions, according to published data for 
melphalan administration (Mougenot et al. 2004, Nath et al. 2010). 


 
 
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Overall, the observations suggest a mechanism where melflufen is rapidly and widely 
distributed to tissues (including any tumor cells present) outside of the blood compartment. 
Melphalan is predominately formed in these tissues and thereafter distributed back to plasma 
and eliminated primarily by spontaneous hydrolysis to non-alkylating metabolites and with a 
small contribution of direct renal elimination. There is no appreciable active metabolism of 
melphalan mediated by drug metabolic enzymes.  Please see IB for details. 
1.5 
OVERVIEW OF BORTEZOMIB 
Bortezomib is a PI that inhibits NFKB, induces caspase-8/9 mediated apoptosis, and disrupts 
IL-6 induced intracellular signaling pathways (Hideshima et al. 2003).  In a landmark Phase 3 
trial, bortezomib was superior to high dose dexamethasone in relapsed MM (Richardson et al. 
2005).  The agent has also been associated with promising results in patients with newly 
diagnosed disease.  In this setting the combination of bortezomib plus melphalan and 
prednisone was superior to melphalan and prednisone alone with respect to response, remission 
duration, and overall survival (San Miguel et al. 2008).  Bortezomib was approved by US FDA 
2003.   
In non-clinical in vitro studies, the combination of melflufen with bortezomib or 
dexamethasone triggered synergistic anti–multiple myeloma activity, evidenced by a 
significant decrease in viability of MM.1S cells.  Importantly, a similar synergism was 
observed between melflufen and bortezomib or dexamethasone in melphalan-resistant LR5 
multiple myeloma cells. The synergy observed in vitro may allow for use of lower doses and 
decreased toxicity (Chauhan et al. 2013). 
A pharmacokinetic drug-drug interaction between melflufen and bortezomib is unlikely to 
occur. Melflufen is very rapidly distributed out of systemic circulation and metabolized to 
melphalan by peptidases and esterases. Hence, renal and hepatic elimination of melflufen and 
binding to drug metabolic enzymes is likely to be negligible.  For melphalan the package insert 
states: Co-administration of melphalan-prednisone increased the exposure of bortezomib by 
17% in 21 patients. However, this increase is unlikely to be clinically relevant. 
The combination of melphalan, bortezomib and prednisone (VMP) is an established 
combination treatment in MM, and is part of the International Myeloma Working Group 
(IMWG) recommendations (Palumbo et al. 2014) for newly diagnosed patients who are not 
eligible for high dose therapy and stem cell transplant, as well as for patients with relapsed 
disease. 
A Phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance 
treatment with bortezomib-thalidomide evaluated a once weekly bortezomib dosing schedule 
and found no difference in efficacy, reduced peripheral neuropathy and reduced 
discontinuation due to this adverse event (Bringhen et al. 2010).    
Additional details regarding bortezomib can be found in the US prescribing information or EU 
Summary of Product Characteristics (SmPC).  
1.6 
OVERVIEW OF DARATUMUMAB 
Daratumumab is a ﬁrst-in-class, human immunoglobulin G1 kappa (IgG1k) (mAb) that binds 
malignant cells expressing CD38 with high afﬁnity and induces tumor cell death through 
several immune-mediated mechanisms of action, including complement-dependent 
cytotoxicity, antibody-dependent cellular phagocytosis, antibody-dependent cell-mediated 
cytotoxicity, induction of apoptosis, and modulation of CD38 enzyme activities (De Weers et 
al. 2011, Lammerts van Bueren et al. 2014). Although normal lymphoid, myeloid, and some 


 
 
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nonhematopoietic cells or tissues express low levels of CD38, (Deaglio et al. 2001) myeloma 
cells overexpress the protein, (Lin et al. 2004, Santonocito et al. 2004) thus providing a clinical 
rationale or the protein as a therapeutic target in MM. In addition to these immune mediated 
killing mechanisms, daratumumab may also have an immunomodulatory role via T-cell 
activation and expansion as well as mitigation of immunosuppression in patients with MM 
(Krejcik et al. 2016).  
Daratumumab was initially studied in monotherapy setting in study GEN501 (Lokhorst et al. 
2015, Usmani et al. 2016) and in the SIRIUS study (Lonial et al. 2016, Usmani et al. 2016). 
The combined results showed an overall response rate of 31% of daratumumab 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 
month). Daratumumab has also been studied 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. These studies resulted in approval for daratumumab in these combinations. 
Daratumumab has been studied in several combination trials and is approved in combination 
with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of 
patients with multiple myeloma who have received at least one prior therapy (Dimopoulos et 
al, 2016, Palumbo et al. 2016). An additional Phase 1/2 study explored daratumumab in 
combination with other backbone regimens in patients with ND and RRMM included a 
combination of daratumumab plus bortezomib, dexamethasone and melphalan (Moreau et al. 
2015).  This study reported that the addition of daratumumab to these therapies improved 
response rates but did not increase the toxicity of the backbone therapy other than 
daratumumab related infusion reactions, including when combined with the alkylating agent 
melphalan.  Study MMY3007/Alcyone study is presently ongoing comparing daratumumab 
and VMP vs VMP.   
Daratumumab was approved by US FDA 2015. Additional details regarding daratumumab can 
be found in the US prescribing information or EU Summary of Product Characteristics 
(SmPC).  
As of 15 Nov 2018, daratumumab has been administered to approximately 4,407 patients in 
the setting of clinical trials, and an estimated world-wide post-marketing exposure of 34,316 
person-years. Hepatitis B (HBV) reactivation, including fatal cases, has been observed in 
association with daratumumab. Janssen determined HBV reactivation is an important 
identified risk and an adverse drug reaction associated with daratumumab. The overall 
frequency of HBV reactivation in daratumumab clinical trials, including serious and non-
serious reports, is uncommon (0.2%).  The protocol was updated to exclude patients with active 
hepatitis B or at risk for reactivation. 
2 
RATIONALE 
2.1 
STUDY RATIONALE 
Recent improvements in therapies have significantly increased the expected life span for MM 
patients.  However, despite the availability of effective therapies, the optimal combinations 
and sequencing of these agents with other therapies and with one another is still unclear.  Only 
20 to 30% of the relapsed-refractory MM patients typically respond to any particular treatment 
and ultimately patients relapse from all available options.  Given the inevitable relapses seen 
in these patients, new approaches to therapy are clearly still needed.   


 
 
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Melflufen has a different bio distribution and bioavailability profile compared to other 
alkylators.  Melphalan is the most potent existing alkylator for the treatment of multiple 
myeloma. Cancer cells receive approximately 50 times higher exposure of alkylators after 
exposure to melflufen compared to melphalan.  In the Phase 2a potion of protocol O-12-M1 
the median PFS was 5.1 months (95% confidence interval 3.7 to 8.5 months) based on 40 
events in 45 patients with available data.  Of the 34 heavily pretreated (median 4 lines of 
therapy) efficacy evaluable patients the overall response rate (ORR) was 41% and 62% 
reported a best response of minimal response (MR) or better.  Given the promising efficacy, 
melflufen represents a reasonable option for evaluation in triple drug combinations. 
2.2 
RATIONALE FOR THE SELECTED PATIENT POPULATION 
The proposed trial will be conducted in relapsed or RRMM patients who have received 1 to 4 
prior lines of therapy 
Many triple drug combinations include the use of IMiDs; however, not all patients are 
candidates for IMiD based therapy, such as those who are refractory, or with co-morbid 
conditions. Only 20 to 30% of the relapsed-refractory MM patients typically respond to any 
particular treatment and ultimately patients relapse from all available options.  Given the 
inevitable relapses seen in these patients, new approaches to therapy are clearly still needed.   
During Phase 2a, enrollment based on number of prior therapies and/or refractory status may 
be further explored to optimize the benefit/risk balance as recommended by the DSMC. 
2.3 
RATIONALE FOR DOSE SELECTION 
The dose and schedule of melflufen was established in the Phase 1/2 trial (O-12-M1) with 
melflufen in combination with weekly dexamethasone in RRMM patients as 40 mg on Day 1 
of a 28-day cycle.   The goal of this trial is to determine the optimal dose, up to 40 mg of 
melflufen, in triple combination regimens. In study O-12-M1 and in an ongoing trial (OP-106 
Horizon of melflufen and dexamethasone in pomalidomide- and/or daratumumab-refractory 
patients), hematologic toxicity is the most common adverse event (AE) reported, with 
thrombocytopenia being the most clinically important AE.  
Bortezomib is approved in the present US FDA label (09/2015) at 1.3 mg/m2 twice weekly 
with one week rest period in combination with melphalan and prednisone in 6-week cycles in 
previously untreated multiple myeloma patients for the first 4 cycles and once weekly beyond 
Cycle 4. In relapsed multiple myeloma, 1.3 mg/m2 bortezomib is administrated twice weekly 
for 2 weeks (Days 1, 4, 8, and 11) followed by 10-day rest period (Days 12-21).  For extended 
therapy of more than 8 cycles, bortezomib may be administered on a maintenance schedule of 
once every 28 days (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35).  
No guidance is provided in the US FDA label for schedule adjustments in relapsed multiple 
myeloma patients when combined with other medications and for cycle lengths that are not 
multiples of 3 weeks. 
The Phase 1 part of the present study will explore the triple combination of melflufen, 
dexamethasone and bortezomib in a step-wise fashion. In the initial cohort, 30 mg melflufen 
(once every 4 weeks) will be given in combination with subcutaneous (SQ) bortezomib at 1.3 
mg/m2 twice weekly on Days 1, 4, 8 and 11 of each 28-day cycle and a fixed dose of 
dexamethasone 20 mg orally (p.o.)  (12 mg for patients ≥ 75 years of age) on Days 1, 4, 8, 11, 
and 40 mg (20 mg for patients ≥ 75 years of age) on Days 15 and 22.  If the side effect profile 
is acceptable in the first cohort, the melflufen dose will be increased to 40 mg every 28 days 
with the other components of the triple combination being unchanged.   


 
 
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It is anticipated that the combination of melflufen with bortezomib and dexamethasone will 
also contribute to hematologic toxicity, thus the initial starting dose of melflufen will be 30 mg 
on Day 1 of each cycle with the goal to increase to 40 mg if feasible or to drop down to 20 mg 
if needed. The twice weekly dosing of bortezomib (Days 1, 4, 8 and 11), was selected based 
on the transient duration and differing mechanism of thrombocytopenia related to bortezomib 
compared to melflufen.  With this schedule, it may be possible to deliver the full anti-tumor 
effect of bortezomib to a patient by front loading the administration of this compound in each 
cycle while the transient and limited anti-thrombocyte count effect has passed before the full 
anti-tumor count effect from melflufen becomes apparent in most patients.  
The once weekly schedule of bortezomib has been shown to have similar antitumor efficacy 
combined with reduced peripheral neuropathy (Bringhen et al. 2010, Mateos et al, 2014). In 
the event that twice weekly bortezomib is not tolerable, once weekly dosing may be explored.   
Changes in the standard doses or schedule of the partner drug, may only be adjusted following 
review and recommendation by the DSMC.  Dose modifications may be made for individual 
patients based on toxicity during therapy.   
The toxicity profile of daratumumab is mainly related to infusion related reactions (Lonial et 
al. 2016).   A study conducted by Moreau and colleagues concluded that daratumumab added 
little additional toxicity to the combination therapies tested (Moreau et al. 2014). However, 
hematologic toxicity was noted in single agent studies (Lonial et al. 2016, Usmani et al. 2016) 
and increased rates of thrombocytopenia were noted in the combination of daratumumab with 
bortezomib and dexamethasone compared to bortezomib and dexamethasone without 
daratumumab, (Palumbo et al. 2016).  For this reason, the same dose levels of melflufen as 
proposed for the combination of melflufen with bortezomib will be implemented in the 
combination of melflufen with the approved dose of daratumumab with the 4-week dosing 
schedule.  The first dose of daratumumab will be administered on Day 2 of Cycle 1 due to 
prolonged infusion times if both melflufen and daratumumab were to be given on Day 1.  
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES 
3.1.1 
Phase 1 Primary Objective 
 The primary objective of the Phase 1 portion of the study is to determine the optimal 
dose of melflufen, up to a maximum of 40 mg, given every 28 days in triple drug 
combination therapy in patients with relapsed or RRMM. Each treatment regimen will 
be evaluated separately.  
3.1.2 
Phase 2a Primary Objective 
 To evaluate the overall response rate (PR or better) of melflufen, in each combination 
regimen, at the dose levels and schedules determined in Phase 1 in  efficacy evaluable 
patients as well as in all treated patients.  Each treatment regimen and dose will be 
evaluated separately.  
3.2 
SECONDARY OBJECTIVES 
 To evaluate the best response including complete response/stringent complete response 
(CR/sCR), very good partial response (VGPR), PR and clinical benefit rate (CBR: 
proportion of patients with ≥ MR), time to response (TTR), duration of response (PR 
or better), duration of CB, progression free survival (PFS) and overall survival (OS) 


 
 
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up to a minimum of 2 years as defined in the SAP..  International Myeloma Working 
Group Uniform Response Criteria (IMWG-URC) guidelines will be used (Rajkumar 
et al. 2011, Appendix C). Each treatment regimen and dose will be evaluated 
separately. 
 To further explore the safety and tolerability of the combination regimens. Each 
treatment regimen and dose will be evaluated separately. 
3.3 
EXPLORATORY OBJECTIVES 
 Pharmacokinetics will be evaluated in patients enrolled at select sites only. 
 To evaluate minimal residual disease (MRD) in patients achieving a CR.  
4 
STUDY DESIGN 
4.1 
DESCRIPTION OF STUDY DESIGN 
This is an open-label, Phase 1/2a, multicenter study which will enroll patients with relapsed or 
RRMM to combination regimens of melflufen with currently approved agents. The currently 
planned combinations include: 
 Regimen A:  Melflufen plus bortezomib and dexamethasone  
 Regimen B:  Melflufen plus daratumumab and dexamethasone 
All patients meeting the required eligibility criteria may be eligible for one or both of the 
defined Regimens.  For patients that are eligible for both Regimens, the Regimen selection 
may be determined by the investigator, given cohort availability for the selected Regimen at 
the time of screening. Only one cohort per patient will be reserved at a given time. If the patient 
fails screening for the reserved Regimen cohort, enrollment in a non-reserved Regimen cohort 
will be based on availability.  Both regimens may enroll simultaneously to an available cohort.   
Each combination will begin with a Phase 1 component which will follow the standard 3 + 3 
Phase 1 design with 3 to 6 patients at each dose level, depending on dose limiting toxicity 
(DLT) observed in the first cycle of each patient. Patients who discontinue treatment during 
Cycle 1 for reasons other than study drug related toxicity and/or are non-evaluable for DLT 
assessment, may be replaced at the discretion of the DSMC.  
Patients who discontinue treatment with one drug in the Regimen (excluding dexamethasone) 
for any reason, may continue treatment with the other drug in the Regimen at the investigator 
discretion if in the patients’ best interest. Patients who discontinue melflufen and continue on 
treatment with the other dug in the Regimen will be followed for response, PFS and OS follow-
up. 
Regimen A: Melflufen plus Bortezomib and Dexamethasone 
Up to 3 dose levels will be tested; i.v. melflufen at 30 mg and 40 mg or 20 mg given on Day 1 
of every 28-day cycle, in combination with subcutaneous (SQ) bortezomib at 1.3 mg/m2 twice 
weekly on Days 1, 4, 8 and 11 of each 28-day cycle and a fixed dose of dexamethasone 20 mg 
orally (p.o.) on Days 1,  4,  8, and 11,  and 40 mg on Days 15 and 22. For patients ≥ 75 years 
of age, 12 mg will be given on Days 1, 4, 8 and 11 and 20 mg on Days 15 and 22.   
Alternate dose levels or schedules of melflufen, bortezomib or dexamethasone may be 
explored based on tolerability following review and recommendation by the DSMC. 


 
 
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Regimen B: Melflufen plus Daratumumab and Dexamethasone 
Up to 3 dose levels of melflufen will be tested; i.v. melflufen at 30 mg and 40 mg or 20 mg 
given on Day 1 of every 28-day cycle, in combination with daratumumab 16 mg/kg according 
to the following daratumumab schedule: in Table 4-1. 
Table 4-1 Daratumumab Schedule 
Daratumumab Schedule 
Cycle  
Days 
1  
2*, 8, 15 and 22 
2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7 + 
1 
*Due to prolonged infusion time of the first dose of daratumumab, the Cycle 1 infusion of 
daratumumab will be given on Day 2 of Cycle 1.  
 
Dexamethasone 40 mg p.o. (20 mg p.o. for patients ≥ 75 years of age) will be given 
weekly.  Due to the need for steroids to prevent infusion reactions with daratumumab, 
dexamethasone dosing may be split prior to the daratumumab infusion, and the day after 
daratumumab on weeks when daratumumab is given.  Refer to the dose and schedule of 
dexamethasone in Table 6-2.    
Alternate dose levels or schedules of melflufen, daratumumab and dexamethasone may be 
explored based on tolerability following review and recommendation by the DSMC. 
All Dosing Regimens:   
Once the optimal dose of melflufen has been determined for each combination regimen in 
Phase 1, approximately 20 additional efficacy evaluable patients will be enrolled in each 
combination regimen and treated at the dose determined in the Phase 1 part of the study. 
Patients will be assessed for response after each cycle according to the IMWG-URC. Patients 
who have benefit from the therapy may continue treatment until disease progression or 
unacceptable toxicity or the patient/treating physician determines it is not in the patient’s best 
interest to continue.  Dose modifications may be implemented to manage toxicity according to 
the protocol guidelines in for each Regimen in Section 6.8.  
Patients who discontinue treatment with any drug in the Regimen (excluding dexamethasone) 
for any reason may continue treatment with the other drug in the Regimen at the investigator 
discretion if in the patients’ best interest. Patients who discontinue melflufen and continue 
treatment with the other drug in the Regimen will be followed for response, PFS and OS 
follow-up. 
A Schedule of Events for the study is outlined in Section 8, Table 8-1. 


 
 
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5 
PATIENT POPULATION 
5.1 
PATIENT SCREENING 
Written informed consent must be obtained before any protocol-specific screening tests or 
procedures are performed.  Patients must meet all the entry criteria detailed in Section 5.2.1 
and Section 5.2.2.  After informed consent is obtained, the screening assessments will be 
performed as detailed in Section 8 of the protocol.  Table 8-1, Schedule of Events, lists all of 
the screening assessments including frequency and time lines of when assessments are to be 
performed.  
Assessments performed as part of the patient’s routine clinical evaluation and not specifically 
for this study need not be repeated after signed informed consent has been obtained provided 
the assessments fulfill the study requirements and are performed within the specified 
timeframe prior to enrollment.    
All patients meeting the required eligibility criteria may be eligible for one or both of the 
defined Regimens.  For patients that are eligible for both Regimens, the Regimen selection 
may be determined by the investigator, given cohort availability for the selected Regimen at 
the time of screening. Only one cohort per patient will be reserved at a given time. If the patient 
fails screening for the reserved Regimen cohort, but is eligible for enrollment in a non-reserved 
Regimen cohort, assignment of that cohort will be based on availability.  Patients may be re-
screened if appropriate. 
5.1.1 
Screening Failures 
Patients who sign an informed consent but fail to be enrolled for any reason, e.g. do not fulfill 
eligibility criteria below, will be considered screen failures.  Patients may be re-screened 
following all the same criteria in the event a screening evaluation changes.   
5.2 
PATIENT ELIGIBILITY 
The Investigator must ensure that patients meet all the following inclusion and exclusion 
criteria.  
5.2.1 
Inclusion Criteria 
Patients will be considered eligible for inclusion in this study if they meet all of the following 
criteria: 
1. Male or female, age 18 years or older;  
2. A prior diagnosis of multiple myeloma with documented disease progression in need 
of treatment at time of screening; 
3. One to four prior lines of therapy (Appendix D); 
4. Measurable disease defined as any of the following: 
 Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) 
  ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis 
(UPEP) 
 Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free 
light chain ratio; 
5. Life expectancy of ≥ 6 months; 


 
 
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6. ECOG performance status ≤ 2. (patients with lower performance status based solely on 
bone pain secondary to multiple myeloma may be eligible following consultation and 
approval of the medical monitor) (Appendix A); 
7. Patient is a female of childbearing potential (FCBP)* with a negative serum or urine 
pregnancy test prior to initiation of therapy and agrees to practice appropriate methods 
of birth control, or is a female not of childbearing potential, or the patient is a male and 
agrees to practice appropriate methods of birth control  (Section 7.1); 
8. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent; 
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula 
(QTcF) interval of ≤ 470 msec (Appendix H);  
10. Adequate organ function with the following laboratory results during screening 
(within 21 days) and immediately before study drug administration on Cycle 1 Day 1: 
 Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors 
cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy) 
 Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions during 
the 10 days prior to initiation of therapy) 
 Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted) 
 Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or 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 and serum creatinine ≤ 2 mg/dL (Appendix G); 
11. Must have, or be willing to have, an acceptable central catheter. (port a cath, 
peripherally inserted central catheter [PICC] line, or central venous catheter);  
 
Regimen Specific Inclusion criteria: 
 
Regimen A – Melflufen + Bortezomib and Dexamethasone 
A1   Must be intolerant or refractory to a prior IMiD; refractory defined as failure to respond 
(MR or better) or progression while on therapy or within 60 days of last dose. 
 
Regimen B – Melflufen + Daratumumab and Dexamethasone 
B1   Must have had a prior IMiD and a proteasome inhibitor (PI); alone or in combination 
and must be refractory or intolerant to an IMiD, PI or both. 
 
During Phase 2a, enrollment based on number of prior therapies and/or refractory status may 
be further explored to optimize the benefit/risk balance as recommended by the DSMC.  


 
 
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*(FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due 
to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months. 
5.2.2 
Exclusion Criteria 
Patients will be ineligible for this study if they meet any one of the following criteria: 
1. Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy); 
2. Evidence of mucosal or internal bleeding and/or platelet transfusion refractory (i.e. 
platelet count fails to increase by > 10,000 cells/mm3 after transfusion of an 
appropriate dose of platelets); 
3. Any medical conditions that, in the Investigator’s opinion, would impose excessive 
risk to the patient or would adversely affect his/her participating in this study. 
Examples of such conditions are: a significant history of cardiovascular disease (e.g., 
myocardial infarction, significant cardiac conduction system abnormalities, 
uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months); 
4. Known active infection requiring parenteral or oral anti-infective treatment within 14 
days of initiation of therapy;  
5. Other malignancy diagnosed or requiring treatment within the past 3 years with the 
exception of adequately treated basal cell carcinoma, squamous cell skin cancer, 
carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in 
active surveillance;  
6. Pregnant or breast-feeding females; 
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or 
confuse compliance or follow-up evaluation; 
8. Known human immunodeficiency virus or active hepatitis B or C viral infection (see 
criterion B5 additional requirements for Regimen B); 
9. Concurrent symptomatic amyloidosis or plasma cell leukemia; 
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein and skin changes); 
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for 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 antibodies (mAb) within 4 weeks of initiation of therapy 
Prednisone up to but no more than 10 mg orally once daily (q.d.) or its equivalent for 
symptom management of comorbid conditions is permitted but dose should be stable 
for at least 7 days prior to initiation of therapy; 
12. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy 
(Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);  
13. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy; 
14. Prior allogeneic stem cell transplantation with active graft-versus-host- disease; 


 
 
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15. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of 
therapy (this does not include limited course of radiation used for management of bone 
pain within 7 days of initiation of therapy); 
16. Known intolerance to the required dose and schedule of steroid therapy as determined 
by the investigator. 
17. Prior treatment with melflufen 
Regimen specific exclusion criteria 
Regimen A – Melflufen + Bortezomib and Dexamethasone 
A1 Refractory to a PI in the last line of therapy prior to enrollment in this trial; refractory 
defined as failure to respond (MR or better) or progression while on therapy or within 
60 days of last dose.  
A2 History of allergic reaction/hypersensitivity attributed to compounds containing boron, 
mannitol, polysorbate 80 or sodium citrate dihydrate (see Appendix K). 
Regimen B – Melflufen + Daratumumab and Dexamethasone 
B1 Prior exposure to an antiCD-38 mAb; 
B2 Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 
second (FEV1) less than 50% of predicted normal; 
B3 Moderate or severe persistent asthma within the past 2 years, or currently has 
uncontrolled asthma of any classification; 
B4 ≥ Grade 3 conduction system abnormalities unless patient has a pacemaker. 
B5 Active hepatitis B (defined as HBsAg+) or those at risk for reactivation (HBsAg-, Anti-
HBs+, Anti-HBc+).  
 Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, 
Anti-HBc-).  
 Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may only be enrolled after 
approval of the sponsor and consideration of risk of reactivation (additional screening 
and monitoring for reactivation of Hepatitis B and consultation with a liver disease 
specialist may be required) (see Table 8-1 footnote u).   
Population diversity:  This study will be available to all eligible patients, regardless of race, 
gender, or ethnic origin.  There is no information currently available regarding differential 
effects of these regimens in subsets defined by race, gender, or ethnicity, and there is no reason 
to expect such differences to exist.  Investigators are encouraged to recruit a diverse population. 
5.3 
PATIENT ENROLLMENT 
5.3.1 
Enrollment Procedure 
Sites must be formally notified of activation before patients can be consented at that site. An 
IRB/EC approved Informed consent form (ICF) must be signed by the patient before any study-
specific tests may be performed.  
Complete details on patient enrollment procedures are provided in the Investigator Site File 
(ISF) at each site. Following completion of the ICF process and Screening activities the site 
will complete a patient enrollment form and submit along with the required documentation to 
the Medical Monitor for approval. Once eligibility is confirmed by the medical monitor, the 


 
 
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patient will be considered enrolled into the study and the site will be notified of the Regimen 
and cohort assignment for patients enrolled in Phase 1 or the established dose and schedule of 
the Regimen for patients enrolled in Phase 2a. Further details will be provided in the 
Investigator Site File (ISF) at each site. 
Patients that do not meet all the eligibility criteria will be considered screen failures and will 
not be enrolled. 
5.3.2 
Patient Numbering 
A unique patient number will be assigned at the time of signing of consent.   
5.3.3 
Replacement Policy  
Patients in Phase 1 who are not fully evaluable for assessment of DLT may be replaced and 
patients in Phase 2a who are not efficacy evaluable may be replaced.  Efficacy evaluable 
patients are those who receive at least 2 doses of melflufen and ≥ 50% of the partner therapy 
(excluding dexamethasone) during Cycles 1 and 2, had a baseline disease assessment, and had 
at least 1 post-baseline disease assessment ≥ 28 days after first dose.   
6 
STUDY TREATMENT 
Treatment may be given in an outpatient treatment setting in cycles.  Each cycle is 28 days. 
Pretreatment tests/procedures and timelines are detailed in Table 8-1, Schedule of Events.  All 
evaluations must be complete prior to enrollment and initiation of treatment.   
6.1 
REGIMEN A AND B: DOSE LEVEL SELECTION 
6.1.1 
Phase 1 
The first cohort of patients (3 - 6) enrolled in the Phase 1 portion of each Regimen will receive 
dose level 1.  A full safety evaluation will be conducted by the DSMC when the planned 
number of melflufen safety evaluable patients have completed the first cycle of combination 
therapy with DLT assessment. Subsequent patients will be enrolled in the dose level based on 
the dose escalation schema.  The optimal dose of melflufen in combination therapy will be 
defined as the highest dose of 20, 30 or 40 mg of melflufen that results in ≤ 1/6 patients with 
DLT during the first cycle of therapy (See Section 6.3).  The dose of melflufen can never be 
reduced to lower than 20 mg. Patients who discontinue treatment for reasons other than study 
drug related toxicity and/or are considered non-evaluable for DLT assessment may be replaced 
at the discretion of the DSMC.   
6.1.2 
Phase 2a 
Patients in Phase 2a will be enrolled in the optimal dose and schedule determined in Phase 1. 
 
