A Phase 1/2 Open-label Study to Investigate the Safety and Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of Modakafusp Alfa (TAK-573) as a Single Agent in Patients With Relapsed Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Teva Branded Pharmaceutical Products R&D LLC



 
PROTOCOL 
A Phase 1/2 Open-label Study to Investigate the Safety and Tolerability, Efficacy, 
Pharmacokinetics, and Immunogenicity of Modakafusp Alfa (TAK-573) as a Single Agent 
in Patients With Relapsed Refractory Multiple Myeloma 
A Safety and Preliminary Efficacy, Pharmacokinetics, and Immunogenicity Study 
 
Sponsor: 
Takeda Development Center Americas, Inc 
95 Hayden Avenue 
Lexington, MA 02421 USA 
Study Number: 
TAK-573-1501  
IND Number: 
130,756 
 
Abbreviated EudraCT Number:  
2021-006038 
 
Compound: 
Modakafusp Alfa (TAK-573)  
Amendment Date:  
03 April 2024 
Amendment Number: 
10 v2 
 
Amendment History: 
Date 
Amendment Number 
Region 
03 April 2024 
Amendment 10 v2 
Global 
26 February 2024 
Amendment 10 v1 (not implemented) 
Global 
02 August 2023 
Amendment 9 
Global 
10 February 2023 
Amendment 8 CH v1 
Local China 
12 July 2022 
Amendment 8 NO v1 
Local Norway 
23 June 2022 
Amendment 8 GB v1 
Local United Kingdom 
01 March 2022 
Amendment 8 
Global 
25 October 2021 
Amendment 7 (not implemented) 
Global  
16 October 2020 
Amendment 6 
Global 
03 July 2019 
Amendment 5 
Global 
22 October 2018 
Amendment 4 
Global 
29 June 2018 
Amendment 3 
Global 
07 November 2017 
Amendment 2 
Global 
05 April 2017 
Amendment 1 
Global 
14 December 2016 
Initial protocol 
Global 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 

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CONFIDENTIAL 
1.0 
ADMINISTRATIVE 
1.1 
Contacts 
A separate study contact list will be provided to each site. 
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.  
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines are 
provided to the site. 
Contact Type/Role 
United States Contact 
Serious adverse event and pregnancy reporting 
See Section 10.0 
 

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CONFIDENTIAL 
1.2 
Approval  
REPRESENTATIVES OF TAKEDA  
This study will be conducted with the highest respect for the individual study participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
SIGNATURES  
The signature of the responsible Takeda medical officer and other signatories, as applicable can 
be found on the signature page. 
Electronic Signatures may be found on the last page of this document. 
 
 
 
  
 
, MD (or designee) 
, 
 
Date 
, MD (or designee) 
, 
Clinical Study Lead 
Date 

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CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
• Responsibilities of the Investigator (Appendix D). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix E of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
 

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CONFIDENTIAL 
1.3 
Protocol Amendment 10 v2 Summary of Changes 
Protocol Amendment 10 v2 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 10 v2. 
The primary reason for this amendment was to implement new dose modification guidelines in 
cases of bleeding treatment-emergent adverse events (TEAEs) as an urgent safety measure to 
mitigate the risk of fatal hemorrhagic events in response to the observation of a suspected 
unexpected serious adverse reaction (SUSAR) in this study. 
New dose modification guidelines have been added to this protocol. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
A summary of changes for all prior protocol amendments is found in Appendix J. 
Protocol Amendment 10 v2 
Summary of Changes Since the Last Implemented Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
1.  
8.4.3 Criteria for Treatment 
Interruption and Dose Reductions 
Specified that “Patients experiencing AEs 
attributed to modakafusp alfa may continue study 
treatment with the same dose, may have 
modakafusp alfa treatment held, dose reduced, 
discontinued, or may be permanently 
discontinued from the study.” 
Specified that “Patients who have study drug held 
because of treatment-related or possibly related 
AEs may resume study drug treatment after 
resolution of the AE at the same dose level or at a 
reduced dose, depending on the nature and 
severity of the AE and whether it is the first 
occurrence or is recurrent unless otherwise 
specified in the protocol” 
Addition of Table 8.e with the dose modifications 
for modakafusp alfa bleeding TEAEs for Parts 1, 
2, and 3. 
Updates to the table captions for Table 8.a, 
Table 8.b, and Table 8.c to indicate guidance for 
management of bleeding TEAEs and IRRs. 
Subheadings for the management of dose 
modifications were added by study part: Parts 1 
and 2; Part 3; and Parts 1, 2, and 3. 
Updated to 
mitigate the 
risk of fatal 
hemorrhagic 
events. 
2.  
8.4.4 Criteria for Discontinuing 
Modakafusp Alfa 
Removal of text related to bleeding TEAEs that 
was present in prior versions of the protocol. 
This section was previously labeled as “Part 3”, 
as numbered. This has been removed and this 
section has been re-named accordingly. 
Updated to 
align with 
changes 
made in this 
protocol 
amendment. 

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CONFIDENTIAL 
Protocol Amendment 10 v2 
Summary of Changes Since the Last Implemented Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
3.  
8.6.3 Other Permitted Concomitant 
Medications and Procedures 
Added “Platelet transfusion should not be applied 
only for the purpose of meeting the treatment 
criterion of platelet count to start a new cycle.” 
Updated to 
align with 
changes 
made in this 
protocol 
amendment. 
4.  
8.7.1.2 Handling of Low Platelet 
Counts 
Addition of mention to reference Table 8.e with 
the dose modifications for modakafusp alfa 
bleeding TEAEs 
Updated to 
mitigate the 
risk of fatal 
hemorrhagic 
events. 
 

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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE ...........................................................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 10 v2 Summary of Changes........................................................5 
2.0 
STUDY SUMMARY.........................................................................................................14 
3.0 
STUDY REFERENCE INFORMATION .........................................................................23 
3.1 
Study-Related Responsibilities ....................................................................................23 
3.2 
Principal Investigator ...................................................................................................23 
3.3 
Committees in Part 3 Dose Extension .........................................................................23 
3.3.1 Independent Review Committee ............................................................................23 
3.3.2 Independent Data Monitoring Committee .............................................................23 
3.4 
List of Abbreviations ...................................................................................................24 
4.0 
INTRODUCTION .............................................................................................................27 
4.1 
Multiple Myeloma .......................................................................................................27 
4.2 
Modakafusp Alfa Targets ............................................................................................27 
4.3 
Modakafusp Alfa .........................................................................................................29 
4.4 
Findings From Nonclinical and Toxicology Studies ...................................................30 
4.4.1 Nonclinical Studies ................................................................................................30 
4.4.2 Toxicology Studies ................................................................................................30 
4.5 
Known and Potential Benefits and Risks of Modakafusp Alfa ...................................30 
4.5.1 Nonclinical Safety Summary .................................................................................30 
4.5.2 Clinical Safety ........................................................................................................31 
4.6 
Rationale for the Proposed Study ................................................................................31 
4.6.1 Rationale for the Part 1 Starting Dose of Modakafusp Alfa ..................................32 
4.6.2 Rationale for Part 3 ................................................................................................32 
4.6.3 Changes to Modakafusp Alfa Infusion ..................................................................37 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................37 
5.1 
Part 1 Dose Escalation Objectives ...............................................................................37 
5.1.1 Part 1 Primary Objective ........................................................................................37 
5.1.2 Part 1 Secondary Objectives ..................................................................................37 
5.1.3 Part 1 Exploratory Objectives ................................................................................37 
5.2 
Part 2 Dose Expansion Objectives ...............................................................................38 
5.2.1 Part 2 Primary Objective ........................................................................................38 
5.2.2 Part 2 Secondary Objectives ..................................................................................38 

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5.2.3 Part 2 Exploratory Objectives ................................................................................38 
5.3 
Part 3 Dose Extension Objectives ................................................................................38 
5.3.1 Part 3 Primary Objective ........................................................................................38 
5.3.2 Part 3 Secondary Objectives ..................................................................................38 
5.3.3 Part 3 Exploratory Objectives ................................................................................39 
5.4 
Endpoints .....................................................................................................................39 
5.4.1 Part 1 Dose Escalation Endpoints ..........................................................................39 
5.4.2 Part 2 Expansion Endpoints ...................................................................................41 
5.4.3 Part 3 Extension Endpoints ....................................................................................42 
6.0 
STUDY DESIGN...............................................................................................................43 
6.1 
Overview of Study Design ...........................................................................................43 
6.2 
Number of Patients ......................................................................................................48 
6.3 
Duration of Study .........................................................................................................48 
6.3.1 Duration of an Individual Patient’s Study Participation ........................................48 
6.3.2 End of Study/Study Completion Definition and Planned Reporting .....................49 
6.3.3 Timeframes for Primary and Secondary Endpoints to Support Disclosures .........49 
6.3.4 Total Study Duration..............................................................................................50 
6.3.5 Posttrial Access ......................................................................................................51 
6.4 
Randomization in Phase 2 Part 3 Extension ................................................................51 
7.0 
STUDY POPULATION ....................................................................................................52 
7.1 
Inclusion Criteria .........................................................................................................52 
7.2 
Exclusion Criteria ........................................................................................................54 
8.0 
STUDY DRUG ..................................................................................................................56 
8.1 
Study Drug Administration ..........................................................................................56 
8.1.1 Administration of Dexamethasone in Modakafusp Alfa Plus Dexamethasone 
Cohort(s) ................................................................................................................57 
8.2 
Definitions of DLT ......................................................................................................57 
8.3 
Part 1 Dose Escalation Rules .......................................................................................58 
8.4 
Dose Modification Guidelines .....................................................................................59 
8.4.1 Part 1 Dose Escalation ...........................................................................................59 
8.4.2 Criteria for Beginning or Delaying a Subsequent Treatment Cycle ......................60 
8.4.3 Criteria for Treatment Interruption and Dose Reductions .....................................60 
8.4.4 Criteria for Discontinuing Modakafusp Alfa .........................................................64 
8.4.5 Dexamethasone Dose Modification .......................................................................65 
8.5 
Excluded Concomitant Medications and Procedures ..................................................65 
8.6 
Permitted Concomitant Medications and Procedures ..................................................65 