6.2 
REGIMEN A AND B:  INITIATION OF THERAPY (CYCLE 1 DAY 1) 
 Prior to initiation of therapy, patients must continue to meet eligibility criteria 
including ECOG performance status of ≤ 2 and the Cycle 1 Day 1 laboratory results 
must also meet the entry criteria 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) 


 
 
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 Platelet count ≥ 75,000 cells/ mm3 (75 x 109/L) (without transfusion during the 
previous 10 days to initiation of therapy) 
 Hemoglobin ≥ 8.0 g/dl (RBC transfusions are permitted)  
 Total Bilirubin ≤ 1.5 x upper limit of normal, except patients diagnosed with Gilbert’s 
syndrome that have been reviewed and approved by the medical monitor 
 AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN 
 Renal function: Estimated glomerular filtration rate by Cockcroft-Gault formula ≥ 45 
mL/min (Appendix G) 
6.3 
REGIMEN A AND B:  DOSE ESCALATION SCHEMA 
 If no DLT is reported in the first three patients at a dose level, that dose level will be 
considered safe and three patients will be enrolled at the next dose level. 
 If 1/3 patients in a cohort at a dose level has a DLT, the dose level will be expanded to 
obtain six evaluable patients. 
 If 2/3 patients in a cohort at a dose level has a DLT, that dose level will not be 
considered safe and no further dose escalation will take place.   
 If there are < 2 patients with a DLT among the expanded cohort of six evaluable 
patients a cohort of three patients will be enrolled in the next higher dose level. 
 If there are 2 or more patients with a DLT among the expanded cohort of six evaluable 
patients, that dose level will not be considered safe and no further dose escalation will 
take place.   
If less than 6 patients have been treated in the next lower dose level, additional patients will be 
entered into this dose level until there are 6 patients treated.  If ≤ 1 of these 6 patients 
encountered DLT, then this dose level will be taken forward to Phase 2a.  If 2 or more of the 
6 patients encounter DLT, a lower dose will be considered.   
NOTE: If a patient discontinues therapy during Cycle 1 for reasons other than treatment related 
toxicity and is considered non-evaluable for DLT assessment, the patient may be replaced at 
the discretion of the DSMC.  
The 6 patients treated in Phase 1 with the dose taken forward to Phase 2a will be the first 6 
patients of the Phase 2a component of the study. 
Patients who discontinue treatment with any drug in the Regimen (excluding dexamethasone) 
for any reason may continue treatment with the other drug in the Regimen at the investigator 
discretion if in the patients’ best interest. Patients who discontinue melflufen and continue on 
treatment with the other drug in the Regimen will be followed for response, PFS and OS 
follow-up. 
Patients starting on 30 mg of melflufen in Phase 1, that did not experience a DLT in Cycle 1 
and did not required a dose reduction in any cycle may be considered for increase in the dose 
of melflufen to 40 mg, following consultation with the medical monitor and sponsor if in the 
best interest of the patient to optimize risk/benefit balance.  In addition, the 40 mg melflufen 
dose cohort must be completed and considered well tolerated.   


 
 
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6.4 
REGIMEN A AND B: DOSE LEVELS TO BE TESTED 
6.4.1 
Regimen A Dose levels 
Up to 3 dose levels will be tested; i.v. melflufen at 30 mg and 40 mg or 20 mg given on Day 1 
of every 28-day cycle, in combination with subcutaneous (SQ) bortezomib at 1.3 mg/m2 twice 
weekly on Days 1, 4, 8 and 11 of each 28-day cycle and a fixed dose of dexamethasone 20 mg 
orally (p.o.)(12 mg for patients ≥ 75 years of age) on Days 1,  4, 8, 11, and 40 mg (20 mg for 
patients ≥ 75 years of age) on Days 15 and 22 of each 28-day cycle  
Table 6-1 Dose Levels to be Tested 
Dose level 
Melflufen 
dose (i.v.) 
Bortezomib dose 
(SQ)* 
Dexamethasone dose## 
(p.o.) 
Days of Cycle 
Day 1 
Days 
1, 4, 8, 11 
Day of bortezomib on Days 1, 4, 8, 11,  
and on Days 15** and 22** 
Level - 1 
20 mg 
1.3 mg/m2 
20 mg** 
Level 1 
Starting dose 
30 mg 
1.3 mg/m2 
20 mg** 
Level 2 
40 mg 
1.3 mg/m2 
20 mg** 
*i.v. administration of bortezomib is acceptable only if the SQ procedure is not tolerated. 
**Dexamethasone dose will be decreased to 12 mg for patients ≥75 years of age on Days 1, 4, 8 and 11. 
Dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) will be given on Days 15 and 22.  See Section 
6.5.2.3 for dexamethasone administration during cycle delays. ##Dexamethasone 40 mg (20 mg for patients ≥ 75 
years of age) may be continued weekly during cycle delays 
 
Dose modifications and delays may be implemented based on patient tolerance as detailed in 
Section 6.8. Alternate dose levels or schedules of melflufen, bortezomib or dexamethasone 
may be explored based on tolerability following review and recommendation of the DSMC. 
6.4.2 
Regimen B Dose Levels 
Up to 3 dose levels will be tested; i.v. melflufen at 30 mg and 40 mg or 20 mg given on Day 1 
of every 28-day cycle, in combination with daratumumab 16 mg/kg weekly for 8 doses, every 
2 weeks for 8 doses and then every 4 weeks (Table 6-2) with dexamethasone 20 mg  pre 
daratumumab infusion and 20 mg the day after the infusion.  For patients ≥ 75 years of age 20 
mg of dexamethasone will be given only prior to each daratumumab infusion.   
Table 6-2 Regimen B Dose Levels 
Dose Level 
Melflufen 
dose (i.v.) 
Daratumumab dose (i.v.) 
Dexamethasone dose 
(p.o.* ) 
Cycle =  
28 days 
Day 1 
Cycle 1 -Days 2**, 8, 15 and 22 
Cycle 2 - Days 1, 8, 15, 22 
Cycle 3 to 6 - Days 1 and 15 
Cycle 7 + - Day 1 
On days when melflufen and 
daratumumab are given in 
combination (Day 1)**: 
Patients < 75 years old - Pre 
melflufen and daratumumab and the 
day after daratumumab 
Patients ≥ 75 years old-  Pre 
melflufen and daratumumab 
All other daratumumab dosing 
days (see daratumumab 
schedule):  


 
 
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Patients < 75 years old -  Pre 
daratumumab and the day after 
daratumumab  
Patients ≥ 75 years old -  Pre 
daratumumab 
On weeks when daratumumab is 
not given (not scheduled or dose 
held) on Days 8, 15, 22 (see 
daratumumab schedule) 
Level – 1 
20 mg 
16 mg/kg 
Melflufen and daratumumab in 
combination:  
Patients < 75 years old - 20 mg Day 
1** and 2 
Patients ≥ 75 years old – 20 mg Day 
1** 
All other daratumumab dosing 
days:  
Patients < 75 years old - 20 mg pre, 
and the day after daratumumab 
Patients ≥ 75 years old – 20 mg pre 
daratumumab 
During cycles when 
daratumumab is not given (not 
scheduled or dose held) on Days 
8, 15 or 22:   
Patients < 75 years old - 40 mg p.o.  
Patients ≥ 75 years old – 20 mg p.o. 
Level 1 
Starting dose 
30 mg 
16 mg/kg 
Melflufen and daratumumab in 
combination:  
Patients < 75 years old - 20 mg Day 
1** and 2 
Patients ≥ 75 years old – 20 mg Day 
1** 
All other daratumumab dosing 
days:  
Patients < 75 years old - 20 mg pre, 
and the day after daratumumab 
Patients ≥ 75 years old – 20 mg pre 
daratumumab 
During cycles when 
daratumumab is not given (not 
scheduled or dose held) on Days 
8, 15 or 22:   
Patients < 75 years old - 40 mg p.o.  
Patients ≥ 75 years old – 20 mg p.o. 
Level 2 
40 mg 
16 mg/kg 
Melflufen and daratumumab in 
combination:  


 
 
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Patients < 75 years old - 20 mg Day 
1** and 2 
Patients ≥ 75 years old – 20 mg Day 
1** 
All other daratumumab dosing 
days:  
Patients < 75 years old –20 mg pre, 
and the day after daratumumab 
Patients ≥ 75 years old – 20 mg pre 
daratumumab 
During cycles when 
daratumumab is not given (not 
scheduled or dose held) on Days 
8, 15 or 22:   
Patients < 75 years old – 40 mg p.o.  
Patients ≥ 75 years old – 20 mg p.o. 
 
*Oral dexamethasone may be substituted with i.v. dexamethasone at the investigators discretion, prior to 
daratumumab infusion only, if this is the standard of care of the site.   
**Due to prolonged infusion time of the first dose of daratumumab, the Cycle 1 infusion of daratumumab will be 
given on Day 2 of Cycle 1. Therefore, the dexamethasone dose of 20 mg will be given on Day 1 prior to melflufen 
and on Day 2 prior to the daratumumab administration in Cycle 1, for patients < 75 years of age.  For patients ≥ 
75 years of age, the Cycle 1, Day 1 dexamethasone 20 mg dose may be split between Day 1 and Day 2 at the 
investigators discretion (e.g dexamethasone 12 mg p.o. on Day 1 prior to melflufen and 8 mg p.o. on Day 2 prior 
to daratumumab) or dexamethasone may also be given i.v. with a split dose (e.g. dexamethasone 10 mg i.v. on 
Day 1 prior to melflufen and 10 mg i.v. on Day 2 prior to daratumumab).  No dexamethasone is required the day 
following daratumumab in Cycle 1.  However, additional steroids may be given as needed to prevent or treat 
hypersensitivity reactions at the investigators discretion and as per the SoC for the site.    See Section 6.5.2.3 for 
dexamethasone administration when drug is held or cycle delays.  
6.5 
STUDY DRUG ADMINISTRATION 
Refer to Section 9 for supply, storage, preparation and accountability of study drugs used in 
each Regimen. 
6.5.1 
Regimen A and B: Melflufen Administration 
Prophylactic treatment with anti-emetic drug(s) prior to melflufen administration is 
recommended. Subsequent anti-emetic drugs against delayed emesis should be administered 
at the discretion of the investigator. Concomitant medication shall be documented in the 
concomitant medication page in the electronic case report form (eCRF). 
On days when melflufen and bortezomib (Regimen A) or daratumumab (Regimen B) are 
scheduled on the same day melflufen should be administered first.  
The study treatment should be administered through a central catheter, which should be 
inserted according to standard local practice.  All patients must have an acceptable central 
catheter for infusion prior to the initiation of the first dose of melflufen.  (Port A Cath, PICC 
line or central venous catheter).   
 
Before infusion: 
 Document vital signs prior to start of infusion 


 
 
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 Prepare the central catheter by flushing with approximately 20 mL of the same type of 
solution (5% glucose or 0.9% saline) that is used for dilution of the melflufen in the 
250 mL bag.  
Infusion: 
 The melflufen should be administered as a 30-minute intravenous infusion 
 Record start and stop time for infusion 
After infusion: 
 Document vital signs at the end of the infusion 
 First flush the central catheter with approximately 20 mL of the same type of solution 
(5% glucose or 0.9% saline) that is used for dilution of the melflufen in the 250 mL 
bag. Then follow with additional flushing as per institutional guidelines if necessary. 
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. Refer to 
Section 9 for melflufen supply, storage and accountability.  Refer to the Pharmacy Manual for 
details on melflufen preparation and administration.   
6.5.2 
Regimen A and B: Dexamethasone Administration 
6.5.2.1 
Regimen A  
Dexamethasone 20 mg (12 mg for patients ≥ 75 years of age) should be administered orally on 
the day of bortezomib on Days 1, 4, 8, and 11.  Dexamethasone 40 mg (20 mg for patients ≥ 
75 years of age) should be administered orally on Day 15 and 22. Dexamethasone is best 
administered prior to melflufen and prior to melflufen and bortezomib on days when both drugs 
are given on the same day (Day 1 of each cycle).  
6.5.2.2 
Regimen B 
Dexamethasone 40 mg p.o. (20 mg p.o. for patients ≥ 75 years of age) will be given weekly.  
Due to the need for steroids to prevent infusion reactions with daratumumab, dexamethasone 
dosing may be split to give a dose prior to daratumumab, and the day after daratumumab on 
weeks when daratumumab is given.  Refer to the dose and schedule of dexamethasone in Table 
6-2.   Oral dexamethasone may be substituted with i.v. dexamethasone, at the investigator’s 
discretion, prior to daratumumab infusion only, if this is the standard of care of the site.   
Due to prolonged infusion time of the first dose of daratumumab, the Cycle 1 infusion of 
daratumumab will be given on Day 2 of Cycle 1. Therefore, the dexamethasone dose will be 
given on Day 1 prior to melflufen and on Day 2 prior to the daratumumab administration in 
Cycle 1 for patients < 75 years of age.  For patients ≥ 75 years of age, the Cycle 1, Day 1 
dexamethasone 20 mg dose may be split between Day 1 and Day 2 at the investigators 
discretion (e.g dexamethasone 12 mg p.o. on Day 1 prior to melflufen and 8 mg p.o. on Day 2 
prior to daratumumab) or dexamethasone may also be given i.v. with a split dose (e.g. 
dexamethasone 10 mg i.v. on Day 1 prior to melflufen and 10 mg i.v. on Day 2 prior to 
daratumumab).  No dexamethasone is required the day following daratumumab in Cycle 1.  
However, additional steroids may be given as needed to prevent or treat hypersensitivity 
reactions at the investigator’s discretion and as per the SoC for the site.     


 
 
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Dexamethasone is best administered prior to melflufen and prior to melflufen and 
daratumumab on days when both drugs are given on the same day (Day 1 of each cycle 
following Cycle 1 as noted above). 
6.5.2.3 
Regimen A and B 
During cycles when daratumumab (Regimen B) is not administered each week (following 
week 9), dexamethasone 40 mg (20 mg for patients ≥ 75 years of age), should be administered 
p.o. weekly.  Resulting in the patient receiving weekly dexamethasone regardless of the 
bortezomib or daratumumab administration schedule.  Dexamethasone may be given if the 
partner drug is held or continued weekly during cycle delays, at the investigator’s discretion.  
6.5.3 
Regimen A: Bortezomib Administration 
The amount (in mg) of bortezomib to be administered will be determined based on body 
surface area (BSA).  The BSA is to be calculated based on body weight using the DuBois 
formula (Appendix J).  The dose should be calculated on Day 1 of the cycle, and should be 
recalculated at the start of the next cycle; the dose administered should remain the same 
throughout the cycle.  If a patient experiences a notable change in weight (i.e., loss or gain of 
5% body weight) within the cycle, as determined by an unscheduled weight assessment, then 
the patient’s dose should be recalculated at that time.  Bortezomib should not be administered 
to patients who have a known allergy to bortezomib, boron or mannitol.   
Bortezomib should be administered SQ.  Sites for injection (thigh or abdomen) should be 
rotated.  New injections should be given at least one inch from an old site and never into areas 
where the site is tender, bruised, erythematous or indurated.  Refer to Section 9 and the 
bortezomib Prescribing Information or SmPC for complete drug preparation and 
administration guidelines for SQ administration. In the event that SQ administration procedure 
is not tolerated, bortezomib may be given i.v. at the investigator’s discretion.  
 
6.5.4 
Regimen B: Daratumumab Administration 
Table 6-3 Daratumumab Dosing Schedule 
Daratumumab Schedule 
Cycle   
Days 
1 
2*, 8, 15 and 22 
2 
1, 8, 15 and 22 
3 to 6 
1 and 15 
7+ 
1 
*Due to prolonged infusion time of the first dose of daratumumab, the Cycle 1 infusion of daratumumab will be 
given on Day 2 of Cycle 1. 
 
6.5.4.1 
Pre-infusion Medications 
Prior to each infusion of daratumumab, administer pre-infusion medications to reduce the risk 
of infusion reactions approximately 1 – 3 hours prior to the infusion of daratumumab as 
follows:   
 Dexamethasone:  See Table 6-2 for dexamethasone dose and schedule 
 Antipyretics: (oral or i.v. acetaminophen 650 – 1000 mg) 
 Antihistamine: (oral or i.v. diphenhydramine 25 – 50 mg or equivalent)  


 
 
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Alternate and or additional medications to reduce the risk of infusion related reactions such as 
montelukast 10 mg may be given at the investigator’s discretion. 
On days when melflufen and daratumumab are scheduled on the same day, dexamethasone 
should be given first (1-3 hours prior to the daratumumab infusion), followed by melflufen 
then followed by the pre-medication for daratumumab approximately 30 minutes prior to the 
start of the daratumumab administration. Dexamethasone should be given prior to melflufen, 
1 – 3 hours prior to the infusion of daratumumab, when both drugs are given on the same day.  
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.  
6.5.4.2 
Infusion Rates 
Administer daratumumab infusion intravenously at the infusion rate described below in Table 
6-4. Consider incremental escalation of the infusion rate only in the absence of infusion 
reactions.  
Table 6-4 Infusion Rates for Daratumumab Administration 
 
Dilution volume 
Initial rate 
(first hour) 
Rate incrementa 
Maximum rate 
First infusion 
1000 mL 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Second 
infusion 
500 mLb 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Subsequent 
infusionsc 
500 mL 
100 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
a) Consider incremental escalation of the infusion rate only in the absence of infusion reactions. Escalation 
not required and may be at the discretion of the investigator. 
b) Use a dilution volume of 500 mL only if there were no Grade 1 (mild) or greater infusion reactions 
during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL 
and instructions for the first infusion. 
c) Use a modified initial rate for subsequent infusions (i.e. third infusion onwards) only if there were no 
Grade 1 (mild) or greater infusion reactions during a final infusion rate of ≥100 mL/hour in the first two 
infusions. Otherwise, continue to use instructions for the second infusion. 
6.5.4.3 
Post-infusion Medications 
For patients with a history of chronic obstructive pulmonary disease, consider prescribing post-
infusion medications such as short and long-acting bronchodilators, and inhaled 
corticosteroids. Following the first four infusions, if the patient experiences no major infusion 
reactions, these additional inhaled post-infusion medications may be discontinued. 
6.5.4.4 
Management of Infusion Reactions 
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion 
and manage symptoms. Management of infusion reactions may further require reduction in the 
rate of infusion, or treatment discontinuation of daratumumab as outlined below. 
 Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion 
at no more than half the rate at which the reaction occurred. If the patient does not 
experience any further reaction symptoms, infusion rate escalation may resume at 


 
 
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increments and intervals as clinically appropriate up to the maximum rate of 200 
mL/hour. 
 Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at 
no more than half the rate at which the reaction occurred. If the patient does not 
experience additional symptoms, resume infusion rate escalation at increments and 
intervals as outlined in Table 6-4. Repeat the procedure above in the event of 
recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the 
third occurrence of a Grade 3 or greater infusion reaction. 
 Grade 4 (life threatening): Permanently discontinue daratumumab treatment. 
6.6 
PHASE 1 DOSE LIMITING TOXICITY 
Toxicity will be graded according to the National Cancer Institute – Common Terminology 
Criteria for Adverse Events Version 4.03 (CTCAE 4.03). The following criteria will apply to 
each cohort to be evaluated in Phase 1, Cycle 1 only.   Each cohort will be assessed by the 
DSMC prior to changes in cohort assignment.  Patients who discontinue therapy during cycle 
1 for reasons other the study drug related toxicity and are considered non-evaluable for DLT 
assessment may be replaced at the discretion of the DSMC. Events that are clearly and 
incontrovertibly due to extraneous causes should not be counted as DLTs.  
6.6.1 
Regimen A: Dose Limiting Toxicity 
The prophylactic use of growth factors and platelet transfusions is not permitted in Cycle 1 of 
the dose escalation cohorts in Phase 1.  
 
 Grade 3 non-hematologic toxicity preventing the administration of > 1 dose of 
bortezomib during the 1st cycle  
o Grade 3 peripheral neuropathy in patients with a baseline neuropathy due to 
prior PI exposure will not be considered a DLT.  These patients may be replaced 
at the discretion of the DSMC. 
 Grade 4 or greater non-hematologic toxicity  
 Grade 4 thrombocytopenia (platelet count < 25,000 cells/ mm3) preventing the 
administration of > 1 dose of bortezomib during the 1st cycle or with clinically 
significant bleeding during the 1st cycle 
 Grade 4 neutropenia (ANC < 500 cells/mm3), lasting more than 7 days during the 1st 
cycle 
 Greater than 14 days’ delay to meet the criteria for the start of a new cycle (Cycle 2) 
due to toxicity  
6.6.2 
Regimen B: Dose Limiting Toxicity 
Toxicity will be graded according to the National Cancer Institute – Common Terminology 
Criteria for Adverse Events Version 4.03 (CTCAE 4.03).  
The prophylactic use of growth factors and platelet transfusions is not permitted in Cycle 1 of 
the dose escalation cohorts in Phase 1.  
The following DLT criteria will apply to Regimen B in Phase 1, Cycle 1 only: 


 
 
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 Grade 3 non-hematologic toxicity preventing the administration of > 1 dose of 
daratumumab during the 1st cycle  
 Grade 4 or greater non-hematologic toxicity  
 infusion related reactions are not considered DLT.  Patients requiring discontinuation 
of daratumumab (Grade 4 or Grade 3 on 3 occasions [see Section 6.5.4.4]) may be 
replaced at the discretion of the DSMC 
 Grade 4 thrombocytopenia (platelet count < 25,000 cells/ mm3) preventing the 
administration of > 1 dose of daratumumab during the 1st cycle or with clinically 
significant bleeding during the 1st cycle 
 Grade 4 neutropenia (ANC < 500 cells/mm3), lasting more than 7 days during the 1st 
cycle. 
 Greater than 14 days’ delay to meet the criteria for the start of a new cycle (Cycle 2)  
due to toxicity  
6.7 
REGIMEN A AND B: INITIATION OF A NEW CYCLE OF THERAPY 
The following guidelines apply to all cycles following Cycle 1.  Patients should be assessed at 
the beginning of each cycle according to the tests and evaluations outlined on Day 1 of each 
cycle in Table 8-1: Schedule of Events.  Refer to Section 6.8 for dose modifications related to 
toxicity. To begin a new cycle of treatment, the following criteria must be met. 
 
Regimen A and B: Criteria for Initiation of a New Cycle of Therapy  
 ANC must be ≥ 1,000 cells/mm3 (1.0 x109/L) 
 Platelet count must be ≥ 50,000 cells/mm3 (50.0 x 109/L) (platelet transfusions not 
recommended within ≤ 5 days of dosing [See Section 7.2]). This is applicable for 
patients in both arms as well as for patients in arm A that have discontinued melflufen 
but remain on bortezomib and dexamethasone. For patients in arm B that have 
discontinued melflufen but remain on daratumumab and dexamethasone the platelet 
count must be ≥ 25,000 cells/mm3 (25.0 x 109/L)  
 All non-hematologic toxicities must be ≤ Grade 1 or returned to baseline (except 
peripheral neuropathy Grade 1 without pain, alopecia and fatigue ≤ Grade 2) 
 (Regimen B only) Absence of daratumumab infusion reactions that require 
discontinuation (Grade 4 or Grade 3 on three occurrences in the previous cycle see 
Section 6.5.4.4)  
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 6.8 for guidelines on dose modification due 
to drug related toxicity.  
The maximum amount of time for which study therapy may be held due to drug related toxicity 
is 28 days from a scheduled Day 1 (Day 57).  If study drug is held for more than 28 days due 
to drug related toxicity the patient will be removed from the study treatment and enter 
progression free survival follow-up (PFS-FU).  If, however the patient was clearly benefiting 
from therapy, the patient may be able to continue treatment at the Investigator discretion and 
in consultation with the medical monitor, after resolution of the AE.  


 
 
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6.8 
DOSE MODIFICATIONS 
No dose modifications are permitted in Phase 1 during Cycle 1, unless the patient experiences 
DLT.  Patients experiencing DLT during Cycle 1 may continue on therapy if the toxicity can 
be managed according to the dose modification guidelines outlined below.  However, the DLT 
event will contribute to the assessment of toxicity for that given cohort.   
Dose modifications are permitted following Cycle 1 in Phase 1 and in all cycles of Phase 2a 
according to guidelines described in this section.  Toxicity should be assessed using the 
common terminology criteria for adverse events (CTCAE) version 4.03 (Appendix B).  All 
dose modifications should be based on the worst preceding toxicity.  Each AE should be 
attributed to a specific drug, if possible, so that the dose modifications can be made 
accordingly.  Reduction of one agent and not the other 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. 
6.8.1 
Dose Reduction Steps 
6.8.1.1 
Dose Reduction Steps for Melflufen 
Dose modifications of melflufen for drug related toxicity are permitted. Multiple dose 
reductions are permitted however, the lowest dose permitted is 20 mg.  If a patient is unable to 
tolerate the lowest dose of melflufen due to drug related toxicity the patient must be withdrawn 
from treatment.  Prior to each cycle of melflufen the criteria for initiation of therapy must be 
met (See Section 6.7).  Patients who discontinue treatment with any drug in the Regimen 
(excluding dexamethasone) for any reason may continue treatment with the other drug in the 
Regimen at the investigator discretion if in the patients’ best interest. Patients who discontinue 
melflufen and continue on treatment with the other drug in the Regimen will be followed for 
response, PFS and OS follow-up.  
Patients in Phase 1, starting on 30 mg melflufen, may have the dose increased to 40 mg 
following consultation with the medical monitor and sponsor, for patients who have not had a 
DLT in Cycle 1 and have not required a dose reduction in any cycle, if in the best interest of 
the patient.  In addition, the 40 mg melflufen dose cohort must be completed and well tolerated. 
Table 6-5 describes the dose reduction depending on the starting dose of melflufen.  
Table 6-5 Dose Reduction Steps for Melflufen 
Starting dose 
Dose reduction 
Step - 1 
Dose reduction 
Step – 2 
40 mg 
30 mg 
20 mg 
30 mg 
20 mg 
Discontinue 
20 mg 
Discontinue 
Discontinue 


 
 
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6.8.1.2 
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 6-7 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 
12 mg 
 4mg 
Discontinue 
*40 mg dose (20 mg for patients ≥ 75 years of age) on scheduled days when bortezomib or daratumumab are not 
administered. Note when bortezomib dosing schedule changes to Days 1, 8, 15 and 22, dexamethasone will also 
be dosed on these days, 40 mg for patients < 75 years of age and 20 mg for patients ≥ 75 years of age. See Table 
6-7. 
6.8.1.3 
Dose Reduction Steps for Bortezomib (Regimen A) 
Dose modifications of bortezomib for drug related toxicity are permitted. Multiple dose 
reductions are permitted however, the lowest dose permitted is 0.7 mg/m2.  If a patient is 
unable to tolerate the lowest dose of bortezomib due to drug related toxicity the patient must 
be withdrawn from treatment.  Prior to each cycle of bortezomib the criteria for initiation of 
therapy must be met (See Section 6.7).  If bortezomib is discontinued for any reason, the patient 
may continue on therapy with melflufen and dexamethasone. 
Table 6-7 Dose Reduction Steps for Bortezomib 
 Starting dose of 
bortezomib 
 
1st Dose reduction 
 
2nd Dose reduction 
 
3rd Dose reduction 
Days 1,4,8,11 
Days 1,4,8,11 
Days 1,8,15,22 
Days 1,8,15,22 
1.3 mg/m2 
1.0 mg/m2 
1.0 mg/m2 
0.7 mg/m2  
OR 
 Days 1, 8, 15 and 
maintain 1.0 mg/m2 
 
Alternate dose and schedules may be considered following consultation with the Medical 
Monitor to best manage the timing of hematologic toxicity.  Note when bortezomib dosing 
schedule changes to Days 1, 8, 15 and 22, dexamethasone will also be dosed on these days 40 
mg for patients < 75 (20 mg or patients ≥ 75 years of age). 
6.8.1.4 
Dose Reductions for Daratumumab (Regimen B) 
No dose reductions of daratumumab are recommended.  Refer to Table 6-4 for changes in the 
rate of infusion for daratumumab infusion related reactions. 


 
 
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6.8.2 
Regimen A: Dose Modification Guidelines Based on Toxicity 
Melflufen is a potent myelosuppressive agent, and bortezomib may contribute to hematologic 
toxicity, therefore 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 as necessary.  It is recommended, at the 
investigator discretion, that platelet transfusion should be avoided within 5 days of the next 
dose of melflufen in order to assess endogenous platelet recovery and avoid the possibility of 
excessive myelosuppression. 
The guidelines for dose modification for both melflufen and bortezomib based on toxicity 
experienced on Day 1 of a cycle and during a cycle are detailed in Table 6-8.  If the criteria for 
initiation of a new cycle of therapy, as detailed in Section 6.7, are not met on Day 29 (the next 
scheduled Day 1 of any given cycle), treatment should be held and the patient should be re-
evaluated weekly. 
Table 6-8 Regimen A: Dose Modification Guidelines for Melflufen and Bortezomib 
Related Toxicity 
Toxicity 
Cycle 
Day 
Action with Melflufen 
Action with Bortezomib* 
Hematologic Toxicity – Supportive therapy with platelets and growth factors is permitted according to 
the guidelines in Section 7.2 
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 6.7). 
 
Hold, evaluate weekly* and 
resume therapy when criteria for 
initiation of a new cycle are met 
(Section 6.7).  
 
 
First occurrence – if resolved in ≤ 
14 days same dose may be 
resumed.  Dose reduction or delay 
may be considered. 
 
First occurrence – if resolved in 
≤ 14 days same dose may be 
resumed.  
If resolved in > 14 days dose 
reduction of bortezomib in 
addition to melflufen is optional. 
If resolved in > 14 days dose 
reduction is required.    
For subsequent episodes of hematologic toxicity, melflufen or 
bortezomib may be dose reduced together or independently at the 
investigators discretion to manage toxicity.  Consultation with the 
Medical Monitor is encouraged. 
ANC  
< 500 mm3  
(0.5 X 109/L) 
Platelet count  
<25,000 mm3 (<25.0 
x 109 /L) 
Any day 
during 
the 
cycle 
 
Hold and evaluate with next 
scheduled administration.  
Resume therapy within the cycle 
if resolved to ≤ Grade 2 within 
the cycle.  
Non-hematologic Toxicity** Each AE should be attributed to a specific drug, if possible, so that the 
dose modifications can be made accordingly.   
Grade 3 drug related 
non-hematologic 
toxicity 
Day 1 
Hold, evaluate weekly* and 
resume therapy when criteria for 
initiation of a new cycle are met 
(Section 6.7). 
Hold, evaluate weekly* and 
resume therapy when criteria for 
initiation of a new cycle are met 
(Section 6.7).  


 
 
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Assess attribution if possible and 
reduce responsible drug*** 
 
Assess attribution if possible and 
reduce responsible drug*** 
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 met*** 
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 reduce by one dose 
level when the criteria for a new 
cycle are met*** 
Grade 4 drug related 
non-hematologic 
toxicity  
Any day 
Discontinue therapy 
Discontinue therapy 
*If cycle prolongation due to study drug related toxicity of more than 28 days (beyond Day 57) is needed, study 
treatment is to be discontinued unless in the investigators opinion the patient is benefitting from therapy.  
Continuation must be discussed with the medical monitor or Sponsor on a case-by-case basis. 
**For bortezomib related peripheral neuropathy please refer to Table 6-9. 
*** 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, transient abnormal 
laboratory value, fatigue).  This must be discussed with the Medical Monitor on a case by case basis.  
Alternate dose modification may be considered in discussion with the medical monitor or the 
Sponsor.  Continued dosing with or without dose reduction may be considered after contact 
with the medical monitor in case of non-study drug related cycle prolongations (for example: 
influenza). 
Patients who discontinue treatment for a study related AE including abnormal laboratory value 
must be followed as described in Section 8.2.6 and 8.2.7.   
Regimen A - Dose Modifications for Bortezomib Related Peripheral Neuropathy 
Patients experiencing new or worsening peripheral neuropathy during bortezomib therapy may 
require a decrease in the dose and/or a less dose-intense schedule (see Table 6-7). For dose or 
schedule modification guidelines for patients who experience bortezomib related neuropathic 
pain and/or peripheral neuropathy see Table 6-9. 
Table 6-9 Dose Modification for Bortezomib Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
Severity of peripheral neuropathy signs 
and symptoms 
Modification of dose and regimen  
Grade 1 (asymptomatic; loss of deep tendon 
reflexes or paresthesia) without pain or loss 
of function  
No action  
Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental Activities 
of Daily Living (ADL)**)  
Reduce bortezomib by one dose level (Table 6-
7)** 
 


 
 
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Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self-care ADL ***)  
Withhold bortezomib therapy until toxicity 
resolves to ≤ Grade 2 without pain. When 
toxicity resolves reinitiate with a reduced dose 
of bortezomib (if already dosing at 0.7 mg/m2, 
discontinue therapy).   
Grade 4 (life-threatening consequences; 
urgent intervention indicated)  
Discontinue bortezomib 
*Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing 
money, etc; 
**A weekly schedule of bortezomib maybe considered based on the current dose and schedule being tested or as 
determined to be safe by the DSMC.  Consultation with the medical monitor is required. 
***Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden 
6.8.3 
Regimen B: Dose Modification Guidelines Based on Toxicity 
6.8.3.1 
Regimen B:  Dose Modifications for Daratumumab 
There are no dose reductions for daratumumab. Refer to Table 6-4 for changes in the rate of 
infusion for daratumumab hypersensitivity infusion related reactions. 
6.8.3.2 
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 a patient has received daratumumab. Type and screen patients prior to starting 
daratumumab. 
Management of Hepatitis B Virus Reactivation 
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately controlled. If the benefits outweigh the 
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local 
standard of care. Consult a liver disease specialist as clinically indicated. Primary antiviral 
prophylaxis is permitted as per local standard of care. 
6.8.3.3 
Melflufen precautions 
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 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 6-10 Dose Modifications for Melflufen and Daratumumab Drug Related Toxicity 
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 7.2 


 
 
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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 6.7). 
 
Hold, evaluate weekly and 
resume therapy when 
criteria for initiation of a 
new cycle are met.   
(Section 6.7). 
For patients that have 
discontinued melflufen, 
dosing may continue if 
platelets are >25,000 
mm3 (>25.0 x 109 /L)  
(Section 6.7) 
 
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 (Refer to 
Table 6-3 for 
daratumumab 
schedule) 
 
Hold until resolved to ≤ 
Grade 2 within the cycle 
(Refer to Table 6-3 for 
daratumumab scheduled) 
For patients that have 
discontinued melflufen, 
see Section 6.7 
 
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 
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 weekly* and 
resume therapy when criteria 
for initiation of a new cycle 
are met (Section 6.7). 
 
 Reduce dose if attributed to 
melflufen*** 
 
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 (Section 6.7).  
 
 


 
 
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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 met*** 
**No dose reduction, 
refer to Section 6.4 for 
rate changes for related 
hypersensitivity reactions 
Grade 4 drug related non-
hematologic toxicity  
Any day 
Discontinue therapy 
Discontinue therapy 
*If cycle prolongation of more than 28 days (beyond Day 57) is needed, study treatment is to be discontinued 
unless in the investigators opinion the patient is benefitting from therapy.  Continuation must be discussed with 
the medical monitor or Sponsor on a case by case basis. 
**For daratumumab related infusion reactions please refer to Section 6.5.4.4 
*** 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.  
Alternate dose modification may be considered in discussion with the medical monitor or the 
Sponsor.  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). 
Patients who discontinue treatment for a study related AE including abnormal laboratory value 
must be followed as described in Section 8.2.6 and 8.2.7.   
6.8.4 
Regimen A and B: Dose Modifications for Dexamethasone 
Dose modifications for dexamethasone are permitted. If a patient is unable to tolerate 
dexamethasone due to dexamethasone related toxicity, dexamethasone may be further reduced 
or discontinued following consultation with the medical monitor.   However, alternate steroids 
may be required for prevention of daratumumab infusion related reactions. Refer to the 
daratumumab Prescribing Information or SmPC for further information.   In the event of a 
cycle delay, unrelated to dexamethasone toxicity, dexamethasone may be continued weekly at 
the investigators discretion.  
Table 6-11 Dose Modifications for Toxicity Related  to Dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2  
(requiring medical 
management) 
Treat with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite 
above measures, decrease dexamethasone 
dose by 1 dose level. 
Gastrointestinal 
 ≥ Grade 3 
(requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled. Restart and decrease 
one dose level of current dose along with 
concurrent therapy with H2 blockers, 
sucralfate, or omeprazole. If symptoms 
persist despite above measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do not 
resume 
Cardiovascular 
Edema 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level; if 
edema persists despite above measures, 


 
 
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Body System 
Symptom 
Recommended Action 
 ≥ Grade 3 (limiting function 
and unresponsive to therapy or 
anasarca) 
decrease dose another dose level. 
Discontinue dexamethasone and do not 
resume if symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood alteration  
 ≥ Grade 3 (interfering with 
function +/- interfering with 
activities of daily living) 
Hold dexamethasone until symptoms 
resolve. Restart with one dose level 
reduction. If symptoms persist despite above 
measures, discontinue dexamethasone and 
do not resume. 
Musculoskeletal 
Muscle weakness  
 ≥ Grade 3 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone dose by one dose 
level. If weakness persists despite above 
measures, decrease dose by one additional 
dose level. Discontinue dexamethasone and 
do not resume if symptoms persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If uncontrolled 
despite above measures, decrease dose by 
one dose level until levels are satisfactory. 
 
Alternate dose modification may be considered in discussion with the medical monitor or the 
Sponsor.  
6.9 
TREATMENT DURATION 
Patients will receive treatment until there is documented PD, according to the IMWG-URC 
guidelines (Rajkumar et al. 2011, Appendix C), to be confirmed on two consecutive 
assessments, unacceptable toxicity or the patient/treating physician determines it is not in the 
patient’s best interest to continue.  Confirmed PD (on 2 consecutive assessments) should be 
verified by the medical monitor prior to treatment discontinuation.  
7 
CONCOMITANT THERAPY  
All blood products and baseline medications that the patient is taking within 21 days prior to 
the initiation of therapy must be recorded.  All additional medications (other than study drug) 
or changes in baseline medications and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study 
must be listed on the Concomitant Medications page of the eCRF.  
7.1 
REQUIRED CONCOMITANT THERAPY 
 Contraceptive measures 
Males and females of child-bearing potential shall be required to use effective 
contraceptive methods (or abstinence) prior to initiation of study drug, while on 
therapy and for 3 months after the last dose of study drug.  The best method should be 
determined in consultation with the Investigator. 
Females: 
- 
Birth control methods that are considered as highly effective include: tubal ligation, 
IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or 


 
 
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implants), or partner’s vasectomy. Microdose progesterone analogues should be 
avoided. 
- 
Reliable contraception is indicated even where there has been a history of 
infertility, unless due to hysterectomy. 
Males: 
Males must use a condom during any sexual contact with females of child-bearing 
potential during therapy and for three months after the last dose of study drug, even if 
they have had a successful vasectomy.  Males should not donate sperm during the study 
and for 3 months after treatment has been stopped.  It is not known if melflufen may 
cause permanent sterility, therefore, male patients may wish to consider cryo-
preservation of semen before initiating therapy with melflufen.   
 Anti-viral prophylaxis 
It is required that patients receive prophylaxis against herpes zoster using oral 
acyclovir (400 mgs twice daily) or valacyclovir (500 mgs twice daily) or equivalent 
antiviral therapy per institutional guidelines and at the discretion of the site 
investigator, unless the participant develops a hypersensitivity to the agents.   
Reactivation of Hepatitis B:  See Section 6.8.3.2, regarding management of patients at 
risk for, or diagnosed with, reactivation of hepatitis B.  
 Regimen specific requirements 
Refer to the specific subsection of each drug for any additional required concomitant 
medications associated with the respective drug in each Regimen. 
7.2 
RECOMMENDED CONCOMITANT THERAPY 
 Pneumocystis prophylaxis  
o All patients are recommended 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 x per week. May require adjustment for renal insufficiency. 
o Patients who are found to be intolerant of pneumocystis prophylaxis while on 
study may continue on study at the discretion of the investigator   
 Prophylactic treatment with anti-emetic(s) prior to melflufen administration is 
recommended. Subsequent anti-emetic drugs against emesis should be administered at 
the discretion of the investigator.  
 Patients should receive full supportive care, including transfusions of blood and blood 
products (with the limitations of prophylactic use noted below), antibiotics, anti-
diarrheals, analgesics, etc. and prophylactic treatment for tumor lysis syndrome when 
appropriate.  
 Other prophylactic treatment for patient related concomitant conditions or risks may 
be considered. 


 
 
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 Bisphosphonate therapy i.v. or p.o. should be administered if indicated in accordance 
with institutional guidelines. 
 Thrombocytopenia and neutropenia are known consequences of MM but also the most 
common expected adverse event (AE)s associated with melflufen.  Careful attention is 
to be paid to the monitoring of blood counts. General supportive measures, together 
with appropriate blood and platelet transfusions and hematological growth factors 
should be instituted if necessary.  It is recommended, at the investigator’s discretion, 
that platelet transfusion should be avoided within ≤ 5 days of the next dose in order to 
assess endogenous platelet recovery and avoid the possibility of excessive 
myelosuppression (Excluding Cycle 1, Day 1 which adheres to the guidelines in 
Section 6.2 for use of growth factors and platelet transfusions prior to the first dose of 
therapy). 
 Recommended Antimicrobial prophylaxis   
o For patients with history of cytomegalovirus (CMV) infection that required 
treatment, prophylactic treatment per NCCN or institutional guidelines is 
recommended.   
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf 
or 
NCCN.org 
o Patients with neutropenia are strongly recommended to receive antimicrobial 
prophylaxis throughout the treatment period per NCCN or institutional 
guidelines. 
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf 
 
or 
NCCN.org 
 Regimen specific recommendations 
o Refer to the drug administration section of each drug for any additional 
recommended concomitant medications associated with the respective drug in 
each Regimen. 
7.3 
PROHIBITED CONCOMITANT THERAPY 
 Concurrent therapy with any approved or investigative anticancer therapeutic drug 
with activity against MM, including alpha interferon and/or chronic use of 
clarithromycin, is not allowed  
 Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel 
disease) > prednisone 10 mg/day (or its equivalent) are not permitted. However, 
steroids required for the treatment of daratumumab infusion related reactions are 
permitted 
 Other investigative agents should not be used during the study 
 Radiation therapy to a limited area for bone pain to a pre-existing lesion may be 
considered in consultation with and approval of the medical monitor 
 The use of live vaccines is prohibited during the study and for 30 days after last dose 
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 The prophylactic use of growth factors and platelet transfusions are not permitted to 
render the patient eligible for trial participation except as described within the inclusion 
criteria Section 5.2.1. Other limitations are detailed in Section 6.7 and Section 7.2. 
 The prophylactic use of growth factors and platelet transfusions is not permitted in 
Cycle 1 of the dose escalation cohorts in Phase 1. 
8 
VISIT SCHEDULE AND ASSESSMENTS 
8.1 
STUDY FLOW AND VISIT SCHEDULE 
Table 8-1 lists all of the assessments required in the study and marked with an “X”, indicating 
when they are to be performed.  Evaluations marked with (X) are only required if indicated.  
All data obtained from these assessments must be supported in the patient’s source 
documentation.  
 


 
 
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Table 8-1 Schedule of Events 
 
 
Evaluation 
Screening 
Days  
-21 to -1 
Regimen A and B (except where specified) 
All Cycles t 
End of 
Treatment q 
PFS -
FUr 
OS-FUs 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
Informed consent a 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria and review on day 1 
X 
X 
 
 
 
 
 
 
Medical and disease history b 
X 
 
 
 
 
 
 
 
Physical examination/symptom assessment c  
X 
X 
(X) 
(X) 
(X) 
X 
 
 
Vital signs and BSA d  
X 
X 
(X) 
(X) 
(X) 
X 
 
 
ECOG performance status 
X 
X 
 
 
 
X 
 
 
Pregnancy test e 
X 
X 
 
 
 
X 
 
 
Blood type and screen for Regimen B only prior to 
first dose of daratumumab 
X 
 
 
 
 
 
 
 
Electrocardiogram f  
X 
 
 
 
 
X 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
Hematology g 
X 
X  
D1 and 4 for 
Reg A 
(X)* 
D8 and 11 
for Reg A 
X 
(X)* 
X 
 
 
Coagulation h 
X 
  
 
 
 
 
 
 
Blood chemistries i 
X 
X  
 
 
 
X 
(X)r 
 
Pulmonary Function Tests Regimen B only 
X 
 
 
 
 
 
 
 
Hepatitis B screen (HBsAg, Anti-HBs, Anti-HBc) 
Regimen B only u 
X 
(X) 
 
 
 
(X) 
(X) 
(X) 
Urinalysis  
X 
 
 
 
 
 
 
 
Bone marrow aspiration j 
X 
(X) 
 
 
 
(X) 
(X)r 
 
M protein assessments (SPEP/UPEP, IFE, SFLC) k 
X 
X  
 
 
 
X 
(X)r 
 
Serum β2-microglobulin  
X 
 
 
 
 
 
 
 
Assessment of extramedullary plasmacytoma l 
X 
(X) 
 
 
 
(X) 
(X)r 
 
Skeletal survey or CT scan  m 
X 
(X) 
 
 
 
(X) 
(X)r 
 
Pharmacokinetic samples n   
 
(X)n 
 
 
 
 
 
 
Dexamethasone administration o and review of patient 
compliance* 
 
Refer to the assigned Regimen for the required days of 
dexamethasone administration. 
 
 
 
Melflufen administration o  
 
X 
 
 
 
 
 
 


 
 
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Evaluation 
Screening 
Days  
-21 to -1 
Regimen A and B (except where specified) 
All Cycles t 
End of 
Treatment q 
PFS -
FUr 
OS-FUs 
Day 1 
Day 8 
Day 15 
Day 22 
Bortezomib administration o Regimen A only 
 
X 
D1 and 4 
X 
D8 and 11 
(X) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
Daratumumab administration o Regimen B only 
 
 
X 
Day 2 C1 
only 
(X)  
(week 1 – 8) 
(X)  
(week 1 – 24) 
(X)  
(week 1-8) 
 
 
 
Concomitant medications p 
X 
 
X 
 
 
AE monitoring 
 
 
X 
 
 
Follow-up (PFS, OS) 
 
 
 
Xr 
X 
(X) Only if indicated 
a) All patients must sign an (IRB/IEC/REB)-approved informed consent document prior to enrollment and prior to any study related procedures. 
b) Medical History including demographics, prior and current medical illness and conditions, prior surgical procedures.  Disease history includes date of initial 
diagnosis, ISS, R-ISS and cytogenetics at diagnosis (if previously evaluated).  ISS and R-ISS stage (Appendix I) at time of study entry.  Prior surgery and/or 
radiation and anticancer therapy, including start and stop dates, documentation of best response, date of progressive disease and relapsed or refractory status 
(Appendix E).   
c) A complete physical exam, including height (screening only) and weight, neurologic assessment and assessment for extramedullary myeloma (if present on PE) 
will be conducted at screening, Day 1 of each cycle and End of Treatment visit.  A symptom directed physical examination will be conducted as needed during 
a cycle.  Plasmacytomas that can be followed by physical exam are to be evaluated on Day 1 of each cycle.  Baseline symptoms and residual toxicity from 
previous therapy is to be assessed within 21 days prior to initiation of therapy.   
d) Vital signs including blood pressure, pulse, respiration rate, temperature, to be assessed at screening and pre and post melflufen infusion and pre and post each 
daratumumab infusion and as clinically indicated.  Regimen A: BSA should be calculated on Day1 of each cycle prior to bortezomib administration.  (See Section 
6.5.3  and Appendix J). 
e) All FCBP must have a medically supervised negative serum or urine pregnancy test prior to the initiation of therapy.   A FCBP is a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months).   
f) 
A12-lead ECG assessment will be performed on all patients at screening and End of Treatment visit and as clinically indicated.  Q-Tc interval to be assessed by 
Fridericia formula (Appendix H). 
g) Hematology: CBC with differential, and platelet count.  Patients are required to have all laboratory evaluations completed at the study center during Cycles 1 
and 2.  Following Cycle 2, CBC evaluations may be done at the study center laboratory or other local laboratory as long as the results are reviewed by the study 


 
 
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center within 24 hours and toxicity assessment is completed.   Repeat CBC is required on Day 4 and 11 only for patients on twice weekly bortezomib (Regimen 
A).  Exceptions and reduced frequency of CBC evaluations may be made only in consultation with the medical monitor.  All CBC values collected in addition 
to protocol specified time points must be recorded in the eCRF.  See Section 10.1.5 for reporting requirements of scheduled and unscheduled results of 
thrombocytopenia and neutropenia.   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 bortezomib administration on 
day 8 in each cycle and before each dose of daratumumab. 
h) Coagulation: prothrombin time (PT), international normalized ratio (INR). 
i) 
Blood chemistry: sodium, chloride, potassium, magnesium, phosphate, uric acid, blood urea nitrogen [BUN](or urea), glucose (fasting at baseline), ALT/AST 
(SGPT/SGOT), alkaline phosphatase, total protein, total bilirubin, albumin, serum creatinine, and estimated glomerular filtration rate by Cockcroft-Gault 
Formula (Appendix G) calcium and lactate dehydrogenase (LDH).  Patients are required to have all evaluations completed at the treatment center during Cycles 
1 and 2.  Following Cycle 2, Chemistry evaluations may be done at the study center laboratory or other local laboratory as long as the results are reviewed by 
the study center within 24 hours and toxicity assessment is completed.  Exceptions may be made only in consultation with the medical monitor.. 
j) 
Bone marrow aspirate (BMA) to be collected at screening for % plasma cells, morphology, and cytogenetics by Fluorescence In-Situ Hybridization (FISH). 
Minimum FISH probes include t(4;14), t(14;16), t(14;20), del(17/17p), gain(1q)(Sonneveld et al 2016). In addition, If cytogenetics by karyotype has been done 
according to institutional guidelines it should be recorded in the CRF.  A BMA sample is to be collected at screening and stored for possible MRD assessment. 
If a bone marrow aspirate and/or biopsy has been collected within 28 days, with the appropriate evaluations, prior to initiation of therapy, it does not need to be 
repeated. A repeat BMA is required to confirm a suspected CR and to assess MRD status. Stored BMA samples may be used for optional future testing if 
requested by Oncopeptides in consenting patients and where regionally acceptable. Refer to Laboratory manual. 
k) SPEP and UPEP and serum and urine IFE (if SPEP or UPEP are not detectable and to confirm a CR), quantitative immunoglobulins per routine lab 
practice and SFLC assay (only required if SPEP and UPEP are not measurable [UPEP is < 200 mg/24 hours and SPEP is < 0.5 g/dL]) are to be conducted 
at screening, Cycle 1 Day 1 and prior to each cycle even if treatment is delayed. Quantitative immunoglobulins only need to be repeated for patients 
with IgA or IgD myeloma.  All assessment of SPEP, UPEP, IFE and FLC must be completed in the same laboratory for a given patient.  In the event 
treatment is delayed, ≥ 6 weeks (beyond Day 43), MM disease response assessments are required to be repeated on the day the new cycle starts (Day 50 
or 57 of the previous cycle). If treatment is discontinued beyond Day 43 the response assessments should be repeated on the day of that determination 
(or as soon as possible ≥ 30 days after last dose of study drug) as part of the end of treatment (EoT) visit. As daratumumab is a monoclonal IgG kappa 
antibody, the SPEP and IFE can be positive due to 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 (refer to 
the lab guidance document for details).  
l) 
Known or suspected extramedullary plasmacytomas are to be assessed at screening (perform necessary imaging to obtain measurements), as clinically indicated 
and to confirm response identified by M protein or suspected progression. The same method of evaluation should be used throughout the study (e.g., 
Computerized tomography [CT]/ magnetic resonance imaging [MRI]/ positron emission tomography [PET]). All imaging assessments with measurements should 
be documented in the eCRF.  


 
 
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m) Skeletal survey includes lateral radiograph of the skull, and anterioposterior views of femur and humeri, anterioposterior and lateral views of the spine, and 
anterioposterior views of the pelvis and ribs. Low dose CT scan may be used in addition or in place of conventional X-ray with the same technique to be used 
with each evaluation.  Required if previous survey > 6 weeks from initiation of therapy and at any time when clinically indicated.  Limited X-rays may be 
performed as clinically indicated to confirm PD. 
n) PK samples will be collected in patients from both Regimens, at selected sites only. Three plasma samples for determination of melphalan concentrations will 
be drawn in connection to the first two melflufen treatment cycles, 10 – 15 minutes after the end of the melflufen infusion, 1 hour after the end of the melflufen 
infusion and for cycle 1 the third sample should be taken 2-4 hours after the end of the melflufen infusion (as late as possible within the time frame). For cycle 
2,in Regimen B, the third sample should be taken at the end of the daratumumab infusion.   Refer to the Laboratory Manual for details on specimen collection 
and processing. 
o) See Section 6 in the protocol for complete details on study drug administration, dose modifications, start of a new cycle of therapy and study drug compliance. 
See Section 9 for study drug supply, storage, preparation and accountability.   
p) Concomitant medications and procedures: - all blood products and medications within 21 days prior to first dose until the End of Treatment Visit. 
q) End of Treatment visit should be scheduled 30 days (accepted time window ±3 days) after last dose of 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) with evaluation of safety variables including 
recording of new and ongoing AEs, review of concomitant medications and any other new disease related therapy.  If a new treatment for MM is to be introduced 
sooner than 30 days after last dose of study drug the EoT visit should occur as close as possible before the first dose of the new drug.  Ongoing neutropenia and 
thrombocytopenia Grade 3-4 at the EoT visit are to be followed until resolution (≤ Grade 2) or initiation of subsequent therapy.  SAEs should be followed until 
resolution or stabilization with no expected resolution.   
r) 
Progression Free Survival Follow-Up (PFS-FU): Patients who discontinue therapy for reasons other than disease progression should continue to have monthly 
disease assessments done until documented progression (confirmed on 2 consecutive assessments) or initiation of subsequent therapy. Schedule the first 
assessment 4 weeks after the EoT visit.  Confirmed PD should be verified by medical monitor prior to discontinuation of therapy. If PD has not been confirmed 
prior to the initiation of subsequent therapy the reason for the subsequent therapy should be documented. Documentation of the start date and regimen of the 
first subsequent therapy is required. Serum calcium and albumin (corrected calcium) required only if evidence of PD.  
s) 
   Overall Survival Follow-up (OS-FU):  Following confirmed disease progression or initiation of subsequent therapy, follow-up for overall survival status and 
second primary malignancies will take place every three months +/- 7 days for 24 months. In the event that Oncopeptides AB would like to determine the OS 
status of patients following 24 months, future inquiries about their health status may be conducted. This information may be recorded outside of the eCRF 
established for this study.  Documentation of the start date and regimen of the first subsequent therapy should be done if it occurs during OS -FU.  Follow-up 
may be completed by phone contact.  SAEs should be followed until resolution or stabilization with no expected resolution.  Death information from public 
sources, e.g. death registry, obituary listing, etc. can also be used when it is available and verifiable.  
t) 
+/- 3 day window permitted (Except Cycle 1 Day 1) for holidays/administrative reasons. 
u) Hepatitis B assessments required for Regimen B screening.  Patients with active hepatitis B (defined as HBsAg+) are excluded. Patients with non-active hepatitis 
B (HBsAg-, Anti-HBs+, Anti-HBc+) may only be enrolled after approval of the sponsor and consideration of risk of reactivation. If approved, additional screening 


 
 
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and monitoring will include HBV-DNA testing by PCR performed locally at screening, every 12 weeks during treatment, at the EoT Visit, then 3 and 6 months 
after the last dose of daratumumab.  Consultation with a liver disease specialist may be required. 
* If patient tolerability is good, i.e. no dose modifications, dose delays or need of supportive therapy (Granulocyte colony stimulating factor (G-CSF), blood or 
platelet transfusion) in the two preceding cycles, then CBC assessments may be excluded as the following; Regimen A Day 22; Regimen B Day 8 and Day 22.  Patients 
should still be contacted weekly to follow up on AE/SAEs and Dexamethasone compliance. 