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8.6.1 Premedication ........................................................................................................65 
8.6.2 Postinfusion Medication ........................................................................................66 
8.6.3 Other Permitted Concomitant Medications and Procedures ..................................66 
8.7 
Precautions and Restrictions ........................................................................................67 
8.7.1 Management of Specific Adverse Reactions .........................................................69 
8.8 
Prophylaxis Against Risk of Infection .........................................................................71 
8.9 
Blinding and Unblinding..............................................................................................71 
8.10 
Description of Investigational Agents .........................................................................71 
8.11 
Preparation, Reconstitution, and Dispensation ............................................................71 
8.12 
Packaging and Labeling ...............................................................................................71 
8.13 
Storage, Handling, and Accountability ........................................................................72 
9.0 
STUDY CONDUCT ..........................................................................................................72 
9.1 
Study Personnel and Organizations .............................................................................72 
9.2 
Arrangements for Recruitment of Patients ..................................................................73 
9.3 
Study Procedures .........................................................................................................73 
9.3.1 Informed Consent...................................................................................................73 
9.3.2 Patient Demographics ............................................................................................73 
9.3.3 Medical History .....................................................................................................73 
9.3.4 Physical Examination.............................................................................................74 
9.3.5 Patient Height.........................................................................................................74 
9.3.6 Patient Weight ........................................................................................................74 
9.3.7 ECOG Performance Status ....................................................................................74 
9.3.8 Concomitant Medications and Procedures.............................................................74 
9.3.9 Safety Evaluations .................................................................................................74 
9.3.10 Disease Assessment ...............................................................................................78 
9.3.11 PK, Immunogenicity, Biomarker, and Pharmacodynamic Samples ......................82 
9.3.12 PRO Assessments ..................................................................................................87 
9.3.13 Healthcare Resource Utilization ............................................................................89 
9.4 
Completion of Study Treatment (for Individual Patients) ...........................................89 
9.4.1 Discontinuation of Treatment with Study Drug and Patient Replacement ............89 
9.4.2 Withdrawal of Patients From Study .......................................................................90 
9.5 
Posttreatment Follow-up Assessments ........................................................................90 
9.6 
Study Compliance ........................................................................................................91 
10.0 
ADVERSE EVENTS .........................................................................................................91 
10.1 
Definitions....................................................................................................................91 

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10.1.1 Pretreatment Event Definition ...............................................................................91 
10.1.2 AE Definition .........................................................................................................91 
10.1.3 Adverse Events of Special Interest ........................................................................91 
10.1.4 SAE Definition.......................................................................................................92 
10.2 
Procedures for Recording and Reporting AEs and SAEs ............................................92 
10.2.1 Monitoring and Reporting IRRs ............................................................................93 
10.3 
Monitoring of AEs and Period of Observation ............................................................94 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........94 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .....................................................................................................................94 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities ...........95 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................95 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................95 
12.1 
eCRFs ...........................................................................................................................95 
12.2 
Record Retention .........................................................................................................96 
13.0 
STATISTICAL METHODS ..............................................................................................97 
13.1 
Statistical and Analytical Plans ....................................................................................97 
13.1.1 Analysis Sets ..........................................................................................................97 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................97 
13.1.3 Efficacy Analysis ...................................................................................................98 
13.1.4 PK Analysis ...........................................................................................................98 
13.1.5 Biomarker and Pharmacodynamic Analysis ..........................................................99 
13.1.6 PRO Analyses ........................................................................................................99 
13.1.7 Immunogenicity Analyses ...................................................................................100 
13.1.8 Safety Analysis ....................................................................................................100 
13.2 
Interim Analyses and Criteria for Early Termination ................................................100 
13.2.1 Part 2 Dose Expansion .........................................................................................100 
13.2.2 Part 3 Extension ...................................................................................................101 
13.3 
Determination of Sample Size ...................................................................................102 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................................103 
14.1 
Study-Site Monitoring Visits .....................................................................................103 
14.2 
Protocol Deviations ....................................................................................................104 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................104 
15.0 
ETHICAL ASPECTS OF THE STUDY .........................................................................104 
15.1 
IRB and/or IEC Approval ..........................................................................................104 
15.2 
Subject Information, Informed Consent, and Subject Authorization ........................105 

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CONFIDENTIAL 
15.3 
Subject Confidentiality ..............................................................................................106 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................107 
15.4.1 Publication ...........................................................................................................107 
15.4.2 Clinical Trial Registration....................................................................................107 
15.4.3 Clinical Trial Results Disclosure .........................................................................108 
15.5 
Insurance and Compensation for Injury .....................................................................108 
16.0 
REFERENCES ................................................................................................................109 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
Reported Distribution of Human CD38 .....................................................29 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...................................49 
Table 8.a 
Parts 1 and 2 Dose Modification Recommendations for Modakafusp 
Alfa Toxicities ...........................................................................................62 
Table 8.b 
Part 3 Dose Modification Recommendations for Modakafusp Alfa 
Hematological Toxicities ...........................................................................63 
Table 8.c 
Part 3 Dose Modification Recommendations for Modakafusp Alfa 
Non Hematological Toxicities ...................................................................63 
Table 8.d 
Part 3 Dose Reduction Levels ....................................................................64 
Table 8.e 
Parts 1, 2, and 3 Dose Modification Recommendations for 
Modakafusp Alfa Bleeding TEAEs ...........................................................64 
Table 8.f 
Highly Effective Methods of Contraception ..............................................68 
Table 8.g 
Recommendations for Managing Grade 1 and Grade 2 IRRs ...................70 
Table 8.h 
Recommendations for Managing Grade 3 IRRs ......................................70 
Table 9.a 
Clinical Chemistry and Hematology Tests ................................................77 
Table 9.b 
Clinical Urinalysis Tests ............................................................................77 
Table 9.c 
Primary Specimen Collection ....................................................................83 
Table 13.a 
Stopping Boundaries for 240 and 120 mg Arms at Each Interim 
Futility Analyses ......................................................................................101 
Table 13.b 
Safety Monitoring Time Points Based on Bayesian Stopping Rules .......102 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Boxplot Comparison of Model-Predicted Single-Dose Cmax (3 mg/kg 
vs 240 mg) and AUC (1.5 mg/kg vs 120 mg and 3 mg/kg  vs 240 
mg) for Fixed Dose and Weight-Based Dosing for Modakafusp Alfa 
for Overall Population................................................................................35 
Figure 6.a 
Overall Study Schematic Diagram.............................................................45 

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CONFIDENTIAL 
Figure 6.b 
Part 3 Study Schematic ..............................................................................47 
Figure 8.a 
Dose Escalation Scheme ............................................................................59 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ...................................................................................111 
Appendix B 
Bone Marrow Collection and Assessment Schedules (Part 1 and Part 
2) ..............................................................................................................153 
Appendix C 
PK Sampling Schedules ...........................................................................155 
Appendix D 
Responsibilities of the Investigator ..........................................................167 
Appendix E 
Investigator Consent to Use of Personal Information ..............................169 
Appendix F 
IMWG Definition of MM (Kumar et al. 2016)........................................170 
Appendix G 
ECOG Scale for Performance Status .......................................................173 
Appendix H 
Operating Characteristics of the Futility Stopping Rules ........................174 
Appendix I 
Statistical Guidance on Unacceptable Toxicity and Treatment 
Related Death ...........................................................................................176 
Appendix J 
Protocol History Including EUCTR Consolidation Table .......................178 
 
LIST OF APPENDIX TABLES 
Appendix A Table 1 Part 1 Schedule A Schedule of Events: Screening, Baseline, Cycle 1, 
and Cycle 2 ..............................................................................................111 
Appendix A Table 2 Part 1 Schedule A Schedule of Events, continued: Cycle 3 to Cycle 
13 and Beyond .........................................................................................114 
Appendix A Table 3 Part 1 Schedule B (Q2W) Schedule of Events: Screening, Baseline, 
Cycle 1, and Cycle 2 ................................................................................117 
Appendix A Table 4 Part 1 Schedule B (Q2W) Schedule of Events, continued: Cycle 3 to 
Cycle 7 .....................................................................................................120 
Appendix A Table 5 Part 1 Schedule B (Q2W) Schedule of Events, continued: Cycle 8 to 
Cycle 13 and Beyond ...............................................................................122 
Appendix A Table 6 Part 1 and Part 2 Schedule C (Q3W) Schedule of Events: Screening, 
Baseline, Cycle 1, and Cycle 2 ................................................................124 
Appendix A Table 7 Part 1 and Part 2 Schedule C (Q3W) Schedule of Events, continued: 
Cycle 3 to Cycle 9 ....................................................................................127 
Appendix A Table 8 Part 1 and Part 2 Schedule C (Q3W) Schedule of Events, continued: 
Cycle 10 to Cycle 17 and Beyond............................................................129 
Appendix A Table 9 Part 1 and Part 2 Schedule D (Q4W) Schedule of Events: Screening, 
Baseline, Cycle 1, and Cycle 2 ................................................................131 

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Appendix A Table 10 Part 1 and Part 2 Schedule D (Q4W) Schedule of Events, continued: 
Cycle 3 to Cycle 13 and Beyond..............................................................134 
Appendix A Table 11 Part 1 and Part 2 EOT and Follow-up ......................................................139 
Appendix A Table 12 Part 3 Extension Schedule of Events: Screening, Baseline, Cycle 1, 
and Cycle 2 ..............................................................................................143 
Appendix A Table 13 Part 3 Extension Schedule of Events, Continued: Cycle 3 through 
EOT and FU .............................................................................................146 
Appendix B Table 1 Part 1 Schedules A, B (Q2W), and D (Q4W) and Part 2 Bone 
Marrow Collection and Assessment Schedule .........................................153 
Appendix B Table 2 Part 1 Schedule C (Q3W): Bone Marrow Collection and Assessment 
Schedule ...................................................................................................154 
Appendix C Table 1 Part 1 Schedule A PK Sampling: Cycle 1 ................................................155 
Appendix C Table 2 Part 1 Schedule A PK Sampling: Cycle 2 ................................................156 
Appendix C Table 3 Part 1 Schedule A PK Sampling: Cycle 3 to Cycle 13 ............................157 
Appendix C Table 4 Part 1 Schedule B (Q2W) PK Sampling: Cycle 1 and Cycle 2 ...............158 
Appendix C Table 5 Part 1 Schedule B (Q2W) PK Sampling: Cycle 3 and Beyond ...............159 
Appendix C Table 6 Part 1 Schedule C (Q3W) PK Sampling: Cycle 1 and Cycle 2 ...............160 
Appendix C Table 7 Part 1 Schedule C (Q3W) PK Sampling: Cycle 3 and Beyond ...............161 
Appendix C Table 8 Parts 1 and 2 Schedule D (Q4W) PK Sampling: Cycles 1 and 2 .............162 
Appendix C Table 9 Parts 1 and 2 Schedule D (Q4W) PK Sampling: Cycle 3 and Beyond ....163 
Appendix C Table 10 Part 3 Extension PK Sampling: Cycles 1 and 2 a .....................................164 
Appendix C Table 11 Part 3 Extension PK Sampling for Chinese Patients With Intensive 
PK Schedule: Cycles 1 and 2 ...................................................................165 
Appendix C Table 12 Part 3 Extension PK Sampling: Cycle 3 and Beyond ..............................166 
Appendix H Table 1 Operating Characteristics for the Treatment Arm of 240 mg ..................174 
Appendix H Table 2 Operating Characteristics for the Treatment Arm of 120 mg ..................175 
Appendix I Table 1 
Bayesian Toxicity Monitoring Boundaries for Grade ≥4 
Nonhematologic Treatment-Related TEAEs and Treatment Related- 
Deaths for Each Treatment Arm ..............................................................176 
Appendix I Table 2 
Operating Characteristics for Monitoring Grade ≥4 Nonhematologic 
Treatment-Related TEAEs Within Each Treatment Arm ........................176 
Appendix I Table 3 
Operating Characteristics for Monitoring Treatment-Related Death 
Within Each Treatment Arm ....................................................................177 
 