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8.2 
STUDY ASSESSMENTS 
Refer to the Table 8-1; Schedule of Events. For details and timelines and explanation of all 
study assessments. Refer to the Laboratory Guidance Document for details on lab testing 
requirements.  
8.2.1 
Screening Disease Assessments 
 M-protein determination using the following procedures  
o SPEP and serum protein IFE with quantitative Ig;  
 Quantitative immunoglobulin evaluation may be based on regional 
availability of the test. 
 Immunofixation of serum is required at screening if M protein by SPEP 
is not detectable 
o UPEP and urine protein IFE (all using the same 24-hour urine collection) 
 Immunofixation of urine is required at screening if M protein by UPEP 
is not detectable 
o SFLC and SFLC ratio 
 FLC assessment is not required at screening in the presence of 
measurable SPEP and/or UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 
mg/24 hours), 
 If the M protein is non-measurable in SPEP and UPEP at screening or 
Cycle 1, Day 1, the FLC is required 
 BMA to quantify percent myeloma cell involvement and morphology, cytogenetics by 
FISH and a sample stored for possible MRD assessment. If cytogenetics by karyotype 
has been done according to institutional guidelines it should be recorded in the CRF. 
 Extramedullary plasmacytoma evaluation of known or suspected lesions (by PE or 
imaging procedures) 
 Skeletal survey: lateral radiograph of the skull, and anterioposterior views of femur and 
humeri, anterioposterior and lateral views of the spine, and anterioposterior views of 
the pelvis and ribs. Low dose CT scan may be used in addition or in place of 
conventional X-ray (with the same technique to be used with each evaluation)   
 Beta2 microglobulin 
 Lactate dehydrogenase (LDH)  
 ISS staging score and revised R-ISS (Appendix I) 
8.2.2 
Efficacy Assessments  
M-protein determination using the following procedures (also refer to footnote k on Table 8-1): 
 SPEP and serum protein IFE with quantitative immunoglobulins (For patients with IgA 
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o As daratumumab is a monoclonal IgG kappa antibody, the SPEP and IFE can 
be positive due to 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. 
o Immunofixation of serum is required at any time when M protein by SPEP 
becomes non-detectable and to confirm a CR. 
 UPEP and urine protein IFE (all using the same 24-hour urine collection); and  
o Immunofixation of urine is required at any time when M protein by UPEP 
becomes not detectable and to confirm a CR. 
 SFLC and SFLC ratio 
o FLC assessment is not required in the presence of measurable SPEP and/or 
UPEP (SPEP ≥ 0.5 g/dL and/or UPEP ≥ 200 mg/24 hours), 
o FLC is required to confirm sCR, regardless of type of measurable disease. 
o It is up to the site to work with the laboratory that performs the response 
analyses to ensure that the laboratory completes the immunofixation and FLC 
evaluations when required, to enable response assessments according to IMWG 
criteria. 
 Extramedullary plasmacytoma evaluation with the same technique to be used with each 
evaluation 
 Bone marrow aspirate to quantify percent myeloma cell involvement  
 Skeletal X-rays and/or CT scans 
 Serum calcium (corrected calcium) 
8.2.3 
Safety and Tolerability Assessments 
 Assessment and grading of AE(s) 
 Physical examination with vital signs, neurologic assessment and assessment of 
performance status 
 Routine safety laboratory tests (CBC with differential and platelets; clinical chemistry, 
coagulation tests and urinalysis) with calculation of the glomerular filtration rate 
according to the Cockcroft-Gault formula. (Appendix G) 
 Chest X-ray (postero-anterior/lateral) 
 Pulmonary function tests (Regimen B only) 
 Hepatitis Screen (Regimen B only) 
 Pregnancy testing (FCBP) 
 Electrocardiogram - Q-Tc interval to be assessed by Fridericia formula (Appendix H)  


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AEs, including clinical laboratory and vital sign abnormalities, will be graded using the CTCAE 
version 4.03 (Appendix B).  Patients are evaluable for toxicity if they receive any dose of study 
treatment. 
8.2.4 
Pharmacokinetic Assessments 
Plasma samples for determination of melphalan concentrations will be drawn in connection to 
2 melflufen treatment cycles, 10 – 15 minutes after the end of the infusion, 1 hour after the end 
of infusion and 2 – 4 hours after the end of infusion (as late as possible within the time frame).  
Refer to the Laboratory Manual for details on collecting and processing specimens.  
8.2.5 
Assessments 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. 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 bortezomib administration on Day 8 in each cycle and before  
each dose of daratumumab. Patients who discontinue melflufen and continue to be treated with 
the other drug in the Regimen should also be followed for response, PFS and OS. 
8.2.6 
End of Treatment 
The End of Treatment (EoT) visit should be scheduled 30 days (accepted time window ±3 days) 
after last dose of study drug or as soon as possible if the decision to remove the patient from 
therapy occurs later than 30 days after last dose (e.g. in the case of prolonged cycle).  At the 
EoT visit evaluation of safety including recording of new and ongoing AEs, review of 
concomitant medications and any other new disease related therapy should be done.  Patients 
with PD as the reason for EoT should have the PD confirmed with 2 consecutive assessments 
and verified by the medical monitor prior to discontinuation of therapy.  If a new treatment for 
MM is to be introduced sooner than 30 days after last dose of study drug, the EoT visit should 
occur as close as possible before the first dose of the new drug.  If PD has not been confirmed 
prior to the initiation of subsequent therapy the reason for the subsequent therapy should be 
documented.  Ongoing neutropenia and thrombocytopenia Grade 3-4 at the EoT visit are to be 
followed until resolution (≤ Grade 2), or initiation of subsequent therapy.  Ongoing SAE’s 
should be followed until resolution or stabilization with no expected resolution.  The date and 
regimen of the first subsequent therapy should be recorded in the eCRF.   
8.2.7 
Follow Up Assessments 
PFS-FU and OS-FU assessments should be completed on all patients unless due to death, lost 
to follow-up or the patient specifically has withdrawn consent for follow-up.  Discontinuation 
from treatment does not preclude the need to complete follow-up assessments. 
8.2.7.1 
Progression Free Survival Follow-up 
Patients who discontinue therapy for reasons other than disease progression should continue to 
have monthly disease assessments done for PFS-FU until progression or initiation of subsequent 
therapy.  Schedule the first assessment 4 weeks after the EoT visit.  If PD has not been 
confirmed prior to initiation of subsequent therapy the reason for the subsequent therapy should 
be documented.  The start date and regimen of the first subsequent therapy should be recorded 
in the eCRF if it occurs during PFS-FU.  


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8.2.7.2 
Overall Survival Follow-up 
Following confirmed disease progression, patients will be followed for OS-FU. Follow-up for 
overall survival status, second primary malignancies and first subsequent therapy will take place 
every three months +/- 7 days for 24 months. In the event that Oncopeptides AB would like to 
determine the OS statusf patients following 24 months, future inquiries about their health status 
may be conducted. This information may be recorded outside of the eCRF established for this 
study.   OS-FU may be completed by phone contact.  Death information from public sources, 
(e.g. death registry, obituary listing, etc.), can also be used when it is available and verifiable.  
The start date and regimen of the first subsequent therapy should be recorded in the eCRF if it 
occurs during OS-FU.  
8.2.7.3 
Lost to Follow-Up 
Patients lost to follow up should be recorded as such on the eCRF.  For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient (e.g., dates of telephone calls, registered letters, 
etc.). 
8.2.8 
Criteria for Premature Patient Withdrawal 
Patients may be withdrawn from treatment if any of the following occur: 
 Documented confirmed disease progression verified by the medical monitor 
(2 consecutive evaluations)  
 Patients may choose to withdraw from the study treatment at any time and continue in 
follow-up 
 AEs that, in the judgment of the investigator, may cause severe or permanent harm or 
which require study drug discontinuation (See Sections 6.8.2 and 6.8.3) 
 Clinical judgment of the investigator: A patient may be withdrawn from the study 
treatment, if in the opinion of the investigator, it is not in the patient's best interest to 
continue 
 Requiring other anti-neoplastic therapies 
 Major deviation of the study protocol (i.e., unable to adhere to study schedule) 
 Confirmed pregnancy 
 Lost to follow-up 
Patients may be withdrawn from the study if any of the following occur: 
 Withdrawal of consent for study participation 
 Death 
 Lost to follow-up 
 Discontinuation of the study by Oncopeptides AB 
 Completed OS follow-up per protocol 


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The reason(s) for withdrawal of study treatment or study participation and the date at which the 
decision is made should be documented. Safety monitoring and follow-up assessments should 
continue as appropriate according to the study schedule, unless the patient has withdrawn 
consent for study participation. 
9 
STUDY DRUG SUPPLY AND HANDLING 
9.1 
MELFLUFEN 
9.1.1 
Melflufen Packaging and Labeling 
Melflufen is formulated as a sterile lyophilized powder for solution for infusion (containing 
melflufen and the excipient sucrose).  The drug product, melflufen powder for solution for 
infusion, is filled in 50 mL glass vials with grey rubber stoppers and flip-off seals.  Each vial 
contains 20 mg of melflufen.  These will be delivered in paper boxes containing enough vials 
for several administrations.  
Please refer to the Pharmacy Manual for further details on packaging and labeling. 
9.1.2 
Melflufen Storage 
Melflufen must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access.  Upon receipt, the temperature log should be checked and notice given 
to supplier of the condition of the shipment.  Melflufen shall be stored at +2 to +8°C 
(refrigerated).   
9.1.3 
Melflufen Supply 
Melflufen will be provided by Oncopeptides free of charge. 
9.1.4 
Melflufen Special Handling 
Melflufen is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and 
handling melflufen solutions. The use of gloves and other appropriate protective clothing is 
recommended.  In case of skin contact, wash the affected area immediately and thoroughly with 
soap and water for at least 15 minutes.  If product contacts eye, immediately flush eye 
thoroughly with water for at least 15 minutes.  Always contact a physician after any form of 
body contact.  All materials that have been used for preparation should be disposed of according 
to standard practices. 
9.1.5 
Melflufen Drug Preparation 
Melflufen powder for solution for infusion is prepared by reconstitution with 5% glucose 
solution and then further diluted in a 250 mL infusion bag of either 5% glucose solution 
(ambient or cold) or 0.9% saline solution (cold). The i.v. tubing must be primed with the same 
solution either before or after the dilution of melflufen in the 250 mL bag. Careful attention and 
documentation of the preparation procedures and time frames are required since melflufen 
degrades in solutions*.   
Time to infusion requirements: 
 250 mL bag of 5% glucose:   


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o Ambient: the 250 mL bag of 5% glucose should be at room temperature prior 
to adding melflufen. The maximum allowed time from start of reconstitution 
until the start of iv infusion is 30 minutes.   
o Pre-cooled: the 250 mL bag of 5% glucose should be pre-cooled prior to adding 
melflufen. The maximum allowed time from start of reconstitution to start of 
infusion 
is 
45 
minutes. 
 
 250 mL bag of 0.9% saline: 
o The 250 mL bag of 0.9% saline should be pre-cooled prior to adding melflufen.  
The maximum allowed time from start of reconstitution until the start of iv 
infusion is 3.5 hours.   
 
 
Refer to the Pharmacy Manual for detailed instruction for reconstitution and dilution of 
melflufen in preparation for infusion.  A well-coordinated plan between the pharmacy and 
treatment room is recommended. (See Pharmacy Manual for details). 
9.2 
DEXAMETHASONE 
9.2.1 
Dexamethasone Packaging and Labeling 
No additional labeling is required for the use of commercial dexamethasone in the USA. 
Dexamethasone will be labeled for investigational use for sites outside of the USA. 
9.2.2 
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.    
9.2.3 
Dexamethasone Supply 
Oral dexamethasone will be supplied by Oncopeptides AB to sites located outside the USA. 
USA sites will use commercially available dexamethasone supplies. 
9.3 
BORTEZOMIB 
9.3.1 
Bortezomib Packaging and Labeling 
Bortezomib for injection is a sterile lyophilized powder for reconstitution and is supplied in 
sterile, single use vials containing bortezomib and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of bortezomib contain 35 mg of mannitol.   
Bortezomib will be labeled for investigational use according to local regulations. 
9.3.2 
Bortezomib Storage 
Vials containing lyophilized bortezomib for injection should be stored according to label 
requirements.  Store at USP controlled room temperature which is 25oC (77oF); excursions 
permitted from 15 to 30oC (59 to 86oF).  Upon receipt, the temperature log should be checked 
and notice given to supplier of the condition of the shipment.    


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9.3.3 
Bortezomib Supply  
Commercial supplies of bortezomib should be used for patients enrolling at sites in the USA. 
Bortezomib will be supplied by Oncopeptides to sites other than USA.  Please refer to the 
Pharmacy Manual for complete details on drug supply and ordering procedures. 
9.3.4 
Bortezomib Special Handling 
Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling bortezomib solutions.  The use of gloves and other appropriate protective clothing is 
recommended.  In case of skin contact, wash the affected area immediately and thoroughly with 
soap and water for at least 15 minutes.  If product contacts eye, immediately flush eye 
thoroughly with water for at least 15 minutes.  Always contact a physician after any form of 
body contact.  All materials that have been used for preparation should be disposed of according 
to standard practices. 
9.3.5 
Bortezomib Drug Preparation 
Please refer to the Prescribing Information or the SmPC for instructions on drug preparation of 
bortezomib for SQ or i.v. administration. 
9.4 
DARATUMUMAB 
9.4.1 
Daratumumab Packaging and Labeling 
Daratumumab is a colorless to yellow, preservative-free solution available as Injection: 
 100 mg/5 mL (20 mg/mL) in a single-dose vial 
 400 mg/20 mL (20 mg/mL) in a single-dose vial 
Daratumumab will be labeled for investigational use for sites according to local regulations. 
9.4.2 
Daratumumab Storage 
Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze or shake. Protect from light. 
This product contains no preservative. Upon receipt, the temperature log should be checked, 
and notice given to supplier of the condition of the shipment.    
Since daratumumab does not contain a preservative, administer the diluted solution 
immediately at room temperature 15°C–25°C (59°F–77°F) and in room light.  Diluted solution 
may be kept at room temperature for a maximum of 15 hours (including infusion time). 
If not used immediately, the diluted solution can be stored prior to administration for up to 24 
hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light.  Do not freeze. 
If stored in the refrigerator, allow the solution to come to room temperature. Administer the 
diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and 
with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore 
size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), 
polybutadiene (PBD), PVC, PP or PE. 
Do not store any unused portion of the infusion solution for reuse. Any unused product or waste 
material should be disposed of in accordance with local requirements. 


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9.4.3 
Daratumumab Supply  
Please refer to the Pharmacy Manual for complete details on drug supply and ordering 
procedures. 
9.4.4 
Daratumumab Drug Preparation 
Refer to the Prescribing Information or the SMPC for instructions on daratumumab preparation 
and requirements for administration.  Also refer to Section 6.5.4. 
9.5 
STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
9.5.1 
Study Drug Compliance 
Compliance will be assured by administration of the study treatment under the supervision of 
the investigator or his/her designee, and should be documented in the study drug administration 
and accountability records.   
9.5.2 
Study Drug Accountability 
All study drug must be stored by the sites in a secure facility with limited access. The 
investigator or designee must maintain an accurate record of the shipment and dispensing of 
study treatment supplied to the site by the Sponsor in a drug accountability log.  Drug 
accountability will be reviewed by the Clinical Research Organization (CRO) monitor during 
site visits and at the completion of the study.  
At study close-out, and as appropriate during the course of the study, all unused study drug 
packaging and any associated supplies should be discarded according to the site drug 
destruction policy following review and approval of the site CRO monitor.  A copy of the drug 
destruction policy and the completed drug accountability log should be provided to the CRO 
monitor.  
10 
SAFETY MONITORING AND REPORTING 
10.1 
ADVERSE EVENTS 
10.1.1 
Definitions 
An AE is any untoward medical occurrence in a study patient administered an investigational 
product and that does not necessarily have a causal relationship with this treatment.  
An AE therefore can be any unfavorable and unintended sign (including laboratory finding), 
symptom or disease temporally associated with the use of a medicinal product, whether or not 
considered drug-related.  In addition to new events, any increase in the severity or frequency of 
a pre-existing condition that occurs after the patient begins study therapy is considered an AE.  
This includes any side effect, injury, toxicity, or sensitivity reaction.  
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current IB or prescribing information for a marketed compound.  Also, 
reports which add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs.  For example, an event more specific or more 
severe than described in the melflufen IB or partner therapy Package Insert would be considered 
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10.1.2 
Grading of Severity 
Whenever possible, the CTCAE version 4.03 should be used to describe the event and for 
assessing the severity of AEs (See Appendix B).  Any 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 (Section 10.1.5).  
For AEs not adequately addressed in the CTCAE, the severity in Table 10-1 may be used: 
Table 10-1 Adverse Event Severity  
Severity 
Description 
Grade 1 – Mild 
Transient or mild discomfort; no limitation in 
activity; no medical intervention/therapy required. 
Grade 2 – Moderate 
Mild to moderate limitation in activity some 
assistance may be needed; no or minimal medical 
intervention/therapy required. 
Grade 3 -  Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
Grade 4 - Life-threatening 
Extreme limitation in activity, significant assistance 
required; life-threatening (immediate risk of death); 
significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
Grade 5 – Fatal 
Death 
10.1.3 
Causality 
The assessment of causality should be based on the information available, and may be changed 
upon receipt of additional information. 
Causality should be assessed using the following categories: 
 Unrelated: Clinical event with an incompatible time relationship to investigational 
agent administration, and that could be explained by underlying disease or other drugs 
or chemicals or is incontrovertibly not related to the investigational agent; 
 Possibly related: Clinical event with a reasonable time relationship to investigational 
agent administration, and that is unlikely to be attributed to concurrent disease or other 
drugs or chemicals; 
 Probably related: Clinical event with plausible time relationship to investigational agent 
administration, and that cannot be explained by concurrent disease or other drugs or 
chemicals. 
The investigator must appraise all abnormal laboratory results for their clinical significance.  
Only if an abnormal laboratory result is considered clinically significant, should it be reported 
as a treatment emergent adverse event. (See Section 10.1.5.1). 
10.1.4 
Adverse Event Reporting 
All AEs that are spontaneously reported by the patient or detected during or between visits by 
non-directive questioning, through physical examination, laboratory test, or other assessments 
should be reported in the eCRF.  As far as possible, each AE should be evaluated to determine: 


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1. The severity grade (CTCAE Grade 1-5); 
2. Its duration (Start and end dates); 
3. Its relationship to the study treatment (causality); 
4. Action taken with study drug (e.g., none, dose reduced, dose held, permanently 
discontinued); 
5. Whether medication or therapy was given (e.g., concomitant medication or procedure); 
6. Outcome (e.g., not resolved, resolved, resolved with sequalae, fatal, unknown); 
7. Whether it is a SAE as defined in Section 10.2.1. 
All AEs should be treated appropriately.  If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the eCRF. 
Any AE (e.g., a new event or an exacerbation of a pre-existing condition) that occurs after the 
first dose of study medication up to 30 days after the last study drug administration must be 
recorded as an AE on the appropriate page(s) of the eCRF.  Should a patient discontinue from 
treatment and commence subsequent anticancer therapy within 30 days of the last study drug 
administration, AEs attributable to this subsequent therapy should not be recorded.   
10.1.5 
Laboratory Test Abnormalities 
10.1.5.1 Definitions and Reporting 
Laboratory abnormalities are usually not recorded as AEs; however, signs and/or symptoms 
that are associated with laboratory findings requiring treatment discontinuation, dose 
modification, or medical intervention (e.g., anemia requiring transfusions or hyperglycemia 
requiring treatment) or other abnormal assessments (e.g., ECG, radiographs, vital signs) must 
be recorded as AE’s (or serious AE’s) if they meet the definition of an AE (or serious AE) as 
described in Section 10.1 or 10.2.  In addition, laboratory abnormalities assessed as clinically 
significant should also be recorded as AEs.  The Investigator will record the grade of the 
clinically significant laboratory abnormality and will evaluate its relationship to the study drug 
and clinical condition.  Laboratory AEs should be recorded using only one event term per event 
such as thrombocytopenia for low platelet count but not as both (thrombocytopenia and low 
platelet count). 
Clinically significant laboratory abnormalities are those that: 
 Induce clinical signs and symptoms 
 Require concomitant therapy  
 Require change in study treatment 
 Investigator considers clinically significant for any reason 
Additional Laboratory Reporting Guidelines 
Extra attention should be given to reporting all Grade 3 and 4 platelet and neutrophil counts. 
They must be: 
 Collected and reported during the study period and the EoT visit; 


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 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 protocol participation, i.e. both those 
collected at protocol specified time points and any additional time points (unscheduled 
assessments), must be reported in the eCRF and if applicable also in the SAE report;  
 All ANC and platelet counts associated with a SAE regardless of the nature of the event, 
must be reported in the details of the SAE report; 
 Supportive care such as platelet transfusions and G-CSF given for AE or prophylactic 
reasons must be reported in the eCRF and if applicable also in the SAE report. 
10.2 
SERIOUS ADVERSE EVENTS 
10.2.1 
Definitions 
A SAE is defined as any AE, occurring at any dose that meets any one or more of the following 
criteria: 
 Is fatal or immediately life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Is medically significant; defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 Requires inpatient hospitalization or prolongation of existing hospitalization,  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or if the patient may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
Note that hospitalizations for the following reasons should not be reported as SAE’s: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition including 
o Hospitalization that is needed to complete a daratumumab infusion or due to an 
infusion related reaction (not due to melflufen) 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 


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 Treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not 
a serious adverse event 
 Disease progression: In instances of SAE’s due to “disease progression” the event or 
condition that met the criteria for the SAE should be indicated as the event term or 
condition rather than disease progression to the extent possible (e.g. “respiratory 
failure” or “renal failure” due to progressive MM)  
10.2.2 
Serious Adverse Event Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has signed informed consent and until 30 days after the last administration of any study 
drug must be reported to the Oncopeptides AB designated CRO and reported in the EDC 
system , within 24 hours of the onset or after the investigator became aware of the SAE. 
An SAE reporting form must be filled out and sent via email to designated CRO.  Fax can be 
used as a back-up method for transmission of information only if emailing reports is not possible 
(fax number is provided in the Investigator Site File).  
 Email:  
 
 
The initial SAE report form should have the following data elements, at a minimum, to 
constitute a valid report: a patient identifier (patient number), an identifiable investigational 
agent (study drug), an identifiable reporting source (investigator’s name or site number) as well 
as an identifiable serious adverse event.  The investigator’s initial causality assessment must 
also be included if available. 
Each re-occurrence, change in grade, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs.  The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated and 
whether the patient continued or withdrew from study participation.  An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one should be reported separately as a new event. 
Any SAE that occurs after the above defined regular SAE reporting period, should also be 
reported if the investigator suspects a causal relationship to the study treatment.  All deaths 
occurring during the regular SAE reporting period must be reported, regardless of cause (See 
Section 10.2.2.1).   
SAEs should be followed until resolution, or stabilization with no anticipation of resolution 
regardless of 30-days reporting time line unless deemed by the investigator as not expected to 
resolve at the last study visit or patient is lost to follow-up and this is documented in the study 
file. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the Health Competent Authorities and concerned Independent Ethics Committees 
(IECs/Institutional Review Boards (IRBs) in accordance with Directive 2001/20/EC or as per 
national regulatory requirements in participating countries.  For the purpose of SUSAR 
reporting, only possibly or probably related SAEs (i.e. there is a reasonable possibility of 
causality) will be considered serious adverse drug reactions.   


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10.2.2.1 Reporting of Death 
 Death is an outcome of a serious adverse event and not a serious adverse event in itself.  
When death is an outcome, the event(s) resulting in death should be reported (e.g., 
“pulmonary embolism” with a fatal outcome).  The appropriate diagnosis or term should 
be recorded and assigned severity Grade 5; 
 In instances of death due to “Disease Progression” the cause of death should be 
indicated as the event or condition resulting in death to the extent possible (e.g., 
“respiratory failure” due to progressive MM);   
 Deaths that occur later than 30 days after the last study drug administration should be 
reported as SAEs only if assessed as related to the study treatment. 
10.3 
PREGNANCY 
All instances of pregnancy occurring in a patient or partner of a patient taking study therapy 
must be reported within 24 hours of awareness of the pregnancy.    
The pregnancy should be followed-up to determine its outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications and possible relationship 
to the study treatment. 
A pregnancy reporting form must be filled out and sent via  email to designated CRO. Fax can 
be used as a back-up method for transmission of information only if emailing reports is not 
possible (fax number is provided in the Investigator Site File.   
 Email: 
 
 
Any SAE experienced during pregnancy (such as congenital anomaly/birth defect/spontaneous 
abortions) must be reported  as noted above. 
Male patients, who impregnate their female partners during study participation, should be 
requested to provide the outcome and details of the pregnancy, with details completed as above. 
11 
DATA COLLECTION AND MANAGEMENT 
11.1 
DATA CONFIDENTIALITY 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations.  Those regulations require a signed patient authorization form informing 
the patient of the following: 
 What personal identifying and health information will be collected from patients in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research patient to revoke their authorization for use of their personal 
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In the event that a patient revokes authorization to collect or use personal identifying and health 
information, the Sponsor and its agents, by regulation, retains the ability to use all information 
collected prior to the revocation of patient authorization.  For patients that have revoked 
authorization to collect or use personal identifying and health information, attempts should be 
made to obtain permission to collect follow-up safety information. 
Access to the data collection system will be controlled by user identification codes and 
passwords, made available only to authorized personnel who have completed prerequisite 
training. 
11.2 
SITE MONITORING 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Oncopeptides 
AB staff (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff.  During the study, the monitor will visit the site regularly to check the completeness 
of patient records, the accuracy of entries on the eCRFs, the adherence to the protocol to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications.  Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments.  All information recorded on eCRFs must be traceable to source documents in the 
patient's file.  The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries.  Oncopeptides AB (or CRO) monitoring standards require 
full source data verification for the presence of signed and dated informed consent, adherence 
to the inclusion/exclusion criteria and documentation of AE/SAEs.  Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. 
11.3 
DATA COLLECTION 
An eCRF is required and should be completed for each patient. The patient’s identity should 
always remain confidential.  The completed original eCRF is the sole property of the Sponsor 
and should not be made available in any form to third parties (except to authorized 
representatives of appropriate regulatory authorities) without written permission from the 
Sponsor. 
The designated investigator staff will enter the data required by the protocol into the eCRF.  The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the electronic data 
capture (EDC) system until they have been trained.  Automatic validation programs will check 
for data discrepancies in the eCRFs and allow modification or verification of the entered data 
by the investigator staff. 
The study Investigators are responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 


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11.4 
DATABASE MANAGEMENT AND QUALITY CONTROL 
Oncopeptides AB personnel (or designated CRO) will review the data entered by 
investigational staff for completeness and accuracy.  Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system.  Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
12 
STATISTICAL METHODS AND DATA ANALYSIS 
12.1 
STUDY ENDPOINTS  
12.1.1 
Primary Endpoints 
Phase 1 
The primary endpoint of Phase 1 is to analyze the frequency and grade of AE’s occurring at 
each dose level to be tested during Cycle 1 of therapy.  Each treatment regimen and dose  will 
be evaluated separately.  
Phase 2a  
The primary endpoint of Phase 2a is the overall response rate (CR, sCR, VGPR, PR) observed 
in patients treated at the optimal dose of melflufen in combination therapy according to IMWG 
-URC. Each treatment regimen and dose will be evaluated separately. 
12.1.2 
Secondary Endpoints 
 Phase 1 and 2a 
Best response during the study (CR/sCR, VGPR, PR, MR, SD, PD or non-evaluable),  
Clinical benefit rate ≥ MR,  
TTP: Time from first dose to first documented confirmed progression, death from causes other 
than progression will be censored, 
TTR: Time from first dose or therapy to first documented confirmed response.  
TTNT: Time from date of initiation of therapy to start of next line of therapy.  
DOR: Time (months) from the first evidence of confirmed assessment of sCR, CR, VGPR, or 
PR to first confirmed disease progression, or to death due to any cause.  DOR is defined only 
for patients with a confirmed PR or better.  
Duration of clinical benefit: time (months) from the first evidence of confirmed assessment of 
sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause.  
Duration of clinical benefit is defined only for patients with a confirmed MR or better. 
PFS: Time (months) from date of initiation of therapy to the earlier of confirmed disease 
progression or death due to any cause or last known assessment. 
Oncopeptides will implement an ongoing review of the response and progression assessments 
performed by the investigator. The investigator will be notified of any discrepancies in the form 
of a data query.  


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OS: Time (months) from date of initiation of therapy to death due to any cause.  Patients still 
alive at end of study, or lost to follow up, will be censored at last day known alive. 
To further evaluate the frequency and grade of all AE’s of the combination including the rate 
and type of second primary malignancies. Each regimen and dose will be evaluated separately. 
 
The maximum grade (according to CTCAE v4.03) for each type of AE will be recorded for 
each patient, and frequency tables will be presented and reviewed to determine patterns.  
Additionally, the relationship of the AE(s) to the study treatment will be taken into 
consideration. 
Laboratory abnormalities will be presented and reviewed.  
Each regimen and dose will be evaluated separately. 
12.1.3 
Exploratory Endpoints  
 PK parameters of melphalan 
 The rate of MRD negative or positive status for patients achieving a CR  
12.2 
SAMPLE SIZE CALCULATION 
The Phase 1 sample size will be based on the number of dose levels to be evaluated within each 
Regimen.  It is anticipated that a maximum of 12 patients are enrolled in each Regimen during 
Phase 1. 
Phase 2a sample size will include approximately 20 additional efficacy evaluable patients in 
order to reach a total of 26 efficacy evaluable patients per Regimen. 
12.3 
GENERAL CONSIDERATIONS FOR THE STATISTICAL ANALYSES 
The statistical analyses as outlined in this section will be further described in the statistical 
analysis plan (SAP), which will be finalized prior to locking the database.  In general, 
summaries of all data will be provided for each Regimen. Statistical analyses will be reported 
using summary tables, inferential analyses, figures, and data listings.   
For continuous variables, the number of patients with non-missing data (n), mean, standard 
deviation, median, minimum, and maximum will be summarized.  For discrete data, the 
frequency and percent distribution will be summarized.  Graphical methods will be used, as 
appropriate, to illustrate study endpoints.  Individual patient data recorded on the eCRFs and 
any derived data will be presented by group and patient in data listings. 
12.3.1 
Analysis Populations 
Patients will be summarized according to the treatment Regimen actually received. 
 
12.3.1.1 Dose Limiting Toxicity Analysis Set 
The DLT analysis set is defined as all patients in Phase 1 that complete Cycle 1 of therapy or 
are discontinued due to a DLT event defined in Section 6.6.1 and Section 6.6.2. Patients that 
have been replaced in the original assigned cohort will not be included in the DLT analysis set.   


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12.3.1.2 Safety Analysis Set 
The Safety analysis set is defined as all patients who received at least one or partial dose of 
melflufen, dexamethasone or partner therapy (drugs defined in the Regimen).  The Safety 
analysis set will be the primary population for the summaries of all efficacy, exposure and safety 
data. The analysis (PFS) will be performed using the Safety analysis set with each regimen and 
dose  evaluated separately.  
12.3.1.3 Efficacy Analysis Set 
The efficacy analysis set will be comprised of all patients who receive at least 2 doses of 
melflufen and ≥ 50% of the partner therapy (excluding dexamethasone) during Cycles 1 and 2, 
had a baseline disease assessment, and had at least 1 post-baseline disease assessment (≥28 days 
after first dose). Each regimen and dose will be evaluated separately. 
12.4 
ANALYSIS OF PRIMARY ENDPOINTS 
12.4.1 
Phase 1 
The frequency and grade of AE’s and defined DLT’s occurring in each cohort will be 
determined. 
Dose escalation study will follow fixed dose schedule with 3-6 DLT evaluable patients at each 
dose level. Depending on the dose level at which DLT is observed, approximately 12 eligible 
patients may be enrolled in Phase 1.   The first cohort of patients enrolled in the Phase 1 portion 
of each Regimen will receive dose level 1 (melflufen 30 mg).  A full safety evaluation will be 
conducted by a DSMC when these patients have completed the first cycle of combination 
therapy with DLT assessment.  The optimal dose of melflufen in combination therapy will be 
defined as the highest of 20, 30 or 40 mg of melflufen that results in ≤ 1/6 patient with DLT 
during the first cycle of therapy.   
12.4.2 
Phase 2a 
Following determination of the optimal dose of melflufen for each Regimen, approximately 20 
additional efficacy evaluable patients will be enrolled at that level for a total of 26 efficacy 
evaluable patients treated at the dose defined in the Phase 1 part of the study per Regimen.  
For patients with more than one post-baseline efficacy assessment, the best response of all 
measurements will be used in the Phase 2a primary endpoint analysis. Patients with incomplete 
disease assessments at screening will not be admitted into the study. 
12.5 
ANALYSIS OF SECONDARY ENDPOINTS 
12.5.1 
Analysis of efficacy endpoints 
12.5.1.1 Overall Response Rate 
The ORR will be estimated as the proportion of patients in each treatment group who achieve 
a confirmed response of sCR, CR, VGPR, or PR as their best response in efficacy evaluable as 
well as all treated patients. The exact binomial 95% confidence interval (CI) for ORR will be 
calculated for each treatment regimen.   