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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 USA 
Compound: 
Modakafusp alfa (TAK-573) 
Title of Protocol: A Phase 1/2 Open-label Study to 
Investigate the Safety and Tolerability, Efficacy, 
Pharmacokinetics, and Immunogenicity of Modakafusp 
Alfa as a Single Agent in Patients With Relapsed 
Refractory Multiple Myeloma  
 
Study Number: TAK-573-1501 
Phase: 1/2 
Study Design 
This is a multicenter, open-label, phase 1/2 study designed to determine the safety, tolerability, and efficacy of 
modakafusp alfa as an intravenous (IV) single agent and in combination with dexamethasone in patients with 
relapsed/refractory multiple myeloma (RRMM).  
Phase 1 will provide a preliminary assessment of modakafusp alfa antitumor activity against RRMM with one or 
more single agent schedules.  
Phase 2, which includes the Part 2 expansion cohorts and the Part 3 extension cohorts, will provide a more robust 
estimate of the safety profile, antimyeloma activity, PK, and pharmacodynamics in order to determine whether 
the maximum tolerated dose (MTD)/optimal biologic dose (OBD) is appropriate for future studies. The Part 2 
expansion cohorts will include at least one combination cohort of modakafusp alfa with dexamethasone using the 
same dose and schedule of modakafusp alfa. The Part 3 extension component is designed to identify the optimal 
dose level of modakafusp alfa. In Part 3, patients will be randomized 1:1 to receive modakafusp alfa 120 or 
240 mg once every 4 weeks (Q4W), stratified by their cytogenetics risk (high risk [del17, t(4;14) and/or t(14;16)] 
vs standard risk) and myeloma type (IgA vs other).  
Part 1 Dose Escalation 
The primary objective of Part 1 of the study was to determine the safety and tolerability of one or more schedules 
of single-agent modakafusp alfa in patients with RRMM.  
Part 1 followed a 3 + 3 dose escalation design to evaluate up to 4 different schedules of administration of 
modakafusp alfa with the objective of determining, with one or more schedules, either an MTD based on the 
observation of DLTs, or an OBD.  
Four single-agent schedules were evaluated during Part 1:  
• 
Schedule A (initial): Modakafusp alfa infusion was given at weekly intervals in a 28-day cycle for 2 cycles 
followed by 1 infusion every 2 weeks (twice per cycle) in Cycles 3 to 6, and once every 4 weeks from Cycle 
7 until treatment discontinuation.  
• 
Schedule B: Modakafusp alfa infusions were administered on a 28-day (4-week) cycle once every 2 weeks 
until treatment discontinuation criterion is met. 
• 
Schedule C: Modakafusp alfa infusions were administered on a 21-day (3-week) cycle once every 3 weeks 
until a treatment discontinuation criterion was met. 
• 
Schedule D: Modakafusp alfa infusions were administered on a 28-day (4-week) cycle once every 4 weeks 
until a treatment discontinuation criterion was met. 
Part 2 Expansion Cohorts 
The primary objective of Part 2 of the study is to provide a preliminary evaluation of the clinical activity of one 
or more schedules of modakafusp alfa given as a single agent in patients with RRMM. Additional cohort(s) in 
combination with dexamethasone will be carried out with one or more selected schedule(s) to be determined 
once the modakafusp alfa MTD or OBD is established. The dexamethasone is to be given as a single oral dose of 
40 mg/day weekly. Patients over 75 years of age will receive a reduced dose of dexamethasone (20 mg, same 

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schedule). The aim of this approach is to obtain preliminary information on the effect of standard doses of 
dexamethasone on modakafusp alfa safety, efficacy, and pharmacodynamic endpoints. The MTD for single-
agent modakafusp alfa was established as 3 mg/kg on a Q4W schedule. 
Part 3 Extension Cohorts: 
The MTD at Q4W dosing was exceeded at 6 mg/kg in June 2021 with 2 DLTs (Grade 3 infusion-related reaction 
[IRR] and a greater than 2 week delay in start of cycle 2 due to thrombocytopenia and neutropenia).  
Based on this, and preliminary efficacy seen in patients in the initial Part 2 expansion cohort receiving 1.5 mg/kg 
Q4W, the protocol is amended to add the Part 3 extension of the study that includes 2 dose levels to identify the 
optimal dose, defined as having the more favorable risk-benefit profile based on the totality of data from both 
arms as well as Parts 1 and 2.  
Fixed dosing is considered an appropriate dosing approach for further clinical development based on collective 
PK and clinical findings and the benefits of fixed dosing due to its lower risk of dosing errors and substantial 
reduction of drug wastage. Accordingly, the 2 doses of 1.5 and 3 mg/kg Q4W will be translated into 2 fixed 
doses of 120 and 240 mg Q4W based on the median bodyweight of approximately 80 kg (from Parts 1 and 2 of 
Study TAK-573-1501) for the Part 3 evaluation.  
Part 3 China Continuation Cohort  
After global patient enrollment is completed in Part 3, enrollment will continue for the China continuation cohort 
until about 15% of the total sample size is reached at the selected dose (eg, 18 patients based on 118 patients 
treated at the selected dose[s]). 
PK, Immunogenicity, and Biomarker Assessments 
Blood samples for PK testing and immunogenicity will be collected at regular time points. Intensive PK samples 
will be collected in up to 8 Chinese patients enrolled in China per dose to assess the modakafusp alfa PK profile 
in Chinese patients. Longitudinal peripheral blood samples will be collected for CD38 receptor 
occupancy/density (applicable to Parts 1 and 2 only), RNA sequencing, immunoprofiling, T-cell and B-cell 
receptor sequencing, and serum biomarkers.  
Within Part 1 dose escalation and Part 2 expansion cohorts, bone marrow aspirates are collected at screening and 
at another 2 time points while on treatment and at progressive disease (PD) for CD38 receptor 
occupancy/density, RNA sequencing, immunoprofiling, and T-cell and B-cell receptor sequencing. An additional 
bone marrow aspirate will be collected if the patient is suspected of being in complete response (CR) for 
assessment of minimal residual disease (MRD). Within Part 3 Extension cohorts, bone marrow aspirates are 
collected at screening, suspected CR, and every 6 months thereafter for assessment of MRD, RNA sequencing, 
immunoprofiling, and DNA sequencing. 
Not all collections are applicable to all cohorts or patients within a cohort.  
Primary Objectives 
Part 1 Dose Escalation: To determine the safety and tolerability of single-agent modakafusp alfa in patients with 
RRMM. 
Part 2 Expansion Cohorts: To provide a preliminary evaluation of the clinical activity of modakafusp alfa as a 
single agent and in combination with dexamethasone in patients with RRMM. 
Part 3 Extension Cohorts: To determine the objective response rate (ORR) as assessed by IRC according to 
International Myeloma Working Group (IMWG) criteria (Appendix F) of modakafusp alfa in patients who have 
MM defined by the IMWG criteria with evidence of PD and are in need of additional myeloma therapy as 
determined by the investigator, have previously received at least 3 lines of myeloma therapy, and are refractory 
to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 PI (ie, bortezomib, 
ixazomib, or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated PD with 
the last therapy. 

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Secondary Objectives 
Part 1 Dose Escalation: 
• 
To determine the MTD/OBD of modakafusp alfa with 1 or more schedules of administration. 
• 
To characterize the PK profile of modakafusp alfa. 
• 
To evaluate the immunogenicity of modakafusp alfa. 
• 
To provide a preliminary evaluation of the clinical activity of modakafusp alfa. 
Part 2 Expansion: 
• 
To further evaluate safety and to determine the suitability of MTD/OBD of modakafusp alfa as a single 
agent and in combination with dexamethasone for further trials as the recommended dose and schedule. 
• 
To further characterize the PK profile of modakafusp alfa as a single agent and in combination with 
dexamethasone. 
• 
To further characterize the immunogenicity of modakafusp alfa as a single agent and in combination with 
dexamethasone. 
Part 3 Extension: 
• 
To determine ORR by investigator assessment, duration of response (DOR), clinical benefit rate (CBR), 
duration of clinical benefit, disease control rate (DCR), duration of disease control, progression-free survival 
(PFS), time to progression (TTP), and overall survival (OS). 
• 
To assess MRD negativity in patients achieving CR. 
• 
To further characterize safety and tolerability of modakafusp therapy. 
• 
To collect PK data to contribute to population PK and exposure-response analyses.  
• 
To further characterize the immunogenicity of modakafusp alfa. 
• 
To assess health care utilization. 
• 
To evaluate patient-reported disease symptoms (includes bone aches or pain, back pain, hip pain, arm or 
shoulder pain, chest pain, and pain increasing with activity).  
• 
To characterize the PK profile of modakafusp alfa in Chinese patients. 
Exploratory Objectives  
Part 1 Dose Escalation: 
• 
To explore potential biomarkers to test their correlation with clinical efficacy and safety parameters. 
Part 2 Expansion: 
• 
To explore potential biomarkers to test their correlation with clinical efficacy and safety parameters. 
Part 3 Extension: 
• 
To explore predictive biomarkers of response and resistance.  
• 
To characterize MRD negativity at a higher sensitivity in patients achieving CR. 
• 
To evaluate generic health-related quality of life/health status as measured by the EuroQoL-5-Dimensions-5 
Levels (EQ-5D-5L) instrument. 
Subject Population: Subjects aged 18 years or older with relapsed/refractory MM. 
Number of Patients 
Part 1 Escalation: 36 to 51 evaluable patients. 
Part 2 Expansion: Approximately 100 patients: 4 planned 
expansion cohorts will each include a total of 25 patients. 
Part 3 Extension: Approximately 236 patients (~118 per 
arm).  
After global patient enrollment is completed in Part 3, 
enrollment will continue for the China continuation cohort 
until about 15% of the total sample size is reached at the 
Number of Sites  
Approximately 100 investigational centers 
globally. 
 