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12.5.1.2 Progression Free Survival 
PFS is measured from the date of initiation of therapy to the date of documented disease 
progression or death in efficacy analysis set as well as the safety analysis set.  PFS will be right-
censored for patients who meet one of the following conditions:  
 No post baseline disease assessments 
 Non-protocol systemic anticancer treatment started before documentation of disease 
progression or death 
 Death or disease progression after more than 1 missed disease assessment visit, or  
 Death or PD between planned disease assessments 
 Death before first disease assessment 
 Alive without documentation of disease progression before a data analysis cutoff date   
These conventions are based on the May 2007 Food and Drug Administration (FDA) Guidance 
for Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics’.   
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm071590.pdf) 
For such patients, the primary analysis of PFS will be right-censored according to the 
conventions described in Table 12-1. 
Table 12-1 Conventions for Censoring for PFS 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior 
to start of new anticancer therapy 
Censored 
Death or PD immediately after more 
than 1 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is 
before the first missed visit 
Censored 
Alive and without PD documentation  
Date of last disease assessment 
Censored 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
Death or PD between planned 
disease assessments 
Date of death or first disease 
assessment showing PD, whichever 
occurs first 
Progressed 
Death before first disease assessment 
Date of death 
Progressed 
The distribution of PFS will be summarized for each Regimen using the Kaplan-Meier (K-M) 
method.  The median PFS will be estimated for each treatment regimen from the 50th percentile 
of the corresponding K-M estimates.  The 95% CI for median PFS will be constructed using the 
method of Brookmeyer (Brookmeyer and Crowley, 1982).  Duration of follow-up for PFS will 
be summarized according to the K-M estimate of potential follow-up also termed “reverse 
Kaplan-Meier” (Schemper and Smith, 1996). 


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12.5.1.3 Other efficacy endpoints 
The DOR will be calculated for patients who achieve a confirmed response of PR or better. The 
DOR is defined as the time from first documentation of response to disease progression or death 
due to any cause.  Dates of progression and censoring will be determined as described for the 
analysis of PFS.  
The duration of clinical benefit is defined as the time from first documentation of response to 
disease progression or death due to any cause. Dates of progression and censoring will be 
determined as described for the analysis of PFS.  
OS is defined as time (months) from the date of initiation of therapy to date of death due to any 
cause. Patients who are alive will be censored at the last follow up visit. The analysis of OS will 
be performed as for PFS. 
Best response (sCR, CR, VGPR, PR, MR, SD or PR) will be summarized without analysis.  The 
exact 95% CIs for sCR, CR, VGPR and PR, will be calculated for each treatment regimen and 
dose. 
CBR will be summarized without analysis.  The exact 95% CI for CBR will be calculated for 
each treatment regimen. 
TTR is defined as the time (months) from initiation of therapy to the date of the first confirmed 
response (≥ PR).  
TTP is defined as the time (months) from initiation of therapy to the date of the first documented 
confirmed progression.  
TTNT is defined as the time (months) from initiation of therapy to the date of the first 
documented next treatment. 
Additional exploratory sub-analysis may be conducted to identify sub populations that may 
benefit from therapy or to more clearly define the safety profile and efficacy and/or to correlate 
biomarkers with clinical outcomes. 
12.5.2 
Analysis of Safety Endpoints 
All safety results will be presented for the safety analysis set.  No formal statistical analysis will 
be performed for the safety endpoints. Each Regimen and dose will be reported separately. 
Study treatment administration, including duration of exposure, total dose, and dose 
modifications will be summarized for each group separately.   
Each reported AE term will be mapped to a preferred term (PT) and a system organ class (SOC) 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  The 
summaries of AEs will be based on TEAEs.  TEAEs are defined as AEs that start on or after 
the first day of study treatment is administered and within 30 days of the last administration of 
study treatment or before start of subsequent anticancer treatment (whichever occurs first) or 
that worsen on or after the first day of study treatment.   
The number (%) of patients experiencing TEAEs will be summarized by MedDRA SOC and 
PT.  The denominator for the percentage will be based on the number of patients 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 


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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 to any study drug, will be 
summarized in the same way. 
Summaries of TEAEs and treatment-related AEs will be provided according to maximum 
toxicity grade.  Grade 3 or higher TEAEs and treatment-related AEs, SAEs, and TEAEs 
resulting in permanent discontinuation of study treatment will be provided.   
Grade 3 and 4 thrombocytopenia and neutropenia will be evaluated to determine their 
frequency, duration, relationship to treatment, associated clinical consequences/medical 
management and associated significant AEs. 
During the Phase 2a portion of the study a DSMC will assess the non-hematologic toxicity 
according to the following study stopping rules:  
Phase 2a (includes all Phase 2a patients, including Phase 1 patients treated at the MTD). 
Previous bortezomib data show that Grade 4 adverse events occurred in 28% of the patients 
treated with bortezomib in combination with melphalan and dexamethasone (San Miguel et al, 
2008) with the majority being hematological events.  Current information shows that Grade 4 
non-hematological toxicity is rare in connection to daratumumab treatment (Daratumumab 
label).  The most common Grade 4 events were thrombocytopenia and neutropenia occurring 
in 5.4% and 2.7% of the daratumumab treated patients (Usmani et al, 2016).  Grade ≥ 4 non-
hematologic melflufen-related toxicity occurred in 6.7 % of RRMM patients treated with 
melflufen (at the MTD of 40 mg/28 days) and dexamethasone in the Phase 2a study. Non-
hematological treatment-related Grade 4 toxicity is therefore expected to occur at a frequency 
of less than 10% in the present study.   
 
The DSMC will meet regularly to assess the benefit/risk profile in the Phase 2a portion of the 
study. All reported Grade 3-4 treatment-related non-hematological AEs, as well as all SAEs, 
and any treatment-related deaths due to hematologic or non-hematologic AEs will then be 
presented to the DSMC.  If the DSMC considers the AE patterns differ from the Reference 
Safety Information for the individual drugs in the combination, the DSMC may recommend 
additional safety monitoring or stopping further recruitment. A recommended stopping rule is 
if three non-hematological treatment-related Grade 4 events occur among the first 10 patients 
or in 20% of the patients at any time thereafter, or if any treatment-related deaths due to 
hematologic or non-hematologic AEs occur at any time. This stopping rule would suspend 
accrual to the study pending DSMC investigation of the benefit/risk profile.  
12.6 
ANALYSIS OF EXPLORATORY ENDPOINTS 
12.6.1 
Pharmacokinetic Analysis 
The pharmacokinetic (PK) evaluation will be performed only at selected centers in a sub-group 
of patients.  
Three plasma samples for determination of melphalan concentrations should be drawn at each 
of the first two melflufen treatment cycles.  The first sample should be taken 10-15 minutes 
after end of infusion, the second sample 1 hour after end of infusion and the third sample 2 to 4 
hours (as late as possible within the time frame) after end of infusion.   


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The relationship between melphalan PK parameters and patient factors, will be assessed, as well 
as the inter-occasion variability in melphalan exposure when comparing data for treatment 
Cycles 1 and 2.  
The melphalan concentration data will be pooled across patients and evaluated using a 
population approach with nonlinear mixed-effect modeling. Actual time points for drug 
administration and plasma sampling will be used.  
Details on the modeling approach will be described in a separate population PK-PD plan which 
will be developed in parallel with the ongoing Phase 3 study OP-103 (OCEAN TRIAL).  Data 
from other melflufen studies may be included in this analysis as appropriate.  
12.6.2 
Minimal Residual Disease 
The rate of positive and negative MRD evaluations will be summarized without analysis. 
12.7 
HANDLING OF DROP-OUTS AND MISSING DATA 
The SAP describes how drop-outs and missing data impact the calculation of the time to event 
variables.  Missing data will not be estimated or carried forward for any of the other summaries 
or analyses.  If only a partial date is available and is required for a calculation (e.g., time since 
diagnosis, time since most recent relapse, determination of whether a medication is concomitant 
or an AE is treatment-emergent), the date will be imputed.  Detail of the methods of imputation 
will be provided in the SAP. 
13 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
13.1 
REGULATORY AND ETHICAL COMPLIANCE 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC 
and US Code of Federal Regulations Title 21), and with the ethical principles laid down in the 
Declaration of Helsinki. 
13.2 
DATA SAFETY MONITORING COMMITTEE 
A DSMC will be convened for this study and will primarily act to safeguard the interests of 
study subjects, assess safety and efficacy data, and for monitoring the overall conduct of the 
study. The committee will consist ofthe lead global investigator, the Oncopeptides Medical 
Expert of the study, the CRO Medical Monitor and will be chaired by an independent multiple 
myeloma expert.  At the end of each cohort, the committee will meet and evaluate all the current 
safety data and make decisions regarding dose escalation or cohort expansion in the Phase 1 
component of the study.  The committee will also determine when the optimal dose has been 
reached and make recommendations on the Phase 2a dose and schedule.   The DSMC may 
provide recommendations for stopping or continuing the study or for alternate dose and 
schedule of a given Regimen after review of the data. The DSMC may also make 
recommendations related to the selection, recruitment, and retention of subjects, their 
management and the procedures for data management and quality control.  Additional details 
regarding the DSMC may be found in the Oncopeptides AB DSMC Charter. 


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13.3 
INDEPENDENT RESPONSE ADJUDICATION 
Oncopeptides will implement an independent adjudication review of the response and 
progression assessments performed by the investigator for the purpose of quality monitoring. 
The investigator will be notified of any discrepancies in the form of a data query.  
13.4 
RESPONSIBILITIES OF THE INVESTIGATOR AND IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB, IEC or REB before study start.  A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Oncopeptides AB (or designated CRO) before study initiation.  Prior to study start, the 
investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Oncopeptides AB 
(or designated CRO) monitors, auditors, Clinical Quality Assurance representatives, designated 
agents of Oncopeptides AB, IRBs/IECs/REBs and regulatory authorities as required. 
13.5 
INFORMED CONSENT PROCEDURES 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.  
Informed consent must be obtained before conducting any study-specific procedures.  The 
process of obtaining informed consent should be documented in the patient source documents. 
The date when a patient’s Informed Consent is obtained will be captured in the eCRFs. 
Oncopeptides AB (or designated CRO) will provide to investigators, in a separate document, a 
proposed informed consent form (ICF) that is considered appropriate for this study and 
complies with the ICH Good Clinical Practice (GCP) guideline and regulatory requirements.  
Any changes to this ICF suggested by the investigator must be agreed to by Oncopeptides AB 
before submission to the IRB/IEC/REB, and a copy of the approved version must be provided 
to the Oncopeptides AB (or designated CRO) monitor after IRB/IEC/REB approval. 
13.6 
DISCONTINUATION OF THE STUDY 
Oncopeptides AB reserves the right to discontinue this study under the conditions specified in 
the clinical study agreement at a single study center or the study as a whole.  Specific conditions 
for terminating the study at any time for reasonable medical or administrative reasons in any 
single center could be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality 
 Inaccurate or incomplete data collection 
 Falsification of records 
 Failure to adhere to the study protocol 
 An incidence or a seriousness of SAEs in this study or other studies indicating a 
potential danger for the patient’s health caused by the study treatment 
13.7 
PUBLICATION OF STUDY PROTOCOL AND RESULTS 
Oncopeptides AB assures that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov.  In addition, upon study completion and 


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finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.  Any publication will 
be a joint publication between Oncopeptides AB and the investigators and authorship will be 
determined by mutual agreement. 
13.8 
STUDY DOCUMENTATION, RECORD KEEPING AND RETENTION OF 
DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients.  As part of participating in an Oncopeptides AB 
sponsored study, each site will permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator.  The study eCRF is the primary data collection instrument for the study. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the eCRFs and all other required reports.  Data reported on the eCRF, that are derived 
from source documents, should be consistent with the source documents or the discrepancies 
should be explained.  All data requested on the eCRF must be recorded. Any missing data must 
be explained. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator must retain the study records for a minimum of 2 years after the last marketing 
application for the indication is approved in an ICH region or for 2 years after the Investigational 
new drug (IND) is withdrawn.  For IND studies conducted outside the US, the investigator must 
retain study records for the time period described above or according to local laws or 
requirements, whichever is longer. 
13.9 
CONFIDENTIALITY OF STUDY DOCUMENTS AND PATIENT RECORDS 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Oncopeptides AB, their agents or Health Authorities.  Signed 
informed consent forms and patient enrollment log must be kept strictly confidential to enable 


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patient identification at the site.  Refer to Section 11.1 for additional details regarding patient 
confidentiality. 
13.10 
AUDITS AND INSPECTIONS 
Source data/documents must be available to inspections by Oncopeptides AB or designee or 
Health Authorities. 
13.11 
FINANCIAL DISCLOSURES 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site prior to study start. 
14 
PROTOCOL ADHERENCE 
Investigators ascertain they will apply due diligence to avoid protocol deviations. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol.  In such cases, Oncopeptides 
AB or designated CRO should be notified of this action and the IRB/IEC at the study site should 
be informed according to local regulations. 
14.1 
AMENDMENTS TO THE PROTOCOL 
Any change or addition to the protocol can only be made in a written protocol amendment by 
Oncopeptides AB.  The amendment must be approved by the Health Authorities where required, 
and the IRB/IEC/REB before it may be implemented.  Only amendments that are required for 
patient safety may be implemented prior to IRB/IEC/REB approval.  
 
 


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15 
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Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group Consensus 
Approach to the Treatment of Multiple Myeloma Patients who are Candidates for Autologous 
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Alkylating Agent, Melphalan-Flufenamide, against Multiple Myeloma Cells.  Clin Cancer Res. 
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CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological 
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Deaglio S, Mehta K, Malavasi F. Human CD38: A Revolutionary Story of Enzymes and 
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Dimopoulos M, Oriol A, Nahi H,et al.  Daratumumab, Lenalidomide, and Dexamethasone for 
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Gullbo J, Lindhagen E, Bashir-Hassan S, et al. Antitumor Efficacy and Acute Toxicity of the 
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Gullbo, J., et al., Activity of Hydrolytic Enzymes in Tumour Cells is a Determinant for Anti-
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Promotes T-cell Expansion, and Skews T-Cell Repertoire in Multiple Myeloma.  Blood. 
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Kumar S, Rajkumar SV, Dispenzieri A, et al.  Improved Survival in Multiple Myeloma and the 
Impact of Novel Therapies. Blood. 2008; 111(5):2516-2520. 
Kumar S, Paiva B, Anderson K, et al.  International Myeloma Working Group Consensus 
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Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct In Vitro Comparison of 
Daratumumab with Surrogate Analogs of CD38 Antibodies MOR03087, SAR650984 and Ab79 
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Tolerability with three Different Bortezomib- Melphalan -Prednisone Regimens in Previously 
Untreated Myeloma Patients who are Ineligible for High-Dose Therapy. Haematologica.  2014; 
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Palumbo A, Chanan‑ Khan A, Weisel, K, et al.  Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma. N Engl J Med. 2016; 375:754-66. 
Rajkumar SV, Richardson P, San Miguel J.  Guidelines for Determination of the Number of 
Prior Lines of Therapy in Multiple Myeloma.  Blood. 2015; 126:921-922. 
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Uniform Reporting of Clinical Trials: Report of the International Myeloma Workshop 
Consensus Panel 1.  Blood. 2011; 117(18):4691-4695. 
Ray A, Ravillah D,1, Das D, et al. A novel alkylating agent Melﬂufen induces irreversible DNA 
damage and cytotoxicity in multiple myeloma cells. British Journal of Haematology, 2016, 174, 
397–409 
Richardson PG, Sonneveld P, Schuster M, et al.  Bortezomib or High-Dose Dexamethasone for 
Relapsed Multiple Myeloma. N Engl J Med. 2005; 352(24):2487-2498. 
Richardson PG, Laubach J, Mitsiades C, et al. Tailoring Treatment for Multiple Myeloma 
Patients with Relapsed and Refractory Disease." Oncology (Williston Park) 2010;24:22–9.  
San Miguel J, Schlag R, Khuageva N, et al.  Bortezomib Plus Melphalan and Prednisone for 
Initial Treatment of Myeloma.  N Engl J Med. 2008; 28 359(9):906-917. 
Santonocito AM, Consoli U, Bagnato S, et al.  Flow Cytometric Detection of Aneuploid 
CD38(11) Plasmacells and CD19(1) B-lymphocytes in Bone Marrow, Peripheral Blood and 
PBSC Harvest in Multiple Myeloma Patients. Leuk Res. 2004; 28(5):469-477. 
Schemper M, and Smith TL. A Note on Quantifying Follow-up in Studies of Failure Time. 
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SEER (2016). "Surveillance, Epidemiology, and End Results Program Cancer statistics Stat 
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Sonneveld P, Avet-Loiseau H, Lonial S.  Treatment of Multiple Myeloma with high-risk 
cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016; 
127:2955-2962 
Usmani S., Brendan I., Weiss B., 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 
Wickström M, J.J., Ponthan F, The Novel Melphalan Prodrug J1 Inhibits Neuroblastoma 
Growth In Vitro and In Vivo. Mol Cancer Ther.  2007; 6:2409-2417. 
Wickström M. The Alkylating Prodrug J1 Can be Activated by Aminopeptidase N, Leading to 
a Possible Target Directed Release of Melphalan. Biochem Pharmacol, 2010; 79:1281-1290. 
Wickström M, Haglund C, Lindman H, et al., The Novel Alkylating Prodrug J1: Diagnosis 
Directed Activity Profile Ex Vivo and Combination Analyses In Vitro. Invest New Drugs, 2008. 
26(3): P. 195-204. 


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16 
APPENDICES 
Appendix A.  Eastern Cooperative Oncology Group (ECOG) Performance Scale  
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous but 
ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead 
Source: Oken MM, et al. 1982.   
 
Appendix B.  National Cancer Institute CTCAE Version 4.03  
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute 
(NCI) v4.03 
 
Publish Date: (v4.03: June 14, 2010)  
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 


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Appendix C.  IMWG Uniform Response Criteria  
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 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. 
 
Response 
IMWG criteria (Rajkumar, et al. 2011) 
Stringent 
Complete 
Response 
(sCR) 
CR as defined below plus:  
 normal FLC ratio and  
 absence of clonal cells in bone marrow by immunohistochemistry 
or 2 – 4 color flow cytometry 
Complete 
Response 
(CR) 
 Negative immunofixation on the serum and urine and  
 disappearance of any soft tissue plasmacytomas and  
  < 5% plasma cells in bone marrow.   
 In patients with only FLC disease, a normal FLC ratio of 0.26–
1.65 is required.  
Very Good 
Partial 
Response 
(VGPR) 
 Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis or 
 ≥ 90% reduction in serum M-protein plus urine M-protein 
level < 100 mg/24 h.   
 In patients with only FLC disease, > 90% decrease in the 
difference between involved and uninvolved FLC levels is 
required. 
Partial 
Response 
(PR) 
 50% reduction of serum M-protein and reduction in 24 hours 
urinary M-protein by ≥ 90% or to < 200 mg/24 h 
 If the serum and urine M-protein are unmeasurable, a > 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
 If serum and urine M-protein are not measurable, and serum free 
light assay is also not measurable, > 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was > 30% 


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 In addition to the above listed criteria, if present at baseline, 
a > 50% reduction in the size of soft tissue plasmacytomas is also 
required 
Minimal 
Response  
(MR) 
EBMT 
Criteria 
  ≥ 25% but < 49% reduction of serum M protein and reduction in 
24-hour urine M protein by 50 – 89%, which still exceeds 200 
mg/24 hours. 
 In addition to above; if present at baseline, 25-49% reduction in 
the size of soft tissue plasmacytomas is also required 
 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-component (the absolute increase must be > 0.5 g/dL) 
and/or  
 Urine M-component (the absolute increase must be > 200 mg/24 
h) and/or  
 Only in patients without measurable serum and urine M-protein, 
the difference between involved and uninvolved FLC levels. The 
absolute increase must be > 10 mg/dL 
 Only in patients without measurable serum and urine M-protein 
and without measurable disease by FLC levels, bone marrow 
plasma cell percentage (absolute % must be ≥ 10%)  
 Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas 
 Development of hypercalcemia (corrected serum 
calcium > 11.5 mg/dL) that can be attributed solely to the plasma 
cell proliferative disorder 
 
All response categories (CR, sCR, VGPR, PR, MR, SD and PD) require two consecutive 
assessments made at any time before the institution of any new therapy; all response categories 
and SD also require no known evidence of progressive or new bone lesions if radiographic 
studies were performed.  VGPR and CR categories require serum and urine studies regardless 
of whether disease at baseline was measurable in serum, urine both or either.  Radiographic 
studies are not required to satisfy these response requirements. Bone marrow assessments need 
not be confirmed.  For progressive disease, serum M-component increases of ≥ 1 g/dL are 
sufficient to define relapse if starting M-component is ≥ 0.5 g/dL. 


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IMWG clarification for coding PD:  Clarified that Bone marrow criteria for PD are to be used 
only in patients without measurable disease by M protein and by FLC levels.  Clarified that 
25% increase refers to M protein, FLC, and bone marrow results and does not refer to bone 
lesions, soft tissue plasmacytomas or hypercalcemia.  Note the lowest response value does not 
need to be a confirmed value.  
Appendix D.  Line of Therapy Definition  
According to the IMWG Consensus panel 1 on uniform reporting criteria in clinical trials 
(Rajkumar, 2011, Rajkumar 2015), a line of therapy consists of at least 1 or more cycles of a 
planned treatment regimen.  This may consist of single-agent or combination therapy or a 
sequence of treatments administered in a planned manner.   For example, a planned induction, 
followed by ASCT followed by maintenance is considered one line of therapy.  A new line of 
therapy starts when a planned course is modified to include other treatment agents as a result of 
progression, relapse or toxicity or when a planned period of observation is interrupted by the 
need for additional treatment of the disease.    
Modification of drug doses or resuming therapy after holding will not be considered a new line 
of therapy provided that there was no evidence of progression of disease as defined in the 
IMWG-URC. 
The definition is further clarified by Rajkumar et al, 2015. 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens (eg, 3-6 
cycles of initial therapy with bortezomib-dexamethasone [VD] followed by stem cell 
transplantation [SCT], consolidation, and lenalidomide maintenance is considered 1 line). 
New line of therapy 
A treatment is considered a new line of therapy if any 1 of the following 3 conditions are met  
 Start of a new line of treatment after discontinuation of a previous line: If a treatment 
regimen is discontinued for any reason and a different regimen is started, it should be 
considered a new line of therapy. A regimen is considered to have been discontinued if 
all the drugs in that given regimen have been stopped. A regimen is not considered to 
have been discontinued if some of the drugs of the regimen, but not all, have been 
discontinued. 
 The unplanned addition or substitution of 1 or more drugs in an existing regimen: 
Unplanned addition of a new drug or switching to a different drug (or combination of 
drugs) due to any reason is considered a new line of therapy. 
 SCT: In patients undergoing >1 SCT, except in the case of a planned tandem SCT with 
a predefined interval (such as 3 months), each SCT (autologous or allogeneic) should 
be considered a new line of therapy regardless of whether the conditioning regimen 
used is the same or different. We recommend that data on type of SCT also be captured. 
 
 
 


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Appendix E.  Definition of Relapsed Disease  
This study will use the IMWG definitions: 
Refractory Myeloma:  
Refractory myeloma is defined as disease that is non-responsive (failure to achieve minimal 
response or develops PD while on therapy) while on primary or salvage therapy, or progresses 
within 60 days of last therapy. There are 2 categories of refractory myeloma. 
 Relapsed and refractory myeloma:  Relapsed and refractory myeloma is defined as 
disease that is non-responsive while on salvage therapy or progresses within 60 days of 
last therapy in patients who have achieved minimal response or better at some point 
previously to then progressing in their disease course. 
 Primary refractory myeloma: Refractory myeloma is defined as disease that is non-
responsive in patients who have never achieved minimal response or better with any 
therapy. It includes patients who never achieve MR or better in whom there is no 
significant change in M protein and no evidence of clinical progression; as well as 
primary refractory, progressive disease where patients meet criteria for true progressive 
disease.     
Relapsed myeloma: 
Relapsed myeloma is defined as previously treated myeloma, which progresses and requires the 
initiation of salvage therapy but does not meet the criteria for either primary refractory myeloma 
or relapsed and refractory myeloma (Rajkumar et al. 2011). 
 