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selected dose (eg, 18 patients based on 118 patients 
treated at the selected dose[s]).  
Dose Levels 
Phase 1 Dose Escalation: Modakafusp alfa infusions will 
be escalated as follows: 0.001, 0.01, 0.1, 0.75, 1.5, 3, 6, 9, 
and 14 mg/kg.  
Evaluation of intermediate doses is permissible following 
discussions between the sponsor and the investigators. 
Part 2 Expansion Cohorts with Dexamethasone: 
Modakafusp alfa infusion at MTD/OBD as determined in 
the Part 1 dose escalation.  
Dexamethasone 40 mg (20 mg if age >75 years). 
Part 3 Extension: Modakafusp alfa 120 mg and 240 mg 
Q4W.  
Route of Administration: 
Modakafusp alfa: Intravenous (IV). 
Dexamethasone: Oral (PO) 
 
Duration of Treatment 
Modakafusp alfa for up to 1 year (Parts 1 and 2); 
however, patients with clinical benefit can continue 
treatment beyond 1 year with explicit sponsor approval. 
Patients in Part 3 may continue treatment until disease 
progression. If the investigator considers that treatment 
after PD is in the patient’s best interest, it can be approved 
after consultation with the sponsor. 
Period of Evaluation 
Patient participation includes up to 21 days of 
screening, 1 year of treatment (Parts 1 and 2) or 
until disease progression (Part 3), and 1 month 
posttreatment follow-up (end-of-treatment [EOT] 
visit). Patients who discontinue for reasons other 
than PD will continue PFS follow-up every 4 
weeks from the EOT visit until the occurrence of 
PD, death, the start of subsequent systemic 
antineoplastic therapy, study termination, or until 6 
months after the discontinuation of study treatment, 
whichever occurs first. OS follow-up continues 
every 12 weeks from the EOT visit until death, 
study termination, or patient withdrawal. 
The estimated time frame for study completion is 
approximately 90 months.  
Main Criteria for Inclusion 
Patients with evidence of disease progression during/after the most recent line of therapy who are in need of 
additional myeloma therapy as determined by the investigator and have previously received ≥3 prior lines of 
therapy.  
Patients in the Part 2 expansion and Part 3 extension cohorts must have measurable disease defined as one of the 
following: serum M-protein ≥500 mg/dL (≥0.5 g/dL); urine M-protein ≥200 mg/24 hours; serum free light chain 
(FLC) assay, with involved FLC level ≥10 mg/dL (≥100 mg/L). During dose escalation only, patients not 
meeting these criteria should, at least, have measurable bone marrow plasmacytosis (≥10%) and/or 
plasmacytoma (≥1 cm in diameter) detected by physical examination or imaging. Patients must have adequate 
organ function as determined by the following laboratory values: absolute neutrophil count (ANC) ≥1000/mm3 
(≥1.0×109/L); platelets ≥75,000/mm3 (≥75 × 109/L); hemoglobin ≥75 g/L; creatinine clearance ≥30 mL/min 
(Cockcroft-Gault); total bilirubin ≤2.0 × upper limit of normal (ULN); and alanine aminotransferase/aspartate 
aminotransferase (ALT/AST) ≤3.0 × ULN.  
Part 1: Until the MTD/OBD is defined, patients who have received daratumumab (or other investigational anti-
CD38 antibody) for at least 5 months (steady state) require a 90-day wash-out period before receiving 
modakafusp alfa. For patients who have received less than 5 months of daratumumab or who have received 
another anti-CD38 monoclonal antibody, the necessary wash-out period needs to be discussed and approved by 
the sponsor. Once MTD/OBD has been confirmed, these patients can be enrolled in the trial (Parts 2 and 3) 

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Part 2 and Part 3: No washout from daratumumab or isatuximab is required. 
Part 3: In addition to the above criteria, patients must have MM defined by the IMWG criteria with evidence of 
disease progression and:  
• 
Are in need of additional myeloma therapy as determined by the investigator. 
• 
Have previously received at least 3 lines of myeloma therapy.  
• 
Are refractory to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 PI 
(ie, bortezomib, ixazomib, or carfilzomib), and refractory to at least 1 anti-CD38 antibody (ie, daratumumab 
or isatuximab) and who have demonstrated disease progression during or after the last therapy (see *NOTE 
below). Patients who are primary refractory to all prior therapies, meaning they never achieved at least a 
minimal response (MR) with any previous treatment line, are not eligible. 
*NOTE: Refractory is defined as ˂25% reduction in M-protein or progression of disease during treatment or 
within 60 days after cessation of treatment.  
Main Criteria for Exclusion 
Patients who have had a history of severe allergic or anaphylactic reactions to recombinant proteins or excipients 
used in modakafusp alfa formulation; a significant history of POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes); monoclonal gammopathy of unknown significance; 
smoldering myeloma; solitary plasmacytoma; amyloidosis; Waldenström macroglobulinemia or immunoglobulin 
M myeloma; lymphoplasmacytic lymphoma; or any significant results from physical examinations or clinical 
laboratory results per the investigator. 
Part 3 Extension: 
In addition to the above criteria, patients must not have plasma cell leukemia or have had primary refractory 
MM, current central nervous system involvement of MM, myelodysplastic syndrome, myeloproliferative 
syndrome, or have had a second malignancy within the previous 3 years, except treated basal cell or localized 
squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous 
polyps, breast cancer in situ, or other malignancy for which the patient is not on active anticancer therapy. 
Endpoints 
Part 1 Primary Endpoints: 
• 
The number of patients with TEAEs overall and per dose level.  
• 
Patients with DLTs at each dose level.  
• 
Patients with Grade 3 TEAEs. 
• 
Patients with serious adverse events (SAEs). 
• 
Patients who discontinue because of TEAEs. 
• 
Patients with dose modifications (delays, interruptions, dose reductions). 
• 
Clinically significant laboratory values. 
• 
Clinically significant vital sign measurements. 
Part 1 Secondary Endpoints: 
• 
DLT-like events (TEAEs meeting DLT definition that occur after phase 1 Cycle 1) frequencies and other 
TEAEs occurring over the course of extended treatment with modakafusp alfa, including information about 
dose modification, treatment discontinuation, and clinically significant laboratory values and vital signs.  
• 
Summary statistics by dose level and cycle day for the following PK parameters: 
– 
Single-dose maximum observed serum concentration (Cmax). 
– 
Time of first occurrence of Cmax (tmax). 
– 
Area under the serum concentration-time curve from time 0 to infinity (AUC∞). 
– 
Area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast). 
– 
Apparent serum modakafusp alfa terminal disposition rate constant (λz). 
– 
Apparent serum modakafusp alfa terminal elimination phase half-life (t1/2z). 

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– 
Total clearance after intravenous administration (CL). 
– 
Volume of distribution at steady state (Vss).  
• 
Antimodakafusp-alfa antibody incidence and characteristics (eg, titer and specificity), neutralizing antibody 
(NAb). 
• 
For patients with measurable disease only: ORR, defined as the proportion of patients who achieved a partial 
response (PR) or better during the study; stringent complete response (sCR), CR, very good partial response 
(VGPR) (as defined by IMWG Uniform Response Criteria in (Appendix F).  
• 
PR as defined by IMWG Uniform Response Criteria (Appendix F). 
• 
CBR (includes patients with a response of sCR, CR, VGPR, PR, or minimal response). 
• 
Disease control rate (DCR; includes patients with a response of sCR, CR, VGPR, PR, minimal response, or 
stable disease). 
• 
For patients with measurable disease only: median DOR, with DoR defined as the time from the date of first 
documentation of response of PR or better to the time of disease progression or death, whichever occurs 
first.  
• 
Progression-free survival (PFS), defined as the time from the date of first dose until the sooner of the date of 
progressive disease (PD), defined by IMWG criteria (Appendix F), or the date of death due to any cause. 
• 
For patients with measurable disease only: time to response, defined as the time from first dose to the date of 
first documentation of response (PR or better). 
Part 1 Exploratory Endpoints: 
• 
CD38 expression on MM cells and other immune cells in bone marrow aspirate and its correlation with 
clinical outcome. 
• 
Pharmacodynamic biomarkers including, but not limited to, neopterin, complement, cytokines/chemokines, 
and gene expression and their correlation with clinical outcome. 
• 
Pharmacodynamic analysis of the presence and changes of immune cells from whole blood and bone 
marrow and their correlation with clinical outcome. 
• 
Effects of modakafusp alfa administration on the electrocardiographic QT/QT interval corrected with 
Fridericia correction method (QTc). 
Part 2 Expansion Primary Endpoint: 
• 
ORR, defined as the proportion of patients who achieved a PR or better during study; sCR, CR, VGPR, and 
PR as defined by IMWG Uniform Response Criteria (Appendix F).  
Part 2 Expansion Secondary Endpoints: 
• 
DOR. 
• 
CBR. 
• 
DCR. 
• 
PFS, defined as the time from the date of first dose until the sooner of the date of PD, defined by IMWG 
criteria, or the date of death due to any cause. 
• 
OS, defined as the date from first dose to the date of death due to any cause. 
• 
Time to response, defined as the time from first dose to the date of first documentation of response (PR or 
better). 
• 
DLT-like (TEAEs meeting DLT definition that occur after Part 1 Cycle 1) frequencies and other TEAEs 
occurring over the course of extended treatment with modakafusp alfa, including information about dose 
modification, treatment discontinuation, and clinically significant laboratory values and vital signs. 
• 
Summary statistics by dose level and cycle day for the following PK parameters: Cmax, AUC∞, AUClast, λz, 
tmax, CL, Vss, and t1/2z.  
• 
Antimodakafusp alfa-antibody incidence and characteristics (eg, titer and specificity), NAb. 