Appendix F.  Declaration of Helsinki  
http://www.wma.net/en/30publications/10policies/b3/ 
 
 
 
 
 
 
 
 
 


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Appendix G.  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 1976 
 
 
 
 
 
 
Appendix H.  Assessment of QTC Interval  
QTc Fridericia Formula  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Oncopeptides AB 
Confidential 
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OP-104 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
 
 
 
 
Appendix I.    ISS and R-ISS Score  
Standard Risk Factors for MM and the Revised -ISS (R-ISS)   
Prognostic Factor 
Criteria 
ISS Stage 
Stage I 
Serum B2-microglobulin < 3.5 mg/L, serum 
albumin ≥ 3.5 g/dL 
Stage II 
Not ISS stage I or III 
Stage III 
Serum B 2-microglobulin ≥ 5.5 mg/L 
  
Chromosomal abnormalities (CA) by interphase by florescent in situ hybridization (iFISH) 
 High Risk  
Presence of del(17p) and/or translocation of 
t(4:14) and/or translocation of t(14:16) 
Standard Risk 
No high risk CA 
LDH 
Normal  
Serum LDH < upper limit of normal 
High 
Serum LDH > upper limit of normal 
A new model for risk stratification of MM R-ISS 
Stage I  
ISS stage I and standard risk CA by iFISH and 
normal LDH 
Stage II 
 Not R-ISS stage I of III 
Stage III 
ISS stage III and either high risk CA by iFISH or 
high LDH 
(Palumbo et al. 2015) 
 
 
 
 
Appendix J    BSA DuBois Formula 
 
 
 
 
 
 
 
 
 


Oncopeptides AB 
Confidential 
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OP-104 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
 
Appendix K  Products containing boron, mannitol, sodium citrate and polysorbate-80 
The following lists may not be all inclusive and product information should be referenced if 
necessary. 
Boron: 
 Bortezomib 
 Tavaborole  
Mannitol:  
 Buprenorphine Hydrochloride (Sublingual)  
 Naloxone Hydrochloride (Sublingual)  
 Clonazepam (dispersible)  
 Gabapentin  
 Hydrochlorothiazide and lisinopril  
 Lisinopril 20 mg 
 Omeprazole Delayed Release  
 Ondansetron Hydrochloride (Orally Disintegrating)  
 Pantoprazole Sodium Delayed-Release  
 Pramipexole Dihydrochloride  
 Tramadol Hydrochloride  
 
Sodium citrate dihydrate: Sodium citrate is the natural salt of citric acid and is often used as 
a food additive.  The following is a list of medications that contain sodium citrate.  
 Alka-Seltzer Heartburn Relief 
 Bicitra, Cytra-2 
 Citra pH 
 Citrate-Phos-Dex 
 Citrocarbonate  
 Citrolith 
 Liqui-Dual Citra 
 Oracit 
 Polycitra  
 Polycitra-LC 


Oncopeptides AB 
Confidential 
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OP-104 
Protocol: Version 6.2, Amendment 8: May 05, 2021 
 Scot-Tussin Original (old formulation) 
 Tricitrasol 
 Tricitrates  
 Tussirex 
 Tussirex Sugar Free 
 Virtrate-3 
 
Polysorbate -80: Polysorbate 80 is commonly used in foods, vitamins, medicines, and 
vaccines, soaps and cosmetics.  Drugs containing polysorbate-80 include:  
 Amitriptyline Hydrochloride  
 Amoxicillin and Clavulanate Potassium  
 Cyclobenzaprine Hydrochloride 
 Escitalopram Oxalate  
 Gabapentin  
 Hydroxychloroquine Sulfate 
 Hydroxyzine Hydrochloride  
 OxyContin  
 Sertraline Hydrochloride  
 

SAP_001.pdf: 
Protocol Number:  OP-104 
Official Title:  An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and 
Dexamethasone in Combination with either Bortezomib or Daratumumab in Patients with Relapsed or 
Relapsed-Refractory Multiple Myeloma 
NCT Number: NCT03481556 
Document Date:  11 September 2020 


Statistical Analysis Plan 
Version Date: 11-Sept-2020 
Sponsor: Oncopeptides AB 
Protocol no: OP-104 
 
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Statistical Analysis Plan 
Sponsor: 
Oncopeptides AB 
Protocol No: 
OP-104 
 Project Id: 
OPP104AN-104ANC 
Version Number/ Date : 
6.1, Amendment 7 / 10 April 2020 
 
Title: 
An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and 
Dexamethasone in Combination with either Bortezomib or Daratumumab in 
Patients with Relapsed or Relapsed-Refractory Multiple Myeloma 
eCRF Version 
No./Date: 
7.0 / 6 Aug 2020 
SAP No. 
Stable SAP v1.0 
 
1 Approvals 
Sponsor 
Sponsor Name: 
ONCOPEPTIDES AB 
Representative/ Title: 
 
Signature /Date: 
 
Representative/ Title: 
 
Signature /Date: 
 
Representative/ Title: 
 
Signature /Date: 
 
 
Project Manager/Title: 
 
Signature /Date: 
 
Biostatistician / Title 
(Owner): 
 
Signature /Date: 
 
 
 
 


Statistical Analysis Plan 
Version Date: 11-Sept-2020 
Sponsor: Oncopeptides AB 
Protocol no: OP-104 
 
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2 Table of Contents 
1 Approvals ................................................................................................................................................... 1 
2 Table of Contents ....................................................................................................................................... 2 
3 Purpose ...................................................................................................................................................... 4 
4 Scope ......................................................................................................................................................... 4 
5 Introduction ................................................................................................................................................ 4 
5.1 Changes from Protocol and Clarification ............................................................................................ 4 
6 Study Objectives ........................................................................................................................................ 5 
6.1 Primary Objectives .............................................................................................................................. 5 
6.1.1 Phase 1 Primary Objective .......................................................................................................... 5 
6.1.2 Phase 2a Primary Objective ........................................................................................................ 5 
6.2 Secondary Objectives ......................................................................................................................... 5 
6.3 Exploratory Objectives ........................................................................................................................ 5 
7 Study Design .............................................................................................................................................. 5 
7.1 Dose Escalation Procedure (Phase 1) ................................................................................................ 6 
7.2 Sample Size Considerations ............................................................................................................... 6 
8 Study Endpoints ......................................................................................................................................... 6 
8.1 Primary Endpoints ............................................................................................................................... 6 
8.1.1 Phase 1 Primary Endpoint ........................................................................................................... 6 
8.1.2 Phase 2a Primary Endpoint ......................................................................................................... 7 
8.2 Secondary Endpoints .......................................................................................................................... 7 
8.3 Exploratory Endpoints ......................................................................................................................... 7 
8.4 Demographics and Baseline Disease Characteristics ........................................................................ 7 
8.5 Monoclonal Protein Spike ................................................................................................................... 9 
8.6 Prior Treatment for Multiple Myeloma ................................................................................................. 9 
8.7 Extent of Exposure ............................................................................................................................ 10 
8.7.1 Overall Exposure ........................................................................................................................ 10 
8.7.2 Melflufen Exposure .................................................................................................................... 11 
8.7.3 Bortezomib Exposure ................................................................................................................. 11 
8.7.4 Dexamethasone Exposure ......................................................................................................... 11 
8.7.5 Daratumumab Exposure ............................................................................................................ 12 
8.8 Efficacy Endpoints ............................................................................................................................. 13 
8.8.1 Best confirmed response ........................................................................................................... 13 
8.8.2 Overall Response Rate .............................................................................................................. 13 
8.8.3 Clinical Benefit Rate ................................................................................................................... 14 
8.8.4 Unconfirmed Responses ............................................................................................................ 14 
8.8.5 Progression Free Survival .......................................................................................................... 14 
8.8.6 Duration of Overall Response .................................................................................................... 14 
8.8.7 Duration of Clinical Benefit ......................................................................................................... 14 
8.8.8 Time to Response ...................................................................................................................... 14 
8.8.9 Time to Progression ................................................................................................................... 14 
8.8.10 Overall Survival ........................................................................................................................ 14 
8.8.11 Time to Next Treatment ........................................................................................................... 15 
8.8.12 Pharmacokinetic Analysis ........................................................................................................ 15 
8.9 Adverse Events ................................................................................................................................. 16 
8.9.1 Treatment-Emergent Adverse Events ........................................................................................ 16 
8.9.2 Relationship to Study Drugs ...................................................................................................... 16 
8.9.3 Adverse Events Leading to Dose Modification .......................................................................... 16 
8.9.4 Adverse Events Leading to Permanent Discontinuation of Study Drug .................................... 16 
8.9.5 Adverse Event Severity .............................................................................................................. 16 
8.9.6 Grouped Adverse Events ........................................................................................................... 16 
8.9.7 Adverse Event Infections ........................................................................................................... 17 
8.9.8 COVID-19 related Adverse Events ............................................................................................ 17 
8.10 Lab Toxicity ..................................................................................................................................... 17 


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Protocol no: OP-104 
 
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8.11 Baseline and Change from Baseline ............................................................................................... 17 
8.12 Visit Windows .................................................................................................................................. 17 
8.13 Handling of Dropouts and Missing Data ......................................................................................... 17 
9 Analysis Sets ............................................................................................................................................ 18 
9.1 Dose Limiting Toxicity Analysis Set .................................................................................................. 18 
9.2 Safety Analysis Set ........................................................................................................................... 18 
9.3 Efficacy Analysis Set ......................................................................................................................... 19 
10 Interim Analyses ..................................................................................................................................... 19 
10.1 Phase 1 ........................................................................................................................................... 19 
10.2 Phase 2a ......................................................................................................................................... 19 
11 Data Review ........................................................................................................................................... 19 
11.1 Data Handling and Transfer ............................................................................................................ 19 
12 Statistical Methods ................................................................................................................................. 20 
12.1 Subject Analysis Sets ...................................................................................................................... 20 
12.2 Subject Disposition .......................................................................................................................... 20 
12.3 Protocol Deviations ......................................................................................................................... 20 
12.4 Demographic and Baseline Disease Characteristics ...................................................................... 21 
12.4.1 Demographics .......................................................................................................................... 21 
12.4.2 Baseline Disease Characteristics ............................................................................................ 21 
12.4.3 Prior Treatment for Multiple Myeloma ...................................................................................... 22 
12.4.4 Medical and Surgical History ................................................................................................... 23 
12.4.5 Prior and Concomitant Medications ......................................................................................... 23 
12.4.6 Concomitant Procedures ......................................................................................................... 23 
13 Treatments ............................................................................................................................................. 24 
13.1.1 Extent of Study Drug Exposure ................................................................................................ 24 
13.1.2 Dose Modification ..................................................................................................................... 24 
14 Efficacy Analyses ................................................................................................................................... 24 
14.1 Primary Endpoint ............................................................................................................................. 24 
14.1.1 Sensitivity Analysis – Primary Endpoint ................................................................................... 25 
14.2 Secondary Endpoints ...................................................................................................................... 25 
14.2.1 Progression Free Survival ........................................................................................................ 25 
14.2.2 Other Efficacy Endpoints ......................................................................................................... 28 
14.3 Exploratory Endpoints ..................................................................................................................... 29 
14.3.1 Minimal Residual Disease ........................................................................................................ 29 
14.3.2 Pharmacokinetics (PK)............................................................................................................. 29 
15 Safety Analyses ..................................................................................................................................... 31 
15.1 Adverse Events ............................................................................................................................... 31 
15.1.1 Laboratory Data ....................................................................................................................... 32 
15.1.2 Vital Signs and Body Surface Area .......................................................................................... 33 
15.1.3 Physical Examinations, ECGs, and Other Observations Related to Safety ............................ 34 
16 Validation ............................................................................................................................................... 34 
17 References ............................................................................................................................................. 34 
Appendix 1 Glossary of Abbreviations ........................................................................................................ 35 
Appendix 2 Tables, Figures, Listings, and Supportive SAS Output Appendices ........................................ 37 
 
Table 1: PK Parameters to be calculated ................................................................................................................ 29 
Table 2: Direction of abnormality of lab parameters ........................................................................................... 32 
 
 
 


Statistical Analysis Plan 
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Protocol no: OP-104 
 
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3 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Oncopeptides Protocol OP-104. 
4 Scope 
This plan is a living document that will be created during the trial start-up. The SAP will be drafted after final 
electronic case report forms (eCRF) are available and maintained throughout the lifecycle of the trial. Each 
version of the SAP will require sign off from the Project Manager and Oncopeptides prior to programming 
starting or being updated based on an amended version of the SAP.   
The SAP outlines the following: 
• 
Study objectives 
• 
Study design 
• 
Variables analyzed and analysis sets  
• 
Applicable study definitions 
• 
Statistical methods regarding important protocol deviations, study drug exposure, efficacy 
analysis, adverse events handling and laboratory data 
5 Introduction 
This SAP should be read in conjunction with the study protocol and eCRF. This version of the plan has 
been developed using the protocol version 6.1 amendment 7 dated 10 April 2020 and eCRF dated 06 
August 2020. Any further changes to the protocol or eCRF may necessitate updates to the SAP. 
The SAP is to be developed in two stages. An initial ‘Stable’ SAP will be created for programming purpose. 
Versions of the SAP up to initial sponsor approval will be known as stable SAP v0.x.The initial approved 
SAP will then be called Stable SAP v1.0. The final version of the SAP, known as Final SAP, will be issued 
for sponsor approval prior to database lock. 
5.1 Changes from Protocol and Clarification  
Clarification to the efficacy analysis set definition 
The definition of the efficacy analysis set from Section 12.3.1.3 of the protocol is “Efficacy evaluable patients 
are those who receive at least 2 doses of melflufen and ≥ 50% of the partner therapy (excluding 
dexamethasone) during Cycles 1 and 2, had a baseline disease assessment, and had at least 1 post-
baseline disease assessment ≥ 28 days after first dose.”.  
To clarify the condition regarding the partner therapy, this means that patients must have had at least 50% 
of the partner therapy across the two first cycles rather than at least 50% within each cycle. 
Additional analysis of time to next treatment (TTNT) 
In Section 12.5.1.3 of the protocol, TTNT is defined as the time (months) from initiation of therapy to the 
date of the first documented next treatment. As the protocol does not specify how deaths or those that do 
not have subsequently therapy will be handled the following two definitions have been added to the SAP: 
TTNTa: Duration will be time (months) from the study treatment start to the start of first subsequent therapy 
(excluding radiotherapy). Patients who have no subsequent therapy will be censored at the earlier of date 
of death and date of last contact. 
TTNTb: Duration will be time (months) from the study treatment start to the start of the first subsequent 
therapy (excluding radiotherapy) or death. Patients who have no subsequent therapy and do not have a 
date of death will be censored at the date of last contact.  
 
 


Statistical Analysis Plan 
Version Date: 11-Sept-2020 
Sponsor: Oncopeptides AB 
Protocol no: OP-104 
 
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Formula for Body Surface Area (BSA) 
Protocol references BSA DuBois Formula in Appendix J but the formula stated is Mosteller (Mosteller, 
1987).This is clarified in the SAP. 
6 Study Objectives 
6.1 Primary Objectives 
6.1.1 Phase 1 Primary Objective 
To determine the optimal dose of melflufen, up to a maximum of 40 mg, given every 28 days, in triple drug 
combination therapy in patients with relapsed or relapsed refractory multiple myeloma (RRMM). Each 
treatment regimen (Regimen A: melflufen plus bortezomib and dexamethasone and Regimen B: melflufen 
plus daratumumab and dexamethasone) and dose will be evaluated separately.   
6.1.2 Phase 2a Primary Objective 
To evaluate the overall response rate (ORR: proportion of patients with ≥ PR) of melflufen, in each 
combination regimen, at the dose levels and schedules determined in Phase 1 in efficacy evaluable patients 
as well as in all treated patients. Each treatment regimen and dose level will be evaluated separately.  
6.2 Secondary Objectives 
• 
To evaluate the best response including the complete response/stringent complete response 
(CR/sCR), very good partial response (VGPR), PR and clinical benefit rate (CBR: proportion of 
patients with ≥ minimal response (MR)), time to response (TTR), duration of response (DOR: PR 
or better), duration of clinical benefit (CB), progression free survival (PFS) and overall survival (OS) 
up to a minimum of 2 years in efficacy evaluable as well as all treated patients. International 
Myeloma Working Group Uniform Response Criteria (IMWG-URC) guidelines will be used 
(Rajkumar et al, 2011). Each treatment regimen and dose level will be evaluated separately. 
• 
To further explore the safety and tolerability of the combination regimens. Each treatment regimen 
and dose level will be evaluated separately.  
6.3 Exploratory Objectives 
• 
Pharmacokinetics will be evaluated in patients enrolled at selected sites only. 
• 
To evaluate minimal residual disease (MRD) in patients achieving a CR.  
7 Study Design 
This is an open-label, Phase 1/2a, multicenter study which will enroll patients with relapsed or RRMM to 
combination regimens of melflufen with currently approved agents. The currently planned combinations 
include:  
• 
Regimen A: Melflufen plus bortezomib and dexamethasone   
• 
Regimen B: Melflufen plus daratumumab and dexamethasone  
Each combination will begin with a Phase 1 component which will follow the standard 3 + 3 Phase 1 design 
with 3 to 6 patients at each dose level, depending on dose limiting toxicity (DLT) observed in the first cycle 
of each patient. Patients who discontinue treatment during Cycle 1 for reasons other than study drug related 
toxicity and/or who are considered non-evaluable for DLT assessment, may be replaced at the discretion 
of the Data Safety Monitoring Committee (DSMC). Patient recruitment will continue until a full cohort of 


Statistical Analysis Plan 
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Sponsor: Oncopeptides AB 
Protocol no: OP-104 
 
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safety evaluable patients has been achieved. A DSMC will evaluate all treated patients in each cohort prior 
to the next dose level decisions. 
Up to 3 dose levels of melflufen will be tested: 30 mg, 40 mg, or 20 mg given on Day 1 of every 28-day 
cycle. Detailed dosing breakdown of each Regimen can be found in protocol Section 4.1. 
Other dose levels or schedules of melflufen, daratumumab, bortezomib and dexamethasone may be 
explored based on tolerability following review and recommendation by the DSMC. 
Once the optimal dose of melflufen has been determined for each combination Regimen in Phase 1, 
approximately 20 additional efficacy evaluable patients will be enrolled in each combination Regimen and 
treated at this dose in a Phase 2a part of the study. Patients will be assessed for response after each cycle 
according to the IMWG-URC.  
7.1 Dose Escalation Procedure (Phase 1) 
The first cohort of patients enrolled in the Phase 1 portion of each Regimen will receive melflufen dose level 
1 (melflufen 30 mg). A full safety evaluation will be conducted by a DSMC when the planned number of 
melflufen safety evaluable patients have completed the first cycle of combination therapy with DLT 
assessment. The optimal dose of melflufen in combination therapy will be defined as the highest of 20, 30 
or 40 mg of melflufen that results in ≤ 1/6 patient with DLT during the first cycle of therapy. The minimum 
dose of melflufen is 20 mg. 
• 
If no DLT is reported in the first three patients at a dose level, that dose level will be considered 
safe and three patients will be enrolled at the next dose level. 
• 
If 1/3 patients in a cohort at a dose level has a DLT, the dose level will be expanded to obtain six 
evaluable patients. 
• 
If 2/3 patients in a cohort at a dose level has a DLT, that dose level will not be considered safe and 
no further dose escalation will take place.   
• 
If there are < 2 patients with a DLT among the expanded cohort of six evaluable patients a cohort 
of three patients will be enrolled in the next higher dose level. 
• 
If there are 2 or more patients with a DLT among the expanded cohort of six evaluable patients, 
that dose level will not be considered safe and no further dose escalation will take place.   
• 
If less than 6 patients have been treated in the next lower dose level, additional patients will be 
entered into this dose level until there are 6 patients treated. If ≤ 1 of these 6 patients encountered 
DLT, then this dose level will be taken forward to Phase 2a. If 2 or more of the 6 patients encounter 
DLT, a lower dose will be considered. 
7.2 Sample Size Considerations 
The Phase 1 sample size will be based on the number of dose levels to be evaluated within each Regimen. 
It is anticipated that a maximum of 12 patients are enrolled in each Regimen during Phase 1. 
Phase 2a sample size will include approximately 20 additional efficacy evaluable patients in order to reach 
a total of 26 efficacy evaluable patients per Regimen to better describe the efficacy and safety of each 
combination. 
8 Study Endpoints 
8.1 Primary Endpoints 
8.1.1 Phase 1 Primary Endpoint 
The primary endpoint of Phase 1 is to analyze the frequency and grade of AE’s occurring at each dose 
level to be tested during Cycle 1 of therapy. Each treatment Regimen and dose level will be evaluated 
separately.  


Statistical Analysis Plan 
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Sponsor: Oncopeptides AB 
Protocol no: OP-104 
 
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8.1.2 Phase 2a Primary Endpoint 
The primary endpoint of Phase 2a is the overall response rate (sCR, CR, VGPR, or PR) observed in patients 
treated at the optimal dose of melflufen in combination therapy according to IMWG-URC. Each treatment 
Regimen and dose level will be evaluated separately.  
8.2 Secondary Endpoints 
The secondary endpoints for Phase 1 and 2a are: 
• 
Best response during the study (sCR, CR, VGPR, PR, MR, stable disease [SD], PD or non-
evaluable)   
• 
Clinical benefit rate (CBR)  
• 
Time to progression (TTP) 
• 
Time to response (TTR)  
• 
Time to next treatment (TTNT) 
• 
Duration of response (DOR)   
• 
Duration of clinical benefit (DCR) 
• 
Progression free survival (PFS)  
• 
Overall survival (OS)  
• 
Frequency and maximum grade of AE’s (according to CTCAE v4.03) 
• 
Laboratory abnormalities 
8.3 Exploratory Endpoints 
• 
PK parameters of melphalan at selected time-points 
• 
The rate of minimal residual disease (MRD) negative or positive status for patients achieving a 
complete response (CR)  
8.4 Demographics and Baseline Disease Characteristics 
Baseline disease characteristics will be obtained from the ‘Multiple Myeloma at Study Entry’ eCRF page. 
Time since initial diagnosis (years) will be calculated as: (Date of first dose of the first study treatment 
administered - Date of diagnosis + 1)/365.25. 
Date of initial multiple myeloma diagnosis will be taken from the ‘Multiple Myeloma History at Diagnosis’ 
from the eCRF page. 
Body surface area (BSA) will be calculated for each patient using the following formula (Mosteller, 1987): 
                                  
                                        BSA =  
                                                               
                                                                OR 
 
                                        BSA= 
 
Height and weight collected at screening will be used. 
3600
)
(
)
(
kg
Weight
cm
Height

3131
)
(
)
(
lbs
Weight
in
Height



Statistical Analysis Plan 
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Protocol no: OP-104 
 
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Both international staging system (ISS) as collected on the eCRF and derived ISS will be summarized. 
ISS will be derived from serum β2-microglobulin and albumin at baseline using the following rules (Palumbo 
et al , 2015): 
ISS Stage 
Criteria 
Stage I 
Serum β2-microglobulin<3.5 mg/L and serum 
albumin ≥ 35 g/L. 
Stage II 
Not ISS stage I or III 
Stage III 
Serum β2-microglobulin≥5.5 mg/L 
Unknown 
If β2-microglobulin and albumin is missing. 
If β2-microglobulin<3.5 mg/L and albumin is 
missing. 
If β2-microglobulin is missing. 
Not Done 
If β2-microglobulin and albumin is specified as ‘Not 
Done’. 
If β2-microglobulin<3.5 mg/L and albumin is ‘Not 
Done’. 
If β2-microglobulin is ‘Not Done’. 
Both revised international staging system (R-ISS) as collected on the eCRF and derived R-ISS will be 
summarized. 
R-ISS will be derived from ISS stage, cytogenetic abnormalities and Lactate Dehydrogenase (LDH) at 
baseline using the following rules  (Palumbo et al, 2015)): 
R-ISS Stage 
Criteria 
R-I 
ISS stage I and standard risk cytogenetic* 
abnormality by iFISH and normal LDH. Normal 
LDH is defined as < ULN (upper limit of normal)  
R-II 
Not R-ISS stage I of III 
R-III 
ISS stage III and either high risk cytogenetic* 
abnormality by FISH or high LDH. High LDH is 
defined as >ULN. 
Unknown 
If ISS stage is ‘Unknown’. 
If ISS stage III and cytogenetic 
abnormalities=‘standard risk’ and LDH is missing. 
If ISS stage III and cytogenetic abnormalities= 
‘Unknown’ and LDH is normal. 
If ISS stage I and either cytogenetic 
abnormality=’Unknown’ or LDH is missing. 
 
Not Done 
If ISS stage is ‘Not Done’. 
If ISS stage III and cytogenetic 
abnormalities=‘standard risk’ and LDH is ‘Not 
Done’. 
If ISS stage III and cytogenetic abnormalities= 
‘Not Done’ and LDH is normal. 


Statistical Analysis Plan 
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Protocol no: OP-104 
 
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R-ISS Stage 
Criteria 
If ISS stage I and either cytogenetic abnormality= 
‘Not Done’ or LDH is ‘Not Done’. 
 
*In derivation of R-ISS Stage, only FISH del(17p), t(4;14), t(4 ;14) (p16 ;q32), t(14;16) and t(14 ;16) 
(q32 ;q23) will be considered as high risk cytogenetic abnormalities. Similarly for this derivation, FISH 
(t(14;20), t(14 ;20) (q32 ;q11) ,gain1q(+1q), gain (1q21) and hypodiploidy will be considered as standard 
risk abnormalities.  
High-risk and standard-risk cytogenetic abnormality is defined as the following (Sonneveld et al, 2016)  
High-risk 
Standard-risk 
FISH: t(4;14), t(4 ;14) (p16 ;q32), t(14;16), 
t(14 ;16) (q32 ;q23), t(14;20), t(14 ;20) 
(q32 ;q11),del(17p),gain1q(+1q), gain (1q21) and 
hypodiploidy. 
All others including: FISH: t (11;14), t (6;14) 
Karyotype: del (13) or del (13q) 
 
8.5 Monoclonal Protein Spike  
Monoclonal protein spike (M-protein) is assessed from serum and urine protein electrophoresis test 
(SPEP/UPEP), and/or serum free light chain (sFLC). The second serum electrophoresis M-protein will also 
be considered when determining measurable SPEP. 
Measurable M-protein at screening and baseline are defined as follows: 
• 
Measurable SPEP is defined as M-protein ≥ 0.5 g/dL. 
• 
Measurable UPEP is defined as M-protein ≥ 200 mg/day. 
• 
Measurable sFLC is defined as involved FLC (Serum Kappa FLC or Lambda Kappa FLC) ≥ 100 
mg/L with abnormal Serum Kappa/Lambda ratio (defined as values outside 0.26-1.65). 
8.6 Prior Treatment for Multiple Myeloma 
Prior treatment for multiple myeloma will be recorded on the Prior Systemic Cancer Therapy 
(Medications) and Prior Systemic Cancer Therapy (Lines of Therapy) pages of the eCRF. 
 
All medications will be coded using version DDE B3 Mar_2019 or later of the World Health Organization 
(WHO) Drug Dictionary (DD). 
 
Prior agents within regimens will be summarized using WHO DD Standardized Drug Groupings (SDG):  
• 
Proteasome inhibitors (PI) is defined as WHO DD SDG ‘Antineoplastic proteasome inhibitors’ 
• 
Immunomodulatory drugs (IMiD) is defined as WHO DD SDG ‘Antineoplastic thalidomide 
analogues’  
• 
Anti-CD38 monoclonal antibodies (mAb) is defined as WHO DD SDG ‘Antineoplastic CD38 antigen 
inhibitors’ 
• 
Other mAb are defined as WHO DD SDG ‘Monoclonal antibodies – antineoplastic’ excluding SDG 
‘Antineoplastic CD38 antigen inhibitors’ 
• 
Alkylators is defined as WHO DD SDG ‘Antineoplastic alkylating drugs’ 
• 
Other antineoplastic drugs for the treatment of multiple myeloma will be referred to as ‘Other’ 
Any experimental or investigational drugs that are not covered by WHO DD SDG will be reviewed manually 
and classified as one of the above therapeutic drug classes if applicable. Classifications will be documented 
as part of the database lock procedures and further described in the Clinical Study Report.  


Statistical Analysis Plan 
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Protocol no: OP-104 
 
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High-dose melphalan is defined as those that have had a transplant and melphalan given on the same 
line of therapy, with melphalan given within a week prior to the transplant and reason for medication being 
stopped is ‘Finished course of therapy’ or ‘Other’ .  
 
Refractory myeloma is defined as disease that is nonresponsive while on therapy or progresses on or 
within 60 days of last therapy, where the last therapy is defined as the last dose of the last line of therapy  
(Anderson et al, 2008). Nonresponsive disease is defined as failure to achieve MR or better as the best 
response to a line of therapy. 
 
Refractory to a single agent (excluding Dexamethasone [identified using preferred term of 
‘Dexamethasone’]) within a regimen will be determined by comparing the date of relapse/PD (as captured 
on the ‘Multiple Myeloma History – Prior Systemic Cancer Therapy (Lines of Therapy)’ eCRF page)  to 
the start and stop date of an agent. If this is on or after the first administration date of the agent and within 
60 days of the last administration date, then the patient should be considered refractory to the agent. In 
addition, if the patient stops taking the agent due to progressive disease, the patient will be considered 
refractory. Start and stop dates for particular agents as well as reasons for stopping are captured on the 
‘Multiple Myeloma History - Prior Systemic Cancer Therapy (Medications) eCRF page. If a patient 
achieves SD or PD as the best response to a line of therapy, the patient would be considered refractory 
to all agents in that line (excluding ‘Dexamethasone’). Refractory statuses will be presented for drug 
classes as listed in bullets above, for individual agents within the classes, and furthermore the fraction of 
double-refractory (refractory to at least 1 PI and at least 1 IMiD in any line of therapy or within the same 
line of therapy) will be presented. 
8.7 Extent of Exposure 
8.7.1 Overall Exposure 
Overall treatment duration time (weeks) = ((last dose date – first dose date) +1)/7  
where the last dose date is the greatest of: 
• 
Last dose of Melflufen + 28 
• 
Last dose of Bortezomib 
• 
Last dose of Dexamethasone 
• 
Last dose of Daratumumab 
The number of treated cycles is calculated as the sum of the cycles where a patient has received at least 
one dose of any study drug during the 28 days of that cycle. 
If a data-cut is being applied to analysis, then if last dose of Melflufen + 28 days > data-cut-off date then 
the last dose of melflufen is equal to data cut-off date. 
The follow-up from Cycle 1, Day 1 to data-cut off with be calculated as (date of study end – date of Cycle 
1, day 1 visit) + 1 for patients who ended the study before data-cut off. For patients that are still ongoing in 
the study the follow-up from Cycle 1, Day 1 will be calculated as (date of cut-off – date of Cycle 1, day 1 
visit) + 1.    


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8.7.2 Melflufen Exposure 
Melflufen will be administered intravenously as a 30-minute infusion on Day 1 of every 28-day cycle. 
Time on melflufen in weeks is defined as (date of last dose + 28 days – date of first dose + 1)/7. 
Total cumulative dose (mg) of melflufen is defined as sum of actual doses administered over time. 
Planned dose of melflufen at a cycle is calculated as the starting melflufen dose assigned to the patient. 
The total melflufen planned dose is calculated as the starting melflufen dose assigned to the patients * the 
number of treated cycles. 
Duration of Infusion (mins) = infusion end time – infusion start time. 
Average duration of infusion (mins) = sum of durations of infusions (mins)/number of infusions. 
Average dose of melflufen (mg/week) = total melflufen cumulative dose administered (mg)/time on  
melflufen (weeks). 
Relative dose intensity of melflufen (%) = total melflufen cumulative dose administered (mg)/total melflufen 
planned dose (mg) * 100. 
Relative dose intensity based on average weekly dose (%) = average dose of melflufen (mg)/ planned dose 
(mg) * 100, where planned dose is either 20, 30 or 40 mg per 4 weeks = 5, 7.5 or 10 mg/week. 
Relative dose intensity by cycle (%) = total melflufen dose administered in each cycle/planned dose in each 
cycle * 100. 
8.7.3 Bortezomib Exposure 
In Regimen A, bortezomib 1.3mg/m2 is will be administered twice weekly on Days 1, 4, 8 and 11 of each 
28-day cycle. Exposure to bortezomib will be defined as the following: 
Time on bortezomib in weeks is defined as (date of last dose – date of first dose + 1)/7. 
Total bortezomib cumulative dose is calculated as the sum of bortezomib dose administered during the 
study.   
Planned dose (mg) in a cycle is calculated as 4 doses * 1.3mg/m2 * baseline BSA (m2)  
The total number of treated cycles is calculated as the sum of the number of cycles where a patient has 
received at least one dose of bortezomib during the 28 days of that cycle. 
The total bortezomib planned dose (mg) is calculated as 4 doses per cycle * 1.3 mg/m2 * baseline BSA (m2)  
* number of treated cycles. 
Relative dose intensity (%) is calculated as the total cumulative dose administered (mg)/total planned dose 
(mg) * 100. 
Relative dose intensity by cycle (%) = total cumulative dose administered in each cycle(mg)/ total planned 
dose in that cycle (mg) * 100. 
8.7.4 Dexamethasone Exposure 
In Regimen A, dexamethasone 20 mg orally (p.o.) (12 mg for ≥ 75 years of age) will be given on Days 1, 4, 
8, 11, and 40 mg (20 mg for patients ≥ 75 years of age) on Days 15 and 22 of each 28-day cycle. 
In Regimen B dexamethasone 40 mg p.o (20 mg p.o, for patients ≥ 75 years of age) will be given weekly. 
Exposure to dexamethasone will be defined as the following: 
Time on dexamethasone in weeks is defined as (date of last dose – date of first dose + 1)/7. 
Total dexamethasone cumulative dose is calculated as the sum of dexamethasone dose administered 
during the study.  


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The total number of treated cycles is calculated as the sum of the number of cycles where a patient has 
received at least one dose of dexamethasone during the 28 days of that cycle. 
The total dexamethasone planned dose for Regimen A is calculated as ((4 doses per cycle * 20 mg or 
12mg, depending on age) + (2 doses per cycle * 40mg or 20mg, depending on age)) * number of treated 
cycles. 
The total dexamethasone planned dose for Regimen B is calculated as ((4 doses per cycle * 40mg or 20mg, 
depending on age) * number of treated cycles. 
Relative dose intensity (%) is calculated as the total cumulative dose administered (mg)/total planned dose 
(mg) * 100.  
Relative dose intensity by cycle (%) = total cumulative dose administered in each cycle/total planned dose 
in that cycle * 100. 
8.7.5 Daratumumab Exposure 
In Regimen B daratumumab 16mg/kg will be given weekly for 8 doses, every 2 weeks for 8 doses and then 
every 4 weeks. See table below for schedule of daratumumab dosing: 
Cycle  
Days 
1 
2*, 8, 15 and 22 
2 
1, 8, 15 and 22 
3 to 6 
1 
and 15 
7+ 
1 
*Due to prolonged infusions time of the first dose of daratumumab, the Cycle 1 infusion of daratumumab 
will be given on Day 2 of Cycle 1. 
Exposure to daratumumab will be defined as the following: 
Time on daratumumab in weeks is defined as (date of last dose – date of first dose + 1)/7. 
Total daratumumab cumulative dose is calculated as the sum of daratumumab dose administered during 
the study.  
The total number of treated cycles is calculated as the sum of the number of cycles where a patient has 
received at least one dose of daratumumab during the 28 days of that cycle. 
The total daratumumab planned dose (mg) is calculated as 4 doses per cycle * 16mg/kg * baseline weight 
(kg) * (number of treated cycles from Cycle 1 to 2) + 2 doses per cycle * 16mg/kg * baseline weight (kg) * 
(number of treated cycles from Cycles 3 to 6) + 16mg/kg * baseline weight (kg) * (number of treated cycles 
after Cycle 7). 
e.g. if patient discontinues at Cycle 3 then total daratumumab planned dose = 2 * 4 * 16mg/kg * baseline 
weight (kg), if patient discontinues at Cycle 6 then 8 * 16mg/kg+3 * 2 * 16mg/kg * baseline weight (kg). 
Relative dose intensity (%) is calculated as the total cumulative dose administered (mg)/total planned dose 
(mg) * 100. 
Relative dose intensity by cycle (%) = total cumulative dose administered in each cycle/ total planned dose 
in each cycle* 100. 


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8.8 Efficacy Endpoints 
All tumor response and progression-dependent endpoints are as assessed by the investigator according to 
the IMWG-URC (Rajkumar et al, 2011). 
8.8.1 Best confirmed response 
At each efficacy assessment visit, the investigator records the myeloma response according to the IMWG 
Uniform Response Criteria on the Myeloma Response Assessment eCRF. Possible responses ordered 
from best to worst are sCR, CR, VGPR, PR, MR, SD or PD. Response can also be recorded as Not 
Evaluable or Unknown. MRD negativity/positivity are subcategories of sCR and CR. The ‘Not Evaluable’ 
category will include patients that do not have sufficient evaluations to assess response according to the 
IMWG-URC and therefore have a missing best response. 
For response categories (sCR, CR, VGPR, PR, MR and SD), the best confirmed response will be the best 
response recorded by the investigator after the patient received the first dose of melflufen until PD or start 
of subsequent treatment. All response categories must be confirmed at a consecutive assessment. A 
response as good as or better than the first response constitutes confirmation of the first response. Two 
consecutive visits should also confirm the lesser of the pair e.g. if a patient has consecutive visit of VGPR 
then PR, PR will be confirmed with unconfirmed response of VGPR. A missing/NE response following an 
initial response will not invalidate confirmation of that response (e.g. CR-NE-CR will still be considered a 
confirmed CR. More than one NE visit (e.g. CR-NE-NE-CR), however, will preclude the initial response 
from being confirmed. In case there are unscheduled assessments between two planned visits the 
unscheduled visit evaluation should not impact the classification of response unless it shows PD. PD also 
requires confirmation at 2 consecutive assessments before the institution of any new therapy, unless the 
progression is due to plasmacytoma in which case, only one assessment is needed. This is determined by 
response of ‘Yes’ to the questions ‘Was there any evidence of a new bone lesion or new extramedullary 
plasmacytomas?’ or ‘Was there any evidence of progression or existing bone lesions or extramedullary 
plasmacytomas?’. All response categories and SD also require no known evidence of progressive or new 
bone lesions or progressive or new plasmacytoma. Progressive or new plasmacytoma will be ascertained 
from the Extramedullary Plasmacytoma Evaluation eCRF page.  
The table below describes possible best responses and confirmation patterns: 
Pattern 
Best Confirmed Response 
Best Unconfirmed Response 
CR-sCR 
CR 
sCR 
CR-NE-CR 
CR 
CR 
CR-NE-NE-CR 
Missing 
CR 
PR-PR 
PR 
PR 
MR-sCR 
MR 
sCR 
PR-NE-CR 
PR 
CR 
PR-NE-PR 
PR 
PR 
VGPR-PR 
PR 
VGPR 
PR-VGPR 
PR 
VGPR 
SD-SD-PD 
SD 
SD 
8.8.2 Overall Response Rate  
The overall response rate is the proportion of patients who achieve a best confirmed response of sCR, CR, 
VGPR, or PR. 


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8.8.3 Clinical Benefit Rate  
The clinical benefit rate is the proportion of patients who achieve a best confirmed response of sCR, CR, 
VGPR, PR or MR. 
8.8.4 Unconfirmed Responses 
Best unconfirmed responses will be derived, as per the rules described in Section 8.8.1 without the 
requirements for response confirmation at consecutive visits (this involves taking into consideration all 
responses from first dose until start of subsequent therapy or PD). Unconfirmed ORR and CBR will be 
derived based on best unconfirmed responses. 
8.8.5 Progression Free Survival 
Progression free survival is defined as the time in months from date of initiation of therapy to the earlier of 
confirmed disease progression or death due to any cause. Patients with unconfirmed PD as the final 
response assessment will use the date of latest PD assessment as the date of progression. Patients without 
confirmed disease progression, without progression as the last assessment, or death will be censored on 
the date of their last evaluable myeloma response assessment, prior to initiation of subsequent therapy.  
8.8.6 Duration of Overall Response 
The duration of overall response is defined as the time in months from first evidence of confirmed 
assessment of sCR, CR, VGPR, or PR to first confirmed disease progression, or to death due to any cause. 
Patients with unconfirmed PD as the final response assessment will use the date of latest PD assessment 
as the date of progression. DOR is defined only for patients with a confirmed PR or better. Patients without 
confirmed disease progression, without progression as the last assessment, or death, will be censored on 
the date of their last evaluable myeloma response assessment, prior to initiation of subsequent therapy. 
8.8.7 Duration of Clinical Benefit 
The duration of clinical benefit is the time in months from the first evidence of confirmed assessment of 
sCR, CR, VGPR, PR or MR to the date to first confirmed disease progression, or death due to any cause. 
Patients with unconfirmed PD as the final response assessment will use the date of latest PD assessment 
as the date of progression. Duration of clinical benefit is only defined for patients with a confirmed MR or 
better. Patients without confirmed disease progression without progression as the last assessment, or 
death, will be censored on the date of their last evaluable myeloma response assessment, prior to initiation 
of subsequent therapy.  
8.8.8 Time to Response  
The time to response is the time in months from first dose of therapy to first documented confirmed 
response. Only patients with confirmed response (sCR, CR, VGPR or PR) are considered for this endpoint. 
8.8.9 Time to Progression  
The time to progression is defined as the time in months from initiation of therapy to the date of the first 
documented confirmed progression. Patients with unconfirmed PD as the final response assessment will 
use the date of latest PD assessment as the date of progression. Patients without confirmed disease 
progression, without progression as the last assessment, will be censored on the date of their last evaluable 
myeloma response assessment or their date of death (whichever occurs sooner), prior to the start of 
subsequent therapy. 
Patients who have no post-study myeloma therapy and do not have a date of death will be censored at the 
date of last contact. 
8.8.10 Overall Survival 
Overall survival is the time in months from date of initiation of therapy to death due to any cause. Patients 
still alive at the end-of -study, or lost to follow-up, will be censored at the last day known alive. 


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8.8.11 Time to Next Treatment  
Analyses of Time to next treatment (TTNT) will use two alternative definitions, referred to as TTNTa and 
TTNTb.  
TTNTa: Duration will be time (months) from the study treatment start to the start of first subsequent therapy 
(excluding radiotherapy). Patients who have no subsequent therapy will be censored at the earlier of date 
of death and date of last contact. 
TTNTb: Duration will be time (months) from the study treatment start to the start of the first subsequent 
therapy (excluding radiotherapy) or death. Patients who have no subsequent therapy and do not have a 
date of death will be censored at the date of last contact.  
8.8.12 Pharmacokinetic Analysis 
PK parameters will be calculated and provided by the Sponsor using Non-Compartmental Analysis (NCA) 
and the software 
 or later (
 The derivation 
of PK parameters is done by the Pharmacokineticist. The following PK parameters will be assessed for 
melphalan: 
• 
Maximum observed concentration (Cmax) 
 
Maximum plasma concentration (Cmax) is defined as the maximum observed drug concentration 
observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter 
calculated by 
 If there is no measurable concentration in the subject’s PK profile, then 
Cmax will be missing for that subject. Cmax will be reported in units of ng/mL. 
 
• 
Area under the concentration-time profile from 0 hours to infinity (AUC(0-∞)) 
 
AUC(0-∞) is defined as the total area under the concentration-time curve from start of infusion (time 
0) to the limit as the end time becomes arbitrarily large. AUC(0-∞) will be obtained from the 
AUCINF_obs parameter calculated by 
. 
 
• 
Elimination half-life 
 
The apparent terminal elimination half-life (t½) is defined as the time required for the drug concentration 
to decrease by a factor of one-half in the terminal phase. t½ can be estimated as ln(2) / Ke, Ke referring 
to terminal phase elimination rate constant of the apparent log-linear decrease as defined by 3 data 
points. It will be obtained from the HL_Lambda_z parameter calculated by 
. t1/2 will be 
reported in units of min. 
 
PK samples will be collected in patients from both Regimens, at selected sites only. Three plasma samples 
for determination of melphalan concentrations will be drawn in each of the first two melflufen treatment 
cycles, 10–15 minutes after the end of infusion, 1 hour after the end of infusion and the third sample 2 to 4 
hours after the end of infusion (as late as possible within the time frame). For Regimen B, the third sample 
will be taken after the daratumumab infusion in cycle 2. 
 
A requirement for a profile to be evaluable is that all 3 samples have measurable concentrations and that 
concentrations are strictly decreasing over time. Actual time points relative to start of melflufen infusion in 
minutes will be derived and used by the Pharmacokinetist for calculating parameters. Actual time in 
minutes will be calculated as datetime of blood sampling minus datetime of start of infusion. 
 
The following statistics will be derived for Cmax, AUC(0-∞) and Elimination half-life: 
Geometric mean = exp (arithmetic mean of the log-transformed data)  
Geometric standard deviation = exp(standard deviation for log transformed data) 


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Geometric CV%= sqrt (exp(variance for log transformed data) - 1)) * 100 
8.9 Adverse Events 
An AE is any untoward medical occurrence in a study patient administered an investigational product and 
that does not necessarily have a causal relationship with this treatment. An AE therefore can be any 
unfavorable and unintended sign (including laboratory finding), symptom or disease temporally associated 
with the use of a medicinal product, whether or not considered drug-related. In addition to new events, any 
increase in the severity or frequency of a pre-existing condition that occurs after the patient begins study 
therapy is considered an AE. This includes any side effect, injury, toxicity, or sensitivity reaction.  
8.9.1 Treatment-Emergent Adverse Events 
A treatment-emergent AE (TEAE) will be defined as any AE that started on or after the first day of study 
treatment, whichever treatment is administered first, 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. 
8.9.2 Relationship to Study Drugs 
AEs will be rated as ‘unrelated’, ‘possibly related’ or ‘probably related’ to each study drug, by the 
investigator. AEs with missing relationship for one of the drugs will be considered as having a ‘missing’ 
relationship to that study drug. AEs that are categorized as ‘possibly related’ or ‘probably related’ to 
melflufen will be considered as ‘melflufen-related’ AEs. The same rule applies to each study drug 
(bortezomib, daratumumab and dexamethasone). 
8.9.3 Adverse Events Leading to Dose Modification 
An AE can lead to a change in drug/dose administrations (drug interrupted; dose reduced) of each of the 
study drugs. An AE leading to dose modification of melflufen is defined as an AE with ‘Action taken with 
melflufen’ recorded as ‘Drug interrupted’ or ‘Dose reduced’. The same rule applies to each study drug and 
respective action taken variable (bortezomib, daratumumab and dexamethasone). Dose modification to 
any study drug is defined as an AE that has led to a change in drug/dose administration of any of 
melflufen, bortezomib, daratumumab and dexamethasone. 
8.9.4 Adverse Events Leading to Permanent Discontinuation of Study Drug 
An AE that leads to permanent discontinuation of study drug, is defined as an AE with ‘action taken with 
any study drug’ of ‘Drug withdrawn’. 
8.9.5 Adverse Event Severity 
AE severity will be rated using the CTCAE (Version 4.03) toxicity grade as ‘Grade 1-mild, ‘Grade 2-
moderate’, ‘Grade 3-severe’, ‘Grade 4-life threatening’ or ‘Grade 5-Death’ by the investigator. 
8.9.6 Grouped Adverse Events 
Adverse events will be grouped as follows: 
• 
Neutropenia (grouped) – preferred terms (PT) ‘Neutropenia’, ‘Neutrophil count decreased’ or 
‘Neutropenia worsening’;  
• 
Thrombocytopenia (grouped) – PTs ‘Thrombocytopenia’ or ‘Platelet count decreased’ or 
‘Thrombocytopenia worsening’; 
• 
Myelodysplastic syndrome: PTs {‘5q minus syndrome’, ‘Chronic myelomonocytic leukemia’, 
‘Myelodysplastic syndrome’, ’Myelodysplastic syndrome transformation’, ’Myelodysplastic 
syndrome unclassifiable’, ‘Refractory anemia with an excess of blasts’, ‘Refractory anemia with 
ringed sideroblasts’,‘Refractory cytopenia with multilineage dysplasia’, ‘Refractory cytopenia with 
unilineage dysplasia’, ‘Sideroblastic anemia’}; 


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• 
Secondary primary malignancies: Standardized MedDRA Query (SMQ ){‘Malignant or unspecified 
tumors’[200000]} + Myelodysplastic syndromes [10028536] (HLT), excluding: Plasma cell 
neoplasms [1003522] (HLGT).  
8.9.7 Adverse Event Infections  
Infections will be identified through the following SOC: Infections and infestations 
8.9.8 COVID-19 related Adverse Events 
COVID-19 AEs will be identified through the following PTs: Asymptomatic COVID-19, COVID-19, SARS-
coV-2 test, , SARS-CoV-2 test positive, COVID-19 immunization, COVID-19 pneumonia, COVID-19 
prophylaxis, COVID-19 treatment, SARS-CoV-2 test false negative, Suspected COVID-19. 
 
Additional PTs will be added as per MedDRA up-versioning. This list will be finalized prior to database lock. 
8.10 Lab Toxicity  
Grade 3 or 4 ANC count will be identified using the following rules : 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology 
ANC (Low) 
<LLN - 1.5 x 109 /L 
<1.5 - 1.0 x 109 /L 
<1.0 - 0.5 x 109 /L 
<0.5 x 109 /L 
 
Onset of Grade 3 or 4 ANC is the date of the lab test assessment. Date of resolution is defined as when 
the Grade has decreased to 2 or lower based on laboratory data. 
8.11 Baseline and Change from Baseline 
Unless otherwise specified, baseline will be defined as the latest assessment taken prior to the first dose 
of the study drug. 
Change from Baseline is defined as: 
 
Observed result at nominal time point – observed result at baseline. 
8.12 Visit Windows 
For the assessments scheduled (all cycles expect for Cycle 1, Day 1) a +/- 3-day window is permitted in 
accordance with the protocol. 
If any assessment for a scheduled visit falls outside of the pre-specified windows, it will nevertheless be 
included for the analyses of that visit. Data from assessments made at the end of trial visit will be assigned 
to the end-of-treatment visit. If more than 1 value is available for a given visit, the worst value will be used 
for summaries by visit, and all data will be listed. 
Extra, unscheduled assessments (e.g. laboratory data or vital signs) will not be considered at individual 
visit analyses, but will be included in assessments which span the entire period (e.g. worst case, potentially 
clinically important etc.). Unscheduled assessments will be labelled as ‘Unscheduled’ in listings. In the event 
multiple protocol-specified assessments are reported within the same visit window the value reported for 
the scheduled visit should be used in summaries by timepoint, and if this value is missing or unknown the 
earliest reported value of scheduled and unscheduled assessments within the visit window should be used. 
8.13 Handling of Dropouts and Missing Data 
Missing data will not be estimated or carried forward for any of the summaries or analysis except for time 
to event variables. Censoring rules for time to event variables are covered in Section 14.2.1.  


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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 an AE is treatment-emergent), the date will be imputed as 
described below for adverse events and diagnosis. 
Handling of Partial or Missing Dates 
If only a partial date is available and is required for a calculation (e.g. time since diagnosis, time since most 
recent relapse, determination of whether a medication is concomitant or an AE is treatment-emergent), the 
following standards will be applied: 
Start dates (e.g. AE onset date or start date of medication, date of diagnosis, date of relapse). 
• 
For missing start day only - Day will be imputed as the first day of the month (i.e., 1) with the 
following exception: if the partial date falls in the same month and year as the date being used in 
the calculation (e.g. first dose date, informed consent date), then the partial date will be imputed to 
equal the date being used for the calculation.  
• 
For missing start day and month - Day and month will be imputed as the first day of the year (i.e., 
1 January) with the following exception: if the partial date falls in the same year as the date being 
used in the calculation (e.g. first dose date, informed consent date), then the partial date will be 
imputed to equal the date being used for the calculation. 
• 
Completely missing dates – AEs will be set to the first study drug administration date and 
concomitant medications will be set to the first study drug administration. Other entirely missing 
dates will not be imputed. 
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). 
• 
For completely missing stop dates, the date of the data cut-off/database lock will be imputed. 
Any partial dates will be displayed in data listings without imputation of missing days and/or months (e.g. 
MAR2011, 2009). No other imputation of missing data will be performed. 
9 Analysis Sets 
9.1 Dose Limiting Toxicity Analysis Set 
The DLT analysis set includes all patients in Phase 1 that complete Cycle 1 of therapy or are discontinued 
due to a DLT event defined in Protocol Sections 6.6.1 and 6.6.2. The DLT analysis set will be used for the 
evaluation of the MTD in Phase 1. Patients that have been replaced in the original assigned cohort will not 
be included in the DLT analysis set.  
Patients will be summarized according to the treatment regimen and actual dose level received. 
9.2 Safety Analysis Set 
The safety analysis set includes all patients that have received at least one dose (or partial dose) of 
melflufen, dexamethasone, or partner therapy (bortezomib or daratumumab).  
The safety analysis set will be the primary population for the summaries of all efficacy, exposure and 
safety data.  
 
Patients will be summarized according to the treatment regimen and actual dose received. 


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9.3 Efficacy Analysis Set 
The efficacy analysis set is a subset of the safety analysis set and includes: 
• 
all patients who receive at least 2 doses of melflufen and ≥50% (on average as opposed to within 
each cycle) of the partner therapy (bortezomib or daratumumab) during Cycles 1 and 2,  
• 
have a baseline disease assessment,  
• 
and have at least 1 post-baseline disease assessment ≥28 days after first dose.  
The efficacy analysis set includes all patients enrolled into Phase 2a and the patients from Phase 1 that 
received the dose that was carried forward for the Phase 2a portion of the study. The efficacy analysis set 
is to be used as supportive analysis for the ORR, CBR and DOR. 
Patients will be summarized according to the treatment regimen and actual dose level received. 
10 Interim Analyses 
10.1 Phase 1 
 
A Data safety monitoring committee (DSMC) will be convened for this study and will primarily act to 
safeguard the interests of study patients, assess safety and efficacy data, and for monitoring the overall 
conduct of the study. The committee will consist of Oncopeptides AB Study Physician, the Global Lead 
Investigator, the CRO Medical Monitor and will be chaired by an independent multiple myeloma expert. At 
the end of each cohort, the committee will meet and evaluate all the current safety data and make decisions 
regarding dose escalation or cohort expansion in the Phase 1 component of the study. The committee will 
also determine when the optimal dose has been reached and make recommendations on the Phase 2a 
dose and schedule. The DSMC may provide recommendations for stopping or continuing the study or for 
alternate dose and schedule of a given Regimen after review of the data. The DSMC may also make 
recommendations related to the selection, recruitment, and retention of patients, their management and the 
procedures for data management and quality control. Additional details regarding the DSMC may be found 
in the DSMC Charter. 
10.2 Phase 2a 
The DSMC will meet regularly to assess the benefit/risk profile in the Phase 2a portion of the study. All 
reported Grade 3-4 treatment-related non-hematological AEs, as well as all serious adverse events (SAEs), 
and any treatment-related deaths due to hematologic or non-hematologic AEs will then be presented to the 
DSMC. If the DSMC considers the AE patterns differ from the Reference Safety Information for the 
individual drugs in the combination (see Protocol Section 12.5.2), the DSMC may recommend additional 
safety monitoring or stopping further recruitment. Please see the DSMC charter for further information 
regarding the stopping rules. 
11 Data Review 
Before each delivery, data management will make every reasonable effort to collect and clean critical data 
as much as possible. Please refer to the data transfer plan for a definition of critical data. 
Oncopeptides will implement an independent review of the myeloma response assessment and 
progression assessments performed by the investigator. This review process is described in a separate 
document. 
11.1 Data Handling and Transfer 
External data to be used for all deliveries will be transferred as per the related data transfer agreements. 
Please refer to the data management plan for further details. 


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12 Statistical Methods 
Statistical analyses will be performed using SAS® Version 9.4 or higher. 
Each treatment regimen and dose level will be evaluated separately. Statistical analysis will be reported 
using summary tables, inferential analysis, figures and data listings. 
For data which are presented in months, a conversion factor of 30.4375 days will be used. 
For data which are presented in years, a conversion factor of 365.25 days will be used.  
The following conventions for presentation of data will be used: 
Categorical variables: 
• 
Categorical variables will be summarized using number of observations and percentages. The 
denominator for percentage will be the number of patients in the population with data available (n) 
unless otherwise stated. Missing categories may be added as appropriate. 
• 
Percentages will be presented to one decimal place and will not be presented for zero counts. 
100% will be presented without decimals. 
Continuous variables: 
• 
The number of patients with non-missing data (n), mean, median, minimum, and maximum will be 
summarized. The minimum and maximum will be summarized with the same number of decimal 
places as the value collected; mean and median will be presented to one more decimal place than 
the value collected. Standard deviation will be presented to two more decimal places. 
Individual patient data recorded on the eCRFs and any derived data will be presented by treatment 
regimen and patient in data listings. 
All TFLs will be based on the actual treatment that a patient has received. 
12.1 Subject Analysis Sets 
Number and percentage of patients in the safety analysis set, DLT analysis set, efficacy analysis set will 
be summarized. The denominator will be the number of patients in the safety analysis set. 
12.2 Subject Disposition 
Subject disposition data will be summarized by dose level and regimen. 
The number and percentage of patients treated and ongoing in the study will be presented. 
Furthermore, patients alive and dead up-to the data-cutoff will be presented. Percentages will be based on 
the number of patients treated. 
An additional summary of number and percentage of patients who completed and discontinued from the 
study, and discontinued treatment, together with a breakdown of the corresponding reasons for 
discontinuation of treatment and discontinuation of study as recorded on the ‘Disposition-End-of-Study’ and 
‘Disposition-End-of-Treatment’ eCRF pages will be presented. This summary will be provided for the safety 
analysis set. Patients that have discontinued the study will be provided in a listing. 
12.3 Protocol Deviations 
Per PRA processes, protocol deviations will be entered into system of record (CTMS). The study team and 
Sponsor will conduct on-going reviews of the deviation data and the resulting set of evaluable subjects 
throughout the study; adjusting the deviation criteria as seems appropriate. The evaluable subjects must 
be finalized prior to database lock. 
The Protocol Deviation Guidance Document defined all important protocol deviations and specified how a 
protocol deviation should be coded.  
A protocol deviation listing of subjects in the safety analysis set will be provided. 


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A separate listing for protocol deviations related to the COVID-19 identified through search of  ‘COVID’  at 
the beginning of the deviation text will be provided. 
12.4 Demographic and Baseline Disease Characteristics 
12.4.1 Demographics 
Descriptive statistics will be produced for demographic baseline characteristics by dose level and regimen. 
Age (years), Age group (<65, ≥65-75 and >75 years), height (cm), weight (kg), and BSA (m2) will be 
summarized as continuous data. Gender (male, female), race (American Indian or Alaska Native, Asian, 
Black or African American, Native Hawaiian or other Pacific Islander, White, Other), and ethnicity (Hispanic 
or Latino, Not Hispanic or Latino) will be summarized as the number and percentage of patients in each 
category. Summaries will be provided for the safety analysis set.  
12.4.2 Baseline Disease Characteristics  
The following variables obtained from the ‘Multiple Myeloma Status at Study Entry’ eCRF page, will be 
summarized descriptively by dose level and regimen: 
• 
ISS stage at study entry 
• 
R-ISS stage at study entry 
• 
Derived ISS at study entry 
• 
Derived R-ISS at study entry 
• 
Type of measurable disease at study entry 
• 
SPEP, UPEP, Serum Kappa/Lambda values at study entry 
• 
Current disease status (Relapsed, Relapsed-refractory) determined by the investigator 
• 
Evidence of lytic bone disease at study entry 
• 
Evidence of extramedullary disease at study entry 
• 
Light chain subtype (kappa, lambda, biclonal, unknown) 
• 
Heavy chain subtype at diagnosis (IgG, IgA, IgD, IgE, IgM, None) 
• 
Time since initial diagnosis (years) 
• 
Time since most recent relapse/progression (months) 
Other Baseline characteristics that will be summarized are: 
• 
Albumin (<35 g/L and ≥35 g/L) 
• 
Baseline LDH (<1.5 x ULN and ≥1.5 x ULN) 
• 
Creatinine Clearance <45 mL/min, ≥45 – 60 mL/min, ≥60 – 90 mL/min, ≥90 mL/min) 
• 
Beta 2 Microglobulin (<3.5 mg/L, ≥3.5 - 5.5 mg/L, >5.5 mg/L) 
• 
Platelets (<75, ≥75-100 109 /L, >100- 150 109/L, >150 109/L) 
• 
Hemoglobin (<80, ≥80 - 100 g/L and >100 g/L)  
• 
ANC (<1.0 109/L, ≥1.0-1.5 109 /L, and >1.5 109 /L) 
• 
ECOG (0, 1, 2, 3, 4) 
The information collected on the ‘Multiple Myeloma Status at Diagnosis’ eCRF page will be presented in a 
similar way in a separate table. 