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Part 2 Expansion Exploratory Endpoints: 
• 
CD38 expression on MM cells and other immune cells in bone marrow aspirate and its correlation with 
clinical outcome. 
• 
Pharmacodynamic biomarkers including, but not limited to, neopterin, cytokines/chemokines, and gene 
expression and their correlation with clinical outcome. 
• 
Pharmacodynamic analysis of the presence and changes of immune cells from whole blood and bone 
marrow and their correlation with clinical outcome. 
• 
Effects of modakafusp alfa administration on the electrocardiographic QT/QT interval corrected with 
Fridericia correction method (QTc).  
Part 3 Extension Primary Endpoint: 
• 
ORR (PR or better) assessed by the IRC according to modified IMWG criteria (Appendix F). 
Part 3 Extension Secondary Endpoints: 
• 
ORR by investigator assessment. 
• 
DOR.  
• 
CBR (response of sCR, CR, VGPR, PR, or minimal response) by IRC and investigator assessment. 
• 
DCR (response of sCR, CR, VGPR, PR, minimal response, or stable disease) by IRC and investigator 
assessment.  
• 
Duration of clinical benefit. 
• 
Duration of disease control.  
• 
PFS (time from the date of first dose until the sooner of the date of PD, defined by IMWG criteria 
[Appendix F]), or the date of death due to any cause by IRC and investigator assessment.  
• 
TTP by IRC and investigator assessment. 
• 
OS (date from first dose to the date of death due to any cause). 
• 
Rate of MRD negative status at a sensitivity of 10-5 in patients achieving CR. 
• 
Duration of MRD negativity at a sensitivity of 10-5 in patients achieving CR. 
• 
AEs, SAEs, laboratory assessments, supportive care use. 
• 
Eastern Cooperative Oncology Group status. 
• 
Antimodakafusp alfa-antibody incidence and characteristics (eg, titer and specificity), NAb. 
• 
Length of hospital stay, types of hospital stay, and other health care resource utilization data as defined in 
Section 9.3.13. 
• 
No worsening of disease symptoms (includes bone aches or pain, back pain, hip pain, arm or shoulder pain, 
chest pain, and pain increasing with activity) from baseline at approximately 12 weeks across doses of 
modakafusp alfa as measured by the patient-reported outcome (PRO) instrument European Organisation for 
Research and Treatment of Cancer MM Module Quality of Life Questionnaire (EORTC QLQ-MY20). 
• 
Summary statistics by dose level and cycle day for the following PK parameters in Chinese patients with 
intensive PK schedule: Cmax, AUC∞, AUClast, λz, tmax, CL, Vss, and t1/2z. 
Part 3 Extension Exploratory Endpoints: 
• 
CD38 expression on MM cells and other immune cells within the bone marrow and its correlation with 
clinical outcome. 
• 
Evaluation of somatic mutations and polymorphisms and their associations with response and/or acquired 
resistance.  
• 
Evaluation of anti-interferon antibodies at baseline and correlation with response.  
• 
Rate of MRD negative status at a sensitivity of 10-6 in patients achieving CR. 
• 
Duration of MRD negativity (10-6) in patients who achieve MRD negative status at CR.  
• 
Evaluation of generic health-related quality of life/health status, measured by the EQ-5D-5L instrument.  

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Statistical Considerations 
The MTD/OBD will be estimated by a standard 3 + 3 method using data collected in the dose escalation phase. 
Adverse events (AEs) will be summarized by treatment group and overall. Categorical variables such as ORR, 
CBR, and DCR will be tabulated by treatment group and overall. Time-to-event variables such as DOR and PFS 
will be analyzed using Kaplan-Meier survival curves, and Kaplan-Meier medians (if estimable) will be provided. 
PK parameters will be summarized as appropriate. An OBD is a dose level that is below or coincides with the 
MTD for which there is evidence of antimyeloma activity plus data supporting of significant pharmacodynamic 
effects in one or more biomarkers. An OBD for one or more schedules can be selected before or after identifying 
MTD. 
The Part 2 Expansion portion will evaluate the clinical activity of one or more schedules of modakafusp alfa 
given as a single agent in patients with relapsed/refractory MM. Additional cohort(s) in combination with 
dexamethasone will evaluate one or more selected schedule(s), which will be determined once the modakafusp 
alfa MTD or OBD is established.  
Part 3 Extension  
The Part 3 extension cohorts will identify the optimal dose level for modakafusp alfa. Patients will be 
randomized 1:1 to receive either 120 mg or 240 mg Q4W and stratified by their cytogenetics risk (high risk 
[del17, t(4;14) and/or t(14;16)] vs standard risk) and myeloma type and myeloma type (IgA vs other). 
Cytogenetic results from samples taken within 5 weeks prior to first dose are acceptable for stratification. All 
patients should also have a sample from screening sent for central analysis. If a previous result is not available 
and the patient is known to have high-risk disease [ie, del17, t(4;14) and/or t(14;16)] from prior cytogenetic 
testing, regardless of timing, they should be stratified as high risk for the purpose of enrollment.  
The primary endpoint of Part 3 is the ORR, defined as the percentage of patients with a confirmed PR or better 
(ie, PR, VGPR, CR, and sCR) according to the IMWG Response Criteria (Appendix F) assessed by the 
independent review committee (IRC). The primary endpoint, ORR assessed by IRC, will be evaluated for all 
treated patients within each treatment arm based on the 95% exact confidence interval (CI) of the observed ORR 
at the primary analysis. No formal statistical analysis will be performed to compare the 2 treatment arms. 
Prespecified subgroup analyses based on stratification factors will be performed as data permits.  
Two interim analyses for futility are planned for the study when approximately 15 and 48 of the planned 
118 patients per arm have been randomized and treated for at least 3 cycles or discontinued treatment 
prematurely. The futility stopping boundary is determined based on the predictive probability of success (Lee 
and Liu 2008) at the primary analysis. The treatment arm will be dropped for futility if the predictive probability 
of success at the primary analysis is found to be smaller than 10% based on the data from the interim analysis.  
Two-sided exact 95% binominal CIs will be computed for all binary secondary endpoints, including ORR as 
assessed by the investigator, DCR, and CBR as assessed by the IRC and the investigator. Kaplan-Meier methods, 
including medians and CIs, will be used to estimate PFS as assessed by the IRC and the investigator, DOR as 
assessed by the IRC and the investigator, OS, and other time to event endpoints.  
Sample Size Justification 
Part 1 of the study will follow a standard 3 + 3 dose escalation design. MTD/OBD will be defined for each 
schedule currently under evaluation (B [Q2W], C [Q3W] and D [Q4W]). A maximum of 9 dose levels are 
planned (from 0.001 mg/kg to 14 mg/kg). For Part 1, the number of evaluable patients is planned to be 36 to 51.  
Part 2 Expansion:  
The study will enroll up to 25 patients in each Part 2 cohort to further characterize safety of the OBD/MTD and 
obtain preliminary clinical efficacy data. An OBD/MTD dose will be considered clinically relevant if at least 11 
out of 25 response-evaluable patients have a confirmed PR or better. With a vague beta prior with shape 
parameters 0.428 and 1 for ORR, 11 responders out of 25 gives a greater than 90% posterior probability of true 
ORR being greater than 30%. The design has reasonable operating characteristics. With a true ORR of 30%, the 
probability of declaring success is 7%. On the other hand, with a true ORR of 50% the probability of declaring 
success is 70%.  

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Part 3 Extension: 
A total sample size of approximately 236 patients (118 patients per arm) will allow the study to have over 90% 
power to rule out an uninteresting response rate of 20% if the true rate is 35% with a 1-sided alpha of 0.025. 
Patients who were randomized but did not receive any study treatment will be replaced. However, all patients 
who received at least one dose of study treatment will be included in the analysis and will not be replaced if they 
drop out after receiving study treatment.  
After global patient enrollment is completed in Part 3, enrollment will continue for the China continuation cohort 
until about 15% of the total sample size is reached at the selected dose(s) (eg, 18 patients based on 118 patients 
treated at the selected dose[s]). 

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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities (Appendix D). The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator  
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study medication, their expertise in the therapeutic area and the conduct of 
clinical research as well as study participation. The Signatory Coordinating Investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study. 
3.3 
Committees in Part 3 Dose Extension  
No committees will be used in Parts 1 and 2. The following committees will be used for Part 3.  
3.3.1 
Independent Review Committee 
An independent review committee (IRC) will review all disease evaluation data to independently 
assess disease response, and the assessments will be used for analysis of endpoints as described 
in Section 13.1. Details regarding the committee and its procedures will be described in the IRC 
charter. Data from the IRC will not be provided to the investigator during the conduct of the 
study. 
3.3.2 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will review safety data and the interim 
analysis data for futility as detailed in the IDMC charter. The charter of the IDMC will specify 
that this committee is charged with providing periodic reports to the Sponsor that contain 
recommendations that include, but are not limited to, (a) continuation of the study, 
(b) continuation with modification, and (c) termination of the study. 

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3.4 
List of Abbreviations  
Abbreviation 
Term 
λz 
terminal disposition phase rate constant 
ADA 
antidrug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
anti-HBs 
antibodies to hepatitis B surface antigen 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
AUC∞ 
area under the serum concentration-time curve from time 0 to infinity 
AUClast 
area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration 
BMA 
bone marrow aspirate 
C1D1 
Cycle 1 Day 1 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CL 
total clearance after intravenous administration 
Cmax 
maximum observed serum concentration 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CT 
computed tomography 
DCR 
disease control rate  
DLT 
dose-limiting toxicity  
DOR  
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EORTC QLQ-
MY20 
European Organisation for Research and Treatment of Cancer Multiple Myeloma Module 
Quality of Life Questionnaire 
EOT 
end of treatment 
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels 
FDA 
[United States] Food and Drug Administration 
FIH 
first-in-human 
FLC 
free light chain 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 

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Abbreviation 
Term 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HRQOL 
health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IFN 
interferon 
IFN-α 
interferon-alpha 
IFN-α 2b 
interferon alpha 2b 
Ig 
immunoglobulin 
IL 
interleukin 
IMiD 
immunomodulatory imide drug  
IMWG 
International Myeloma Working Group 
IRB 
institutional review board 
IRC 
independent review committee  
IRR 
infusion-related reaction 
IV 
intravenous(ly) 
IVIG 
IV immunoglobulins 
mAb 
monoclonal antibody 
MABEL 
minimum anticipated biological effect level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
Modakafusp alfa 
TAK-573 
MR 
minimal response 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NAb 
neutralizing antibody 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
natural killer 
NSAID 
nonsteroidal anti-inflammatory drugs 
OBD 
optimal biological dose 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease; disease progression 

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Abbreviation 
Term 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes 
PET-CT 
positron emission tomography–computed tomography 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PK 
pharmacokinetic(s) 
PO 
orally 
PoS 
probability of success 
PPOS 
posterior probability of success 
PR 
partial response 
PRO 
patient-reported outcome 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
QD 
quaque die (once daily) 
QTcF 
QT interval with Fridericia correction method 
RBC 
red blood cells 
RRMM 
relapsed/refractory multiple myeloma 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SCT 
stem cell transplant 
SD 
stable disease 
SOC 
System Organ Class 
SOE 
schedule of events 
SPEP 
serum protein electrophoresis 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2z 
terminal disposition phase half-life 
TAK-573 
modakafusp alfa  
TEAE 
treatment-emergent adverse event 
tmax 
time of first occurrence of maximum observed serum modakafusp alfa concentration 
TMDD 
target-mediated drug disposition 
TTP 
time to progression 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US 
United States  
Vc 
central volume of distribution 
Vd 
volume of distribution 
VGPR 
very good partial response 
Vss 
volume of distribution at steady state 