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The following variables for the bone marrow assessments, obtained from the ‘Cytogenetic Abnormalities at 
Study Entry – FISH’ and ‘Cytogenetic Abnormalities at Study Entry - Karyotype’ eCRF pages, will be 
summarized descriptively by dose level and regimen:  
• 
Was Cytogenetics performed by FISH at study entry? [Yes, No, Unknown] (from the ‘Multiple 
Myeloma Status at Study Entry’ eCRF page) 
• 
Cytogenetics performed by FISH Abnormalities at study entry [t(4; 14), t(4;14) (p16;q32) etc…]   
• 
Cytogenetics identified by FISH (High-risk, Standard risk, Unknown);- High-risk group: consist of 
subjects that have cytogenetics performed by FISH at study entry, where abnormalities have 
been found as such: genetic subtype t(4; 14), t(14:16), have deletion 17p, presence of gain 1q, 
t(14;20) or presence of hypodiploidy. 
- Standard-risk group: consists of subjects that have cytogenetics performed by FISH at study 
entry were abnormalities selected are not high-risk features. 
- Unknown risk group: consists of subjects with procedure being not done or failed. Cytogenetics 
performed is ‘No’ or ‘Unknown’. 
• 
Was Cytogenetics performed by Karyotype at study entry? [Yes, No, Unknown] (from the ‘Multiple 
Myeloma Status at Study Entry’ eCRF page) 
• 
Cytogenetics performed by Karyotype Abnormalities at study entry [t(4; 14), t(4;14) (p16;q32) etc]   
• 
Cytogenetics identified by Karyotype (High-risk, Standard risk, Unknown); 
- High-risk group: consist of subjects that have cytogenetics performed by Karyotype at study 
entry, were abnormalities have been found as such: consists of subjects who have presence of 
del(13)  
- Standard risk group: consists of subjects that have cytogenetics performed by Karyotype who 
have absence of del(13) 
- Unknown risk group: consists of subjects with procedure being not done or failed. Cytogenetics 
performed is ‘No’ or ‘Unknown’ 
• 
Cytogenetics identified by FISH and Karyotype (High-risk, Standard risk, Unknown); 
- High-risk group: Consists of patients with at least 1 of any of the high-risk factors by either FISH 
or Karyotype 
- Standard-risk group: Both procedures performed but none of the high-risk features are present. 
- Unknown risk group: Both procedures were not done or failed, or only one was performed and 
the results did not indicate the patient was high-risk. 
• 
Multi-high risk identified by FISH and Karyotype 
- High risk patients are identified as for the combined group in the previous bullet but at least 2 of 
the identifiers were met. 
• 
Bone marrow Plasma Cell Involvement (%) [descriptive statistics] 
The information collected on the ‘Cytogenetic Abnormalities at Diagnosis – FISH’ and ‘Cytogenetic 
Abnormalities at Diagnosis – Karyotype’ eCRF pages will be presented in a similar way in a separate table. 
All summaries will be provided for the safety analysis set. 
All demographic and baseline disease characteristic data will be provided in a listing. 
12.4.3 Prior Treatment for Multiple Myeloma 
Prior medications are coded using version WHODrug DDE B3 Mar_2019 or later.  
The following information will be summarized by dose level and regimen for the safety analysis set: 
• 
Number and percentage of patients with at least one transplant (Autologous and Allogeneic) 
• 
Number and percentage of patients with a tandem transplant [Yes, (Autologous-Autologous, 
Allogeneic-Allogeneic, Autologous-Allogeneic, Allogeneic-Autologous), No] 


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• 
Time from frontline transplant to relapse (continuous and categorical [<1 year, ≥1 year - <1.5 years, 
≥1.5 years - <2 years, ≥2 years] 
• 
Number and percentage of patients with a salvage transplant (defined as any transplant where the 
patient has already had 1 or more transplants in earlier lines (planned tandem or double transplants 
are considered one transplant)) 
• 
Type of salvage transplant (Autologous and Allogeneic) 
• 
Number and percentage of patients with a tandem transplant as part of salvage transplant [Yes, 
(Autologous-Autologous, Allogeneic-Allogeneic, Autologous-Allogeneic, Allogeneic-Autologous), 
No]; 
• 
Number of prior regimens (continuous and categorical [1,2,3,4,>4]) 
• 
Best response to last prior regimen 
• 
Refractory status to last prior regimen 
• 
Number and percentage of patients with a prior regimen that has an agent in the categories defined 
in Section 8.6 
• 
Number and percentage of patients with an agent in the categories defined in Section 8.6, in most 
recent prior regimen 
• 
Patients refractory to any prior agent 
• 
Patients refractory to agent in at least one prior regimen 
• 
Patients refractory to agent in last prior regimen 
• 
Patients double refractory (refractory to both Proteasome inhibitors and Immunomodulatory drugs) 
12.4.4 Medical and Surgical History 
Medical and surgical history will be coded according to MedDRA dictionary version 23.0 or later. Summaries 
will be presented by dose level, regimen, SOC and PT for the safety analysis set. 
12.4.5 Prior and Concomitant Medications 
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) classification codes 
and preferred drug names from version March 2019 of WHO DD version or later.  
The medication data will be summarized descriptively for the safety analysis set, by study dose level, 
regimen, ATC level 2, ATC level 4 and preferred term. 
Medications with a stop date before the first date of study medication will be considered prior 
medications. Medications with start date or stop date on or after the first date of study medication and the 
start date is before the date of the last dose + 30 days, or are ongoing at the time of first dose, will be 
considered concomitant medications. The prior and concomitant medications will be summarized 
separately. For handling of partial dates, please refer to Section 8.13. 
12.4.6  Concomitant Procedures 
Medications identified as procedures via the question ‘Is this a procedure?’ will be classified using the 
version 23.0 or later of the MedDRA dictionary. 
These will be presented in a separate listing.  


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13 Treatments 
13.1.1 Extent of Study Drug Exposure 
13.1.1.1 Exposure to Melflufen, Bortezomib, Dexamethasone and Daratumumab 
Exposure will be based on the safety analysis set. 
The overall treatment duration as defined in Section 8.7.1 along with the number of cycles that any study 
drug was taken and the number of patients taking any study drug in each cycle will be presented 
descriptively by dose level and regimen. In addition, the extent of exposure of melflufen, bortezomib, 
dexamethasone and daratumumab separately will be presented by dose level and regimen. 
The median follow-up time from Cycle 1, Day 1 to data cut-off or end of study will also be presented in 
months as per derivation in Section 8.7.1. 
The extent to exposure of melflufen, bortezomib, dexamethasone and daratumumab will be characterized 
by: 
• 
Total cumulative dose administered (mg) (continuous) 
• 
Time on treatment (weeks) (continuous) 
• 
Relative dose intensity (%) (continuous) 
• 
Relative dose intensity by cycle (%) (continuous) 
• 
Average relative dose intensity for melflufen (%) (continuous)  
• 
Total number of treated cycles (continuous and categorical) 
• 
Average dose of melflufen (mg/week) (continuous) 
• 
Average duration of infusion of melflufen (min) (continuous) 
• 
Total planned dose (mg) (continuous) 
 
Frequency counts and percentages will be presented for the length of delay (relative to the last cycle) for 
each cycle and for each drug. 
Extent of exposure will be provided in a separate listing. 
13.1.2 Dose Modification 
The action taken on melflufen, daratumumab, bortezomib and dexamethasone (No action taken, dose 
reduced, dose held, dose delayed, permanently discontinued, other) will be summarized overall (all (any) 
study drug/all cycles), overall and by cycle for each treatment. This will be presented by dose and regimen.  
A separate, similar summary will be presented showing only modifications for when the reason for action 
taken is AE. 
A summary of modifications due to COVID-19, identified through search of ‘COVID’ in the reason for action 
taken ‘Other – specify’ text field on the eCRF. 
14 Efficacy Analyses 
Efficacy data will be summarized by dose level and regimen, for patients in the efficacy analysis set and by 
dose level and regimen for the safety analysis set (as specified). 
14.1 Primary Endpoint 
Phase 2a 
The primary endpoint of Phase 2a is the overall response rate (sCR, CR, VGPR, PR) observed in patients 
treated at the optimal dose of melflufen in combination therapy according to IMWG -URC in the efficacy 
analysis set.  
 


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A summary of the confirmed best overall response (sCR, CR, VGPR, PR, MR, SD, PD, NE) as 
determined by the investigator according to the IMWG-URC  (Rajkumar et al, 2011) will be presented 
without analysis. The ORR will also be presented. The exact binomial 95% confidence interval (CI) for 
ORR as well as for the separate best response categories of sCR, CR, VGPR and PR will be calculated 
for each treatment regimen and dose level. 
 
This analysis will be presented for patients in the efficacy analysis set and repeated for the safety 
analysis set. 
The above analysis will be repeated based on the best unconfirmed response, as determined by the 
investigator. 
 
A listing for myeloma response assessment will be provided. 
14.1.1 Sensitivity Analysis – Primary Endpoint 
In order to assess the impact of COVID-19 pandemic the following additional analysis will be conducted for 
the safety analysis set by dose level and regimen: 
1) For patients who have an AE of COVID-19, only response assessments up to the start date of the 
COVID-19 AE will be included. 
2)  Unconfirmed responses on or after the date of WHO declared COVID-19 as a pandemic (11th     
             March 2020) will be evaluated as confirmed until WHO declare it to be over. 
14.2 Secondary Endpoints 
14.2.1 Progression Free Survival 
PFS is measured from the date of initiation of therapy to the date of documented disease progression or 
death. PFS will be right-censored according to the following conventions: 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of new anticancer therapy 
Censored 
Death or PD immediately after more than 
1 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is before 
the first missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
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 
 
These conventions are based on the May 2007 Food and Drug Administration (FDA) Guidance for 
Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics’. 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071590.p
df) 
The number of PFS events, the number of censored events and the reasons for censoring will be presented 
by dose level and regimen and the distribution of PFS will be summarized and plotted for each dose level 
and regimen using the Kaplan-Meier (K-M) method. The median PFS along with the first and third quartiles 
will be estimated for each treatment dose and regimen from the 25th, 50th and 75th percentiles of the 


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corresponding K-M estimates. The 95% CIs for median PFS along with the quartiles will be constructed 
using the method of Brookmeyer (Brookmeyer & Crowley, 1982)(. Duration of follow-up for PFS will be 
summarized according to the K-M estimate of potential follow-up also termed “reverse Kaplan-Meier” 
(Schemper & Smith, 1996). 
This analysis will be presented for the safety analysis set and repeated for the efficacy analysis set. A listing 
of progression free survival times will be provided. 
14.2.1.1 Sensitivity Analysis –  Progression Free Survival 
In order to evaluate the effect of the COVID-19 pandemic the following sensitivity analysis will be performed 
based on the safety analysis set. 
Regional restrictions due to the COVID-19 pandemic may have caused delays in response assessments 
regardless of whether a patient contracted COVID-19. The following three sensitivity analyses with modified 
censoring conventions will be performed on the analysis of PFS to assess the impact of delays in myeloma 
response assessments.  
Sensitivity analysis 1-  >2 Consecutively Missed Myeloma Response Assessments 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of new anticancer therapy 
Censored 
Death or PD immediately after more than 
2 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is before 
the first missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
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 
 
Sensitivity analysis 2->3 Consecutively Missed Myeloma Response Assessments 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of new anticancer therapy 
Censored 
Death or PD immediately after more than 
3 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is before 
the first missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
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 
 


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Sensitivity analysis 3- Discontinued Study due to COVID-19 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of new anticancer therapy 
Censored 
Death or PD immediately after more than 
1 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is before 
the first missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
Unconfirmed PD as the final response 
assessment and no record of COVID-19 
related study discontinuation 
Date of latest PD assessment 
Progressed 
Patient discontinued study due to COVID-
19 with an unconfirmed PD as the final 
response assessment 
Date of study discontinuation 
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 
 
To further assess the impact of patients who contracted or potentially contracted COVID-19, the following 
censoring conventions will be applied for additional sensitivity analysis. 
Sensitivity analysis 4- COVID-19 Fatal Adverse Event 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of new anticancer therapy 
Censored 
Death or PD immediately after more than 
1 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is before 
the first missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
COVID-19 fatal adverse event (identified 
using the criteria specified in Section 
8.9.8) 
AE start date 
Censored 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
Death (other than COVID-19 fatal 
adverse events)  or PD between planned 
disease assessments 
Date of death or first disease assessment 
showing PD, whichever occurs first 
Progressed 
Death (other than COVID-19 fatal 
adverse events) before first disease 
assessment 
Date of death 
Progressed 
 


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Sensitivity analysis 5- COVID-19 Adverse Event 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease assessments, 
except in the case of death 
Date of initiation of therapy 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior to 
start of new anticancer therapy 
Censored 
Death or PD immediately after more than 
1 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
without documentation of PD that is before 
the first missed visit 
Censored 
Alive and without PD documentation 
Date of last disease assessment 
Censored 
COVID-19 adverse event prior to PD 
(identified using the criteria specified in 
Section 8.9.8) 
Date of AE start date 
Censored 
Unconfirmed PD as the final response 
assessment 
Date of latest PD assessment 
Progressed 
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 
14.2.2 Other Efficacy Endpoints 
DOR will be calculated for patients who achieve a confirmed response of PR of better. Dates of progression 
or censoring will be determined as described for the analysis of PFS in Section 14.2.1. Distribution of DOR 
will be summarized for each regimen and dose level using the Kaplan-Meier method as described for the 
analysis of PFS.  
The same COVID-19 pandemic-related sensitivity analysis described for PFS will also be performed for 
DOR using the safety analysis set.  
DCB will be calculated for patients who achieve a confirmed response of MR or better. Dates of progression 
or censoring will be determined as described for the analysis of PFS in Section 14.2.1. Distribution of DCB 
will be summarized for each regimen and dose level using the Kaplan-Meier method as described for the 
analysis of PFS. 
OS is defined as time (months) from the date of initiation of therapy to date of death due to any cause. 
Patients who are alive will be censored at the last follow-up visit. The analysis of OS will be performed by 
the Kaplan-Meier method as for PFS. 
Sensitivity analysis 4 and 5 which refer to patients who contracted or potentially contracted COVID-19 
adverse events will also be applied to OS for the safety analysis set. Patients with COVID-19 fatal adverse 
event will be censored as date of AE start date. Those with COVID-19 adverse events prior to PD will be 
censored to date of AE start date. 
A summary of the CBR will be presented without analysis. The exact binomial 95% CI for CBR will be 
calculated for each treatment regimen and dose level. This analysis will be repeated based on the best 
unconfirmed response, as determined by the investigator. 
 
TTP and TTNT, will be summarized using the same methods as for PFS. TTR will be summarized 
descriptively. 
All secondary endpoints will be summarized primarily using the safety analysis set and ORR, DOR and 
CBR will be repeated using the efficacy analysis set. 


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Additional exploratory sub-analysis may be conducted to identify sub populations that may benefit from 
therapy or to clearly define the safety profile and efficacy more clearly and/or to correlate biomarkers with 
clinical outcomes. 
14.3 Exploratory Endpoints 
14.3.1 Minimal Residual Disease 
The number and rate of positive and negative MRD evaluations will be summarized without analysis for 
patients who achieve a CR for each treatment regimen and dose level separately. 
To evaluate the diagnostic value of bone marrow aspirate in the detection of negative MRD, sensitivity 
assessments are conducted.  For patients with negative MRD, the following bone marrow test parameters  
from the same assessment will be presented in the listing: Plasma cells (%).   
14.3.2 Pharmacokinetics (PK) 
 All PK parameters provided by the PK program for melphalan are listed in Table 1: PK Parameters to be 
calculated. The derivation of PK parameters is done by the Pharmacokineticist. All parameters will be 
presented in a listing in minimum.  
Table 1: PK Parameters to be calculated 
Phoenix WinNonLin ID 
Unit 
Parameter code 
CDISC submission value 
Rsq 
R2 
R Squared 
Rsq_adjusted 
R2ADJ 
R Squared Adjusted 
Corr_XY 
CORRXY 
Correlation Between TimeX and Log ConcY 
No_points_lambda_z 
LAMZNPT 
Number of Points for Lambda z 
Lambda_z 
min 
LAMZ 
Lambda z 
Lambda_z_int 
ng/mL 
LAMZINT 
Lambda z Intercept  
Lambda_z_lower 
min 
LAMZLL 
Lambda z Lower Limit 
Lambda_z_upper 
min 
LAMZUL 
Lambda z Upper Limit 
Lambda_z_span 
min 
LAMZSPN 
Lambda z Span  
*HL_Lambda_z 
min 
LAMZHL 
Half-Life Lambda z 
Tmax 
min 
TMAX 
Time of CMAX 
*Cmax 
ng/mL 
CMAX 
Max Conc 
Cmax_D 
ng/mL/mg 
CMAXD 
Max Conc Norm by Dose 
Tlast 
min 
TLST 
Time of Last Nonzero Conc 
Clast 
ng/mL 
CLST 
Last Nonzero Conc 
Clast_pred 
ng/mL 
CLSTP 
Last Nonzero Conc Pred  
AUClast 
min*ng/mL 
AUCLST 
AUC to Last Nonzero Conc 
AUClast_D 
min*ng/mL 
AUCLSTD 
AUC to Last Nonzero Conc Norm by Dose  
AUCall 
min*ng/mL 
AUCALL 
AUC All 
*AUCINF_obs 
min*ng/mL 
AUCIFO 
AUC Infinity Obs 
AUCINF_D_obs 
min*ng/mL/mg 
AUCIFOD 
AUC Infinity Obs Norm by Dose 


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Phoenix WinNonLin ID 
Unit 
Parameter code 
CDISC submission value 
AUC_%Extrap_obs 
% 
AUCPEO 
AUC %Extrapolation Obs 
Vss_obs 
L 
VSSO 
Vol Dist Steady State Obs  
Vz_obs 
L 
VZO 
Vz Obs  
Cl_obs 
L/min 
CLO 
Total CL Obs 
AUCINF_pred 
min*ng/mL 
AUCIFP 
AUC Infinity Pred 
AUCINF_D_pred 
min*ng/mL/mg 
AUCIFPD 
AUC Infinity Pred Norm by Dose 
AUC_%Extrap_pred 
% 
AUCPEP 
AUC %Extrapolation Pred 
Vss_pred 
L 
VSSP 
Vol Dist Steady State Pred  
Vz_pred 
L 
VZP 
Vz Pred  
Cl_pred 
L/min 
CLP 
Total CL Pred 
AUMClast 
min*min*ng/mL 
AUMCLST 
AUMC to Last Nonzero Conc 
AUMCINF_obs 
min*min*ng/mL 
AUMCIFO 
AUMC Infinity Obs 
AUMC_%Extrap_obs 
% 
AUMCPEO 
AUMC % Extrapolation Obs 
AUMCINF_pred 
min*min*ng/mL 
AUMCIFP 
AUMC Infinity Pred 
AUMC_%Extrap_pred 
% 
AUMCPEP 
AUMC % Extrapolation Pred 
MRTlast 
min 
MRTIVLST 
MRT Intravasc to Last Nonzero Conc 
MRTINF_obs 
min 
MRTIVIFO 
MRT Intravasc Infinity Obs 
 MRTINF_pred 
min 
MRTIVIFP 
MRT Intravasc Infinity Pred 
* Summarized with descriptive statistics as continuous variables and with the geometric mean and 
geometric coefficient of variation. 
  
Cmax will be presented with the same number of decimals as the concentration measurements and time 
points, while the derived PK variables will be presented with an appropriate number of significant digits 
based on the general practice.  
Descriptive statistics for drug concentrations by time point and PK variables will be provided for melphalan 
by cycle, dose and regimen. For Cmax, AUC(0-∞),  and t½ arithmetic mean ± standard deviation, geometric 
mean with coefficient of variation, median with minimum and maximum will be given. Other PK parameters 
will provided in a listing. 
A mean value graph (with arithmetic means) by cycle, dose and regimen will be generated for melphalan 
concentrations in plasma from all subjects based on planned time (min) relative to start of melflufen 
infusion.  


Statistical Analysis Plan 
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15  Safety Analyses 
All safety results will be presented for the safety analysis set and by actual treatment. No formal statistical 
analysis will be performed for the safety endpoints. Safety endpoints will be presented by dose level and 
regimen.  
15.1 Adverse Events 
All AEs will be coded to a primary system organ class (SOC) and preferred term (PT) using MedDRA 
version 23.0 dictionary or later. 
An overall summary of TEAEs will be provided showing the number and percentage of patients for the 
following: 
• 
Any TEAEs 
• 
Any Grade 3 or Higher TEAEs 
• 
Any treatment-related TEAEs (relationship to any treatment and relationship to individual 
treatments) 
• 
Any TEAEs in Phase 1 
• 
Any TEAEs in Phase 2 
• 
Any Grade 3 or Higher treatment-related TEAEs 
• 
Any serious TEAEs 
• 
Any non-serious TEAEs 
• 
Any treatment-related serious TEAEs 
• 
Any TEAE leading to discontinuation of study treatment 
• 
Any COVID-19 TEAE leading to discontinuation of study treatment 
• 
Any TEAE leading to modification (reduction or interruption) of study treatment 
• 
Any TEAEs leading to Death 
• 
Grouped terms for neutropenia, thrombocytopenia, myelodysplastic syndrome and secondary 
primary malignancies  as defined in Section 8.9.6 
• 
Any grade 3 or 4 grouped terms for neutropenia, thrombocytopenia, myelodysplastic syndrome and 
secondary primary malignancies as defined in Section 8.9.6 
The number and percentage of patients who experience at least one TEAE will be summarized by SOC 
and PT for the following types of events: 
• 
Any TEAE 
• 
Any TEAEs in Phase 1 
• 
Any TEAEs in Phase 2 
• 
Any TEAE by maximum CTCAE Grade (Grade 1- Grade 5) 
• 
Any treatment-related (overall, melflufen, daratumumab, bortezomib and dexamethasone) TEAE 
• 
Any treatment-related (overall, melflufen, daratumumab, bortezomib and dexamethasone) by 
maximum CTCAE Grade (Grade 1-Grade 5) 
• 
Any treatment-emergent SAE 
• 
Any treatment-emergent non-SAE 


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• 
Any treatment-related (overall, melflufen, daratumumab, bortezomib and dexamethasone) 
treatment-emergent SAE 
• 
Any TEAE resulting in dose modification of study drug (drug interrupted, dose reduced) (any, 
melflufen, daratumumab, bortezomib, and dexamethasone) 
• 
Any TEAE leading to permanent discontinuation of study drug 
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 to 
any study drug, will be summarized in the same way. The number and percent of patients who experience 
a grouped AE will be summarized for each treatment regimen and dose level. 
All AEs will be listed. 
In all AE summaries data will be ordered by decreasing frequency in the overall population by SOC and PT 
within SOC.  
For all summaries of treatment-related and dose modification, each study drug (melflufen, daratumumab, 
bortezomib and dexamethasone) will be presented separately and overall. 
Furthermore, infections with an onset date within +/- 7 days of the onset and/or resolution date of Grade 3 
or 4 ANC, will be summarized by SOC and PT. A listing will also be provided. 
An additional summary of all deaths (based on the Patient Death eCRF page) will be presented, regardless 
of treatment emergence. Summaries will include death prior to first dose (based on the safety analysis set), 
deaths that occurred ≤30 and >30 days after last dose of study treatment, deaths ≤60 days after first dose 
(early deaths), related/non-related deaths to study drug and primary cause of death. Overall counts will be 
provided, and events will also be presented by SOC and PT. 
A corresponding listing of deaths will be provided.  
Furthermore, the number of subjects diagnosed with a second primary malignancy in overall survival follow-
up will be presented (based on the Overall Survival eCRF page).  
15.1.1 Laboratory Data 
All clinical laboratory parameters will be converted to consistent units according to the International System 
of Units (SI) before summarization and the baseline measurement will be the last measurement taken prior 
to first study drug administration. 
Shift tables will be presented based on CTCAE criteria, using Grade 1 – Grade 4 as well as Grade 0 
indicating no abnormality. For some laboratory parameters, deviations from the normal range in both 
directions (either above or below) are of interest; these parameters are shown in Table 2: Direction of 
abnormality of lab parameters. In such cases, the parameter will be summarized by direction of abnormality. 
Table 2: Direction of abnormality of lab parameters 
Category  
Parameter  
Direction of Worst Value  
Hematology  
Hemoglobin  
Decrease  
Leukocytes   
Increase and Decrease  
Neutrophils  
Decrease  
Platelets  
Decrease  
Lymphocytes  
Increase and Decrease  
Chemistry   
ALT  
Increase  
AST  
Increase  


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Category  
Parameter  
Direction of Worst Value  
Albumin  
Decrease  
Alkaline phosphatase  
Increase  
  
Calcium  
Increase and Decrease  
  
Creatinine  
Increase  
  
Glucose  
Increase and Decrease  
 
Magnesium 
Decrease 
  
Phosphate  
Decrease  
  
Potassium  
Increase and Decrease  
  
Sodium  
Increase and Decrease  
  
Bilirubin  
Increase  
 
• 
Numeric parameters: Actual values and change from baseline for each parameter will be 
summarized with descriptive statistics by visit, including a separate summary for the last on-
treatment measurement. 
• 
Categorical laboratory parameters: The distribution of the categories will be summarized by visit. 
• 
Parameters for which there are NCI-CTCAE Grades defined: The shift from baseline to the worst 
grade on-treatment will be presented.  
• 
Neutrophils and Platelets will be presented by maximum CTCAE toxicity grade (Grade 1-Grade 5) 
and cycle (1,2,3,4,5 etc.). 
• 
Number of Grade ≥ 3 Neutrophils and Platelets events by cycle will be presented.  
Myeloma-Specific lab tests, Hepatitis B, Urinalysis, Bone marrow aspirate and biopsy results and change 
from baseline will be listed 
15.1.2 Vital Signs and Body Surface Area 
All vital sign data will be listed for the safety analysis set. Parameters include: Body surface area (m2), 
Diastolic blood pressure (DBP) (mmHg), Height (cm), Pulse rate (beats/min), Respiratory rate 
(breaths/min), Systolic blood pressure (SBP) (mmHg), Temperature (C) and Weight (kg).  


Statistical Analysis Plan 
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Protocol no: OP-104 
 
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15.1.3 Physical Examinations, ECGs, and Other Observations Related to Safety 
Listings will also be provided for the following safety assessments using the safety analysis set: 
• 
Pregnancy test summary 
• 
Electrocardiogram (ECG) 
• 
Complete physical examination 
• 
Direct physical examination 
• 
ECOG results 
• 
Chest X-ray 
• 
Pulmonary function testing 
Results from the extramedullary plasmacytoma evaluation and the bone lesion assessment will be listed. 
16 Validation 
 goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our quality control 
procedures will be documented separately in the study specific quality control plan.  
17 References 
Anderson, K. C., Kyle, R. A., Rajkumar, S. V., Stewart, A. K., Weber, D., & Richardson, P. (2008, Feb). 
Clinically relevant end points and new drug approvals for myeloma. Leukemia, 2, 231-239. 
Brookmeyer, R., & Crowley, J. (1982). A Confidence Interval for the Median Survival Time. Biometrics, 
29-41. 
Mosteller, R. D. (1987). Simplified calculation of body-surface area. The New England journal of 
medicine, 317:1098. 
Palumbo, A., Avet-Loiseau, H., & Oliva, S. (2015). Revised International Staging System for Multiple 
Myeloma: A Report from International Myeloma Working Group. Journal of Clinical Oncology, 
2863-2869. 
Rajkumar, S. V., Harousseau, J. L., & Durie, B. e. (2011). Consensus Recommendations for the Uniform 
Reporting of Clinical Trials:Report of the International Myeloma Workshop. Blood, 117(18):4691-
4695. 
Schemper, M., & Smith, T. L. (1996). A Note on Quantifying Follow-up in Studies of Failure Time. 
Controlled Clinical Trials, 343-346. 
Sonneveld, P., Avet-Loiseau, H., & Lonial, S. (2016). Treatment of Multiple Myeloma with high-risk 
cytogenetics: a consensus of the International Myeloma Working Group. Blood, 2955-2962. 
 
 
 
 
 
 


Statistical Analysis Plan 
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Protocol no: OP-104 
 
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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse event 
ATC 
Anatomic therapeutic classification 
BSA 
Body surface area 
CBR 
Clinical benefit rate 
CRF/eCRF 
Case report form/electronic case report form 
CR 
Complete response 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of variation 
DD 
Drug dictionary 
DIRA 
Daratumumab interference reflex assay 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DSMC 
Data safety monitoring committee 
ECG 
Electrocardiogram 
HLT 
Higher level term 
IMiD 
Immunomodulatory drug 
IMWG-URC  
International myeloma working group uniform response criteria 
ISS 
International staging system 
IVRS 
Interactive voice response system 
i.v. 
Intravenously 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical dictionary for regulatory activities 
MM  
Multiple myeloma 
MR 
Minimal response 
MRD 
Minimal residual disease 
MTD 
Maximum tolerated dose 
NCI 
National cancer institute 
ORR 
Best objective response 
OS 
Overall survival 
PD 
Progressive disease 


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PFS 
Progression free survival 
PI 
Proteasome inhibitors 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Preferred term 
R-ISS 
Revised international staging system 
RRMM 
Relapsed refractory multiple myeloma 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SDG 
Standardized drug groupings 
sFLC 
Serum free light chain 
SI  
International system of units 
SOC 
System organ class 
SPEP 
Serum protein electrophoresis 
TEAE 
Treatment emergent adverse event 
TTNT 
Time to next treatment 
TTP 
Time to progression 
TTR 
Time to response 
UPEP 
Urine protein electrophoresis 
VGPR 
Very good partial response 
WHO 
World health organization 


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Appendix 2 Tables, Figures, Listings, and Supportive SAS Output 
Appendices 
The TOC and TFL shells will be provided in a separate document.