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4.0 
INTRODUCTION 
4.1 
Multiple Myeloma 
Multiple myeloma (MM) is a plasma cell-derived malignancy characterized by bone lesions, 
hypercalcemia, anemia, and renal insufficiency. The 5-year survival rate of patients diagnosed 
with MM is approximately 45% (Siegel et al. 2013). MM persists as a mostly incurable disease 
because of its highly complex and diverse cytogenetic and molecular abnormalities (Chapman et 
al. 2011). There has been an improvement in the outcome for MM patients in the last decade 
with the discovery, development, and approval of proteasome inhibitors (PI) (eg, bortezomib) 
and immunomodulatory imide drugs (IMiDs); however, patients who become refractory or are 
ineligible to receive bortezomib and IMiDs have a dismal prognosis (Kumar et al. 2012). 
Daratumumab, a CD38 antibody, is currently approved in many countries for the treatment of 
MM. (Poh 2016). Daratumumab was studied in patients who had received at least 3 prior lines of 
therapy, including a PI and an IMiD, or who were double-refractory to these agents. An objective 
response rate (ORR) of 29% was documented, including a 3% rate of complete response 
(CR)/stringent complete response (sCR). The main toxicity associated with daratumumab was 
infusion-related reactions (IRRs), which could be severe in some patients. Other common 
adverse drug reactions (ADRs) were fatigue, nausea, back pain, pyrexia, cough, and upper 
respiratory tract infection ((Darzalex (daratumumab) injection 2015)daratumumab United States 
(US) Package Insert (2015). However, not all patients respond to daratumumab, and many 
patients eventually develop PD (Nijhof et al. 2016). Response to daratumumab therapy is 
significantly associated with CD38 expression levels on the tumor cells, and pretreatment levels 
of CD38 expression on MM cells were significantly higher in patients who achieved at least a 
partial response (PR) compared with patients who did not achieve a PR. In addition, CD38 
expression in these patients was reduced in both bone marrow–localized and circulating MM 
cells following the first daratumumab infusion, and increased again following daratumumab 
discontinuation (Nijhof et al. 2016). There is still a need for development of novel targeted 
therapies that act specifically on the biology of the tumor cells, overcoming limitations related to 
the CD38 expression level. 
4.2 
Modakafusp Alfa Targets 
The tumor cell surface–expressed antigen CD38 is uniformly and highly expressed on MM cells 
(Lin et al. 2004; Santonocito et al. 2004) and at lower levels on various lymphoid and myeloid 
cells and some solid organs (Deaglio et al. 2008). Being highly expressed on the myeloma cell 
surface and showing lower expression on normal cells makes CD38 an appropriate target for 
delivering drugs (cytokines, radioisotopes (Green et al. 2014), and toxins (Bolognesi et al. 2005; 
Goldmacher et al. 1994) to receptor-expressing cells. A promising moiety to be conjugated to an 
anti-CD38 monoclonal antibody (mAb) is the cytokine interferon-alpha (IFN-α), which is 
currently used by clinicians as a potential maintenance treatment option for MM following 
primary treatment and autologous and allogeneic stem cell transplant (SCT). IFN-α has direct 
inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive 
immune systems. Systemic toxicity of IFN-α, however, precludes the use of the cytokine at 

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therapeutically effective doses for the majority of patients. By reducing the binding affinity of 
IFN-α (KD) for its receptor, interferon alpha receptor, modakafusp alfa (previously known as 
TAK-573) is expected to reduce binding of IFN-α to nontargeted, CD38-negative cells. In 
contrast, binding of modakafusp alfa with high affinity via its CD38 targeting moieties is 
expected to increase the local concentration attenuated IFNα on these CD38+ target cells, 
thereby inducing desired on-target IFN pathway activation. In addition, IFN-α pathway 
activation induces up-regulation of CD38 messenger RNA and protein levels in malignant cells 
of patients with B cell chronic lymphocytic leukemia (Bauvois et al. 1999), suggesting that 
modakafusp alfa may be able to increase CD38 target expression in MM and other CD38+ 
immune cells, thus overcoming the limitations seen with anti-CD38-depleting antibodies such as 
daratumumab. Modakafusp alfa increases CD38 expression on MM cells in vitro, which further 
supports this hypothesis (Report TPA-38-051). 
CD38 is a multifunctional ectoenzyme involved in cell adhesion and transmembrane signaling. It 
is over expressed in hematologic tumors, where it is believed to play a role in tumor cell 
migration and metastasis. CD38 has been reported to be highly expressed in 80% of MM 
patient-derived tumor cells (Lin et al. 2004). CD38 is an approximately 45kDa transmembrane 
glycoprotein expressed by immature hematopoietic cells, down regulated in mature cells, and 
re-expressed at higher levels by activated lymphocytes such as T cells, B cells, dendritic cells, 
and natural killer (NK) cells (Funaro et al. 1990). Early bone marrow cells, which are crucial for 
long-term (sustained) marrow recovery, do not express CD38 but committed progenitor bone 
marrow cells, B cells in germinal centers, terminally differentiated plasma cells, and activated 
tonsils are CD38+ (Chillemi et al. 2013). Deaglio et al (Deaglio et al. 2008) reviewed the main 
tissues and cells where CD38 is present, as summarized in Table 4.a. CD38 is also found in a 
soluble form in normal and pathological fluids. 

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Table 4.a 
Reported Distribution of Human CD38 
Tissue 
Cellular Distribution 
Putative Function 
Bone marrow 
hematologic precursors plasma cells 
Homing and apoptosis; marker of 
precursor cell commitment 
Thymus 
Throughout thymic development 
Unknown 
Spleen/lymph nodes 
Germinal center B cells 
Rescue from apoptosis 
Blood 
T, B, NK, and monocyte subsets; platelets and 
erythrocytes; hematologic precursors plasma cells 
Interaction with endothelium 
Gut 
Intra-epithelial and lamina propria lymphocytes 
Mucosal immunity 
Brain 
Purkinje cells; neurofibrillary tangles 
Memory process 
Prostate 
Epithelial cells 
Unknown 
Pancreas 
β cells 
Insulin secretion 
Bone 
Osteoclasts 
Bone resorptions 
Eye 
Retinal cells 
Vision process 
Muscle 
Sarcolemma of smooth and striated muscle 
Muscle contraction 
Source: (Deaglio et al. 2008). 
NK: natural killer. 
 
4.3 
Modakafusp Alfa  
Modakafusp alfa is a recombinant humanized immunoglobulin (Ig) G4 anti-CD38 monoclonal 
antibody fused to attenuated interferon alpha 2b (IFN-α 2b). Modakafusp alfa is produced by 
recombinant DNA technology in a mammalian cell expression and is purified by a process that 
includes specific viral inactivation and removal steps. The CD38 antibody portion of 
modakafusp alfa directs the attenuated IFN-α portion to CD38+ cells, thus achieving a high local 
concentration on IFNα2b at the surface of these target cells. On CD38- cells the attenuation 
results in approximately 130,000-fold reduced potency compared with IFNα2b. 
Modakafusp alfa has a high binding affinity (dissociation constant [KD]) for human and 
cynomolgus CD38, with a KD of 168 pM and 1.25 nM, respectively (Report TPA-38-009). 
Modakafusp alfa can potently inhibit proliferation of CD38+ MM cells (half-maximal inhibitory 
concentration 19.9 pM), whereas potency on CD38- cells is approximately 2500-fold lower. The 
antibody portion of modakafusp alfa is an IgG4 isotype (unlike the IgG1 isotype of daratumumab) 
and is therefore unlikely to induce antibody-dependent cell mediated cytotoxicity of normal 
CD38+ cells. Modakafusp alfa does not modulate the adenosine diphosphate-ribosyl cyclase 
activity of CD38, unlike daratumumab (Report TPA-38-045). Interferon-α2b (Intron A) by 
comparison has similar potency to modakafusp alfa on CD38+ cells (IC50 12.3 pM) but on 
CD38- cells is approximately 130,000-fold more potent than modakafusp alfa (EC50 ~0.37 pM). 

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4.4 
Findings From Nonclinical and Toxicology Studies 
Brief summaries of nonclinical pharmacology, pharmacokinetics (PK), and toxicology studies 
are provided in the following sections. More-detailed information is provided in the 
Investigator’s Brochure (IB). 
4.4.1 
Nonclinical Studies 
Modakafusp alfa effectively induces apoptosis in high-expressing CD38+ human myeloma cells 
as demonstrated in a caspase activation assay (half-maximal effective concentration 23 pM); no 
apoptotic effects are observed with normal human peripheral blood mononuclear cells (PBMCs). 
Modakafusp alfa elicited a low level of cytokine release (tumor necrosis factor alpha, interleukin 
[IL] 6, IL-8, IFN-γ, and IL-2) from human PBMCs in vitro, less than or comparable to 
palivizumab (IgG1 against the syncytial respiratory virus) and is, therefore, unlikely to induce 
cytokine storm in the clinic. 
Modakafusp alfa is active in multiple human myeloma xenograft models and induces complete 
regressions at tolerated doses. A single dose of 10 mg/kg modakafusp alfa in the NCI-H929 
human myeloma xenograft model resulted in complete regressions in all treated animals. In 
comparative xenograft studies using the H929 model, modakafusp alfa had more robust 
antitumor activity than established myeloma therapies including bortezomib, lenalidomide, and 
daratumumab. Furthermore, under conditions of suboptimal dosing of modakafusp alfa, strong 
synergy has been observed with other standard treatment agents such as bortezomib and 
lenalidomide. 
4.4.2 
Toxicology Studies 
A series of toxicological studies in cynomolgus monkeys was conducted to support the phase 1/2 
clinical trial TAK-573-1501. Please refer to the IB for additional information.  
As described in International Conference on Harmonisation (ICH) Guidance S6 (R1), the range 
and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to 
biotechnology-derived pharmaceuticals. ICH Guidance S9, Nonclinical Evaluation for 
Anticancer Pharmaceuticals, also states that genotoxicity studies are not considered essential to 
support clinical trials for therapeutics intended to treat patients with advanced cancer. Therefore, 
genotoxicity studies have not been conducted with modakafusp alfa.  
4.5 
Known and Potential Benefits and Risks of Modakafusp Alfa  
4.5.1 
Nonclinical Safety Summary 
On the basis of nonclinical studies and clinical experience with related antidrug antibodies 
(ADAs), the following ADRs may be associated with modakafusp alfa administration: IRRs 
(pyrexia, chills, nausea, vomiting, ﬂushing, dyspnea, cough, headache, dizziness, rash, and 
hypertension), cytokine release syndrome, changes in blood cell counts, elevations in liver 
enzymes, and ADA-mediated hypersensitivity reactions. Additional information regarding 
benefits and risks to patients can be found in the IB. 

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4.5.2 
Clinical Safety 
The most common treatment-emergent adverse events (TEAEs) reported have been hematologic, 
which have been mitigated by dosing Q4W to allow count recovery after observing inadequate 
recovery at more frequent dosing.  
Patients receiving modakafusp alfa have experienced IRRs. Premedications and treatment should 
be provided as described in Section 8.7.1.1. 
Neuropsychiatric events have been reported in modakafusp alfa clinical studies.  
Dose modifications should be applied per the guidelines in Section 8.4.  
For more detailed information on the adverse events (AEs) associated with modakafusp alfa, as 
well as the identified and potential risks, please refer to the most recent IB. 
Clinical safety will be monitored per the assessments described in the Schedule of Events. 
4.6 
Rationale for the Proposed Study 
This is a first-in-human (FIH) study of the anticancer product modakafusp alfa. The drug is a 
fusion protein that binds CD38 with high affinity and the IFN receptor with low affinity. 
Therefore, it is expected that its effect will be restricted predominantly to CD38-positive cells. 
The study is designed with a slow dose escalation design with a starting dose defined with the 
minimum anticipated biological effect level (MABEL) approach (Section 4.6.1). Due to CD38 
targeting and the solid evidence of anti-myeloma activity in xenograft models, multiple myeloma 
is selected as the initial indication to test the safety and efficacy of modakafusp alfa. The trial 
also aims to collect translational research information in support of the nonclinical hypothesis of 
the activation of the innate immunity through the Type I interferon pathway.  
The trial is currently enrolling at different dose levels and schedules with modakafusp alfa as a 
single agent. After Protocol Amendment 5 was implemented, the trial also included one 
combination arm with dexamethasone.  
Corticosteroids have been a mainstay of MM treatment for decades (Alexanian et al. 1992). They 
are highly active against the disease and are considered standard of care treatment in many 
combination regimens. For example, dexamethasone is combined seemingly by default with 
cytotoxic chemotherapies predating the novel agent era as well as relatively newer agents with 
novel mechanisms of action such as PIs and immunomodulators. At the same time, 
corticosteroids have immunosuppressive effects as illustrated by their longstanding use as 
anti-inflammatory agents and in the treatment of autoimmune disease (Coutinho and Chapman 
2011). Recent advances applying immunotherapy in the oncology setting have raised the 
question of whether steroid therapy may reduce the efficacy of immunotherapy (Arbour et al. 
2018; Giles et al. 2018). Given that modakafusp alfa affects the immune pathway via IFNα2b 
signaling, it is hypothesized that investigating the effect of corticosteroids in the setting of 
modakafusp alfa therapy will provide a platform to further understand the safety, efficacy, and 
biology of modakafusp alfa in MM. 

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4.6.1 
Rationale for the Part 1 Starting Dose of Modakafusp Alfa  
In view of the marked decrease in modakafusp alfa plasma concentrations observed in repeated 
dosing in the nonhuman primate toxicology studies, a MABEL calculation was used to provide a 
framework for determining the FIH starting dose. 
The calculation of the MABEL was based on projection of CD38 occupancy that would be 
maximally achievable at peak concentrations of modakafusp alfa following intravenous (IV) 
dosing (Saber et al. 2016). Although modakafusp alfa was initially (prior to Amendment 5) 
administered over a 4-hour ramped infusion (Section 8.1), in the absence of clinical PK data on 
modakafusp alfa, the calculation conservatively assumed dilution of the entire dose 
instantaneously in total plasma volume (2.8 L for a 70 kg patient). As such, a dose of 0.001 
mg/kg (70 µg for a 70 kg patient) would be expected to achieve a maximum serum concentration 
of modakafusp alfa of no greater than 25 ng/mL (134 pM based on a molecular weight of 186 
KDa). On the basis of the in vitro estimate of the CD38 target KD of 168 pM (determined by a 
surface plasmon resonance assay), this translates to a projected receptor occupancy of <44% at 
the proposed starting dose of 0.001 mg/kg.  
4.6.2 
Rationale for Part 3 
The rationale for conducting Part 3 of Study TAK-573-1501 is based on the totality of the data 
from Part 1 (dose escalation) and Part 2 (dose expansion) of Study TAK-573-1501.  
Part 1 of Study TAK-573-1501 involved extensive dose exploration with 10 modakafusp alfa 
dose levels ranging from 0.001 mg/kg to 6.0 mg/kg on 4 different dosing schedules. The optimal 
schedule for modakafusp alfa was determined to be every 4 weeks (Q4W) based on the recovery 
time of hematological toxicities. The maximum tolerated dose (MTD) at this schedule was 
established as 3 mg/kg as 6 mg/kg exceeded the MTD with 2 dose-limiting toxicities (DLTs) 
(Grade 3 IRR and a greater than 2-week delay in start of cycle 2 due to thrombocytopenia and 
neutropenia). No DLTs were seen at 3 mg/kg. Preliminary efficacy activity was also seen in 
dose-escalation with 1 PR and 2 minimal responses (MRs) in 5 patients at 1.5 mg/kg on the Q4W 
schedule and 1 PR and 1 CR (patient ongoing at Cycle 21) in 7 patients at 3 mg/kg on the Q4W 
schedule.  
Part 2 of Study TAK-573-1501 included a dose-expansion cohort of 25 patients treated at 
1.5 mg/kg Q4W. A response rate of 44% was seen. The median duration of response has not yet 
been reached. 
Toxicities were primarily hematologic, with thrombocytopenia and neutropenia observed at rates 
of 73% (17% Grade 4) and 70% (30% Grade 4) respectively. IRRs have been observed at a rate 
of 30%. Toxicities have been managed with dose delays and supportive care and have rarely 
resulted in study drug discontinuation or dose reduction. 
In addition, the dose- and exposure-response relationship based on the preliminary 
pharmacodynamics (M-protein and free light chain), efficacy, and safety data indicate that 
1.5 and 3 mg/kg Q4W dosing are within the optimal biological dose range.  

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Based on the preliminary risk/benefit profile seen in the dose escalation and expansion cohorts 
and the increased efficacy signals seen with increasing doses up to and including the MTD of 
3 mg/kg Q4W, a randomized noncomparative trial of modakafusp alfa 120 mg or 240 mg Q4W 
(fixed dosing equivalents of 1.5 and 3 mg/kg) was designed to identify the dose with an optimal 
benefit/risk profile for patients with this incurable disease. 
4.6.2.1 
Rationale for Fixed Dosing 
At the initiation of clinical development of modakafusp alfa, early phase 1 clinical studies 
empirically used a body weight-based (in mg/kg) dosing approach that has been traditionally 
used in the development of cytotoxic anticancer agents. The appropriateness of the conventional 
body weight-based approach for dosing therapeutic mAb has been critically questioned in the 
recent scientific literature (Bai et al. 2012; Mould 2015; Wang et al. 2009). Because of its in vivo 
properties, including linear catabolic degradation and saturable target-mediated elimination 
pathways, the PKs of a therapeutic mAb can be affected by multiple potential factors, including 
target cell trafficking, target antigen expression levels per cell/tissue, serum protein levels, and 
disease status in addition to patient demographics such as age, body size, and sex. Thus, the 
impact of body weight may only explain a small portion of the overall interindividual variability 
of the PK parameters of mAb, especially in cases where the contribution of the target-mediated 
elimination pathway exceeds that of the linear catabolic elimination pathway (Bai et al. 2012; 
Mould 2015; Wang et al. 2009).  
Following a single-dose administration, the increase of modakafusp alfa exposure was greater 
than dose-proportional in the dose range of 0.1 to 3 mg/kg and approximately dose-proportional 
in the dose range of 3 to 6 mg/kg. Both visual inspection of the serum PK profiles and the 
apparent nonlinear PK across dose groups indicated saturable target-mediated elimination for 
modakafusp alfa. Despite the body weight-based dosing, between-subject exposure variability 
was moderate (30%-100%) to high (>100%). 
A preliminary population PK analysis was performed using emerging data from the 2 ongoing 
phase 1/2 studies (Study TAK-573-1501 in MM patients and Study TAK-573-1001 in patients 
with solid tumors). A quasi-equilibrium bispecific mAb 2-compartment population PK model 
with both linear total clearance after IV administration (CL) and saturable target-mediated drug 
disposition (TMDD) represented a semi-mechanistic structural model to account for target 
engagement with both IFNɑ and CD38 receptors and was shown to adequately describe the 
modakafusp alfa PK. The effect of body weight on the central volume of distribution (Vc) 
parameter for modakafusp alfa was characterized using a power model with the exponent 
estimated to be 0.664 on Vc. The relationship between body weight and CL, CLd, and Vp was 
not statistically significant. The impact of body weight on TMDD parameters including target 
capacity (Rtot) for CD38 was explored graphically and was not warranted.  
The model-based simulation was conducted to assess the impact of body weight on the PK of 
modakafusp alfa. Boxplots of the simulated exposures with the 2 dosing approaches, for the 
overall population, are shown in Figure 4.a. Comparison of the 2 dosing approaches was 
conducted based on the simulated exposures following Cycle 1 single dose administration to 

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minimize the confounding impact of the potential time-varying factors (eg, ADA) on the 
assessment of body weight effect on PK. Figure 4.a illustrates the comparable PK variability and 
exposure for the overall patient population between the fixed dose and weight-based dosing 
approaches. In addition, the projected exposures (ie, maximum observed serum concentration 
[Cmax] area under the serum concentration-time curve concentration [AUC]) at the proposed 
fixed doses (120 and 240 mg) are generally below the exposures for a patient administered 
6 mg/kg who exhibited a DLT and model-predicted exposure for 6 mg/kg.  

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Figure 4.a 
Boxplot Comparison of Model-Predicted Single-Dose Cmax (3 mg/kg vs 240 
mg) and AUC (1.5 mg/kg vs 120 mg and 3 mg/kg  vs 240 mg) for Fixed 
Dose and Weight-Based Dosing for Modakafusp Alfa for Overall 
Population 
 

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Figure 4.a 
Boxplot Comparison of Model-Predicted Single-Dose Cmax (3 mg/kg vs 240 
mg) and AUC (1.5 mg/kg vs 120 mg and 3 mg/kg  vs 240 mg) for Fixed 
Dose and Weight-Based Dosing for Modakafusp Alfa for Overall 
Population 
 
AUC: area under the serum concentration-time curve; AUC0-tau BW: body weight; Cmax: maximum observed 
serum concentration; DLT: dose-limiting toxicity; Q4W: once every 4 weeks. 
Red dots are means. The purple line denotes the exposure based on the noncompartmental analysis of the 
observed data for a patient of the 6 mg/kg Q4W dose group who exhibited DLT (delayed platelet count recovery). 
The cyan line denotes the mean simulated exposure for 6 mg/kg dose group.  
 
Overall, the data and preliminary population PK analysis suggest that there is a low impact of 
body weight on the PK of modakafusp alfa (ie, no appreciable impact of body weight on CL and 
a weight exponent of 0.664 on Vc only), likely because the contribution of the TMDD pathway 
exceeds that of the linear catabolic elimination pathway. Additionally, exploratory population 
PK-PD modeling of serum m-protein and free light-chain, which are 2 potential outcome 
biomarkers for efficacy, have been conducted. These preliminary population PK-PD analyses are 
not presented here, but no apparent effect of body weight on any PK-PD parameters was 
observed. Although the final population PK model included weight effect on Vc, the impact of 
body weight was not expected to be clinically meaningful, based on the totality of the PK 
(eg, moderate to high PK variability despite of fixed-dosing in phase 1 and clinical data, 
including the magnitude of the PD variability in the PK-PD models for efficacy. Based on these 
collective findings and the benefits of fixed dosing due to its convenience, better compliance, 
less risk for dosing errors, and reduced drug wastage, fixed dosing is considered an appropriate 
dosing approach for further clinical development. Accordingly, the 2 modakafusp alfa body 

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weight–based doses of 1.5 and 3 mg/kg Q4W will be translated into 2 fixed doses of 120 and 
240 mg Q4W based on the median bodyweight of approximately 80 kg (from Parts 1 and 2 of 
Study TAK-573-1501) for the Part 3 evaluation. 
4.6.3 
Changes to Modakafusp Alfa Infusion  
The initial administration over 4 hours with premedications and postmedication was based on the 
administration schema of the only commercialized anti-CD38, daratumumab. Daratumumab is 
an IgG1 monoclonal antibody with intact antibody-dependent cellular cytotoxicity, 
antibody-dependent cellular phagocytosis and immune-mediated tumor cell lysis through 
complement dependent cytotoxicity. Modakafusp alfa belongs to the IgG4 class which does not 
have immune-effector properties. 
Amendment 05 allowed optional administration of premedications and shortened the infusion 
time of modakafusp alfa to 1 hour. As of Amendment 6, based on the experience with infusion 
reactions in patients not receiving premedications per the guidance set forth in Amendment 05, it 
was strongly recommended that all patients receive premedications prior to modakafusp alfa 
dosing and any decision to stop premedications would have to be discussed with and agreed 
upon by the sponsor. In addition, patients receiving modakafusp alfa doses ≥6 mg/kg are treated 
with additional premedication and the dose is delivered over a longer infusion time. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Part 1 Dose Escalation Objectives  
5.1.1 
Part 1 Primary Objective 
To determine the safety and tolerability of single agent modakafusp alfa in patients with 
relapsed/refractory MM. 
5.1.2 
Part 1 Secondary Objectives 
• To determine the MTD/ optimal biological dose (OBD) of modakafusp alfa with 1 or more 
schedules of administration. 
• To characterize the PK profile of modakafusp alfa. 
• To evaluate the immunogenicity of modakafusp alfa. 
• To provide a preliminary evaluation of the clinical activity of modakafusp alfa. 
5.1.3 
Part 1 Exploratory Objectives 
• To explore potential biomarkers to test their correlation with clinical efficacy and safety 
parameters.  

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5.2 
Part 2 Dose Expansion Objectives 
5.2.1 
Part 2 Primary Objective 
To provide a preliminary evaluation of the clinical activity of modakafusp alfa as a single agent 
and in combination with dexamethasone in patients with relapsed/refractory multiple myeloma 
(RRMM). 
5.2.2 
Part 2 Secondary Objectives 
• To further evaluate efficacy and safety and to determine the suitability of the modakafusp 
alfa MTD/OBD as a single agent and in combination with dexamethasone for further trials as 
the recommended dose and schedule. 
• To further characterize the PK profile of modakafusp alfa as a single agent and in 
combination with dexamethasone. 
• To further characterize the immunogenicity of modakafusp alfa as a single agent and in 
combination with dexamethasone. 
5.2.3 
Part 2 Exploratory Objectives 
• To explore potential biomarkers to test their correlation with clinical efficacy and safety 
parameters.  
5.3 
Part 3 Dose Extension Objectives 
5.3.1 
Part 3 Primary Objective 
To determine the ORR as assessed by IRC according to International Myeloma Working Group 
(IMWG) criteria (Appendix F) of modakafusp alfa in patients who have MM defined by the 
IMWG criteria with evidence of disease progression and are in need of additional myeloma 
therapy as determined by the investigator, have previously received at least 3 lines of myeloma 
therapy, and are refractory to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide 
excluded]), at least 1 PI (ie, bortezomib, ixazomib, or carfilzomib), and refractory to at least 
1 anti-CD38 antibody and who have demonstrated disease progression during or after the last 
therapy.  
5.3.2 
Part 3 Secondary Objectives 
• To determine ORR by investigator assessment, duration of response (DOR), clinical benefit 
rate (CBR), duration of clinical benefit, disease control rate (DCR), duration of disease 
control, progression-free survival (PFS), time to progression (TTP), and overall survival 
(OS). 
• To assess minimal residual disease (MRD) negativity in patients achieving CR. 
• To further characterize safety and tolerability of modakafusp therapy. 

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• To collect PK data to evaluate population PK and exposure-response (safety/efficacy) 
analysis.  
• To characterize the PK profile of modakafusp alfa in Chinese patients. 
• To further characterize the immunogenicity of modakafusp alfa. 
• To assess healthcare resource utilization. 
• To evaluate patient-reported disease symptoms (includes bone aches or pain, back pain, hip 
pain, arm or shoulder pain, chest pain, and pain increasing with activity).  
5.3.3 
Part 3 Exploratory Objectives 
• To explore predictive biomarkers of response and resistance. 
• To characterize MRD negativity at a higher sensitivity in patients achieving CR. 
• To evaluate generic health-related quality of life (HRQOL)/health status, measured by the 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) instrument. 
5.4 
Endpoints 
5.4.1 
Part 1 Dose Escalation Endpoints 
5.4.1.1 
Part 1 Primary Endpoints 
• The number of patients with TEAEs overall and per dose level.  
• Patients with DLTs at each dose level.  
• Patients with Grade 3 TEAEs. 
• Patients with SAEs. 
• Patients who discontinue because of TEAEs. 
• Patients with dose modifications (delays, interruptions, dose reductions). 
• Clinically significant laboratory values. 
• Clinically significant vital sign measurements. 
5.4.1.2 
Part 1 Secondary Endpoints 
• DLT-like (TEAEs meeting DLT definition that occur after phase 1 Cycle 1) frequencies and 
other TEAEs occurring over the course of extended treatment with modakafusp alfa, 
including information about dose modification, treatment discontinuation, and clinically 
significant laboratory values and vital signs.  

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• Summary statistics by dose level and cycle day for the following PK parameters: 
– Single-dose Cmax. 
– Time of first occurrence of Cmax (tmax). 
– Area under the serum concentration-time curve from time 0 to infinity (AUC∞). 
– Area under the serum concentration-time curve from time 0 to time of the last 
quantifiable concentration (AUClast). 
– Apparent serum modakafusp alfa terminal disposition rate constant (λz). 
– Apparent serum modakafusp alfa terminal elimination phase half-life (t1/2z). 
– CL. 
– Volume of distribution at steady state (Vss).  
• Anti-modakafusp alfa-antibody incidence and characteristics (eg, titer and specificity), Nab. 
• Preliminary evaluation of antitumor activity of modakafusp alfa:  
– For patients with measurable disease only: ORR, defined as the proportion of patients 
who achieved a PR or better during the study; sCR, CR, very good partial response 
(VGPR), and PR as defined by IMWG Uniform Response Criteria (Appendix F), CBR 
(includes patients with a response of sCR, CR, VGPR, PR, or minimal response); DCR 
(includes patients with a response of sCR, CR, VGPR, PR, minimal response, or stable 
disease). 
– For patients with measurable disease only: median DOR, with DoR defined as the time 
from the date of first documentation of response PR or better to the time of disease 
progression or death, whichever occurs first.  
– For patients with measurable disease only: time to response, defined as the time from first 
dose to the date of first documentation of response (PR or better). 
– Progression-free survival (PFS), defined as the time from the date of first dose until the 
sooner of the date of PD, defined by IMWG criteria (Appendix F), or the date of death 
due to any cause. 
5.4.1.3 
Part 1 Exploratory Endpoints 
• CD38 expression on MM cells and other immune cells in bone marrow aspirate (BMA) and 
its correlation with clinical outcome. 
• Pharmacodynamic biomarkers including, but not limited to, neopterin, complement, 
cytokines/chemokines, and gene expression and their correlation with clinical outcome. 
• Pharmacodynamic analysis of the presence and changes of immune cells from whole blood 
and bone marrow and their correlation with clinical outcome. 

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• Effects of modakafusp alfa administration on the electrocardiographic QT/QT interval with 
Fridericia correction method (QTcF). 
5.4.2 
Part 2 Expansion Endpoints 
5.4.2.1 
Part 2 Primary Endpoints 
• ORR, defined as the proportion of patients who achieved a PR or better during study; sCR, 
CR, VGPR, and PR as defined by IMWG Uniform Response Criteria (Appendix F). 
5.4.2.2 
Part 2 Secondary Endpoints 
• DOR. 
• CBR. 
• DCR.  
• PFS, defined as the time from the date of first dose until the sooner of the date of PD, defined 
by IMWG criteria (Appendix F), or the date of death due to any cause. 
• OS, defined as the date from first dose to the date of death due to any cause. 
• Time to response, defined as the time from first dose to the date of first documentation of 
response (PR or better). 
• DLT-like events (TEAEs meeting DLT definition that occur after Part 1 Cycle 1) frequencies 
and other TEAEs occurring over the course of extended treatment with modakafusp alfa, 
including information about dose modification, treatment discontinuation, and clinically 
significant laboratory values and vital signs. 
• Summary statistics by dose level and cycle day for the following PK parameters: Cmax, 
AUC∞, AUClast, λz, tmax, CL, Vss, and t1/2z.  
• Anti-modakafusp alfa antibody incidence and characteristics (eg, titer and specificity), NAb.  
5.4.2.3 
Part 2 Exploratory Endpoints 
• CD38 expression on MM cells and other immune cells in BMA and its correlation with 
clinical outcome. 
• Pharmacodynamic biomarkers including, but not limited to, neopterin, 
cytokines/chemokines, and gene expression and their correlation with clinical outcome. 
• Pharmacodynamic analysis of the presence and changes of immune cells from whole blood 
and bone marrow and their correlation with clinical outcome. 
• Effects of modakafusp alfa administration on the electrocardiographic QT/QT interval with 
Fridericia correction method (QTcF). 

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5.4.3 
Part 3 Extension Endpoints 
5.4.3.1 
Part 3 Primary Endpoint  
• ORR (PR or better) assessed by IRC according to modified IMWG criteria (Appendix F).  
5.4.3.2 
Part 3 Secondary Endpoints  
• ORR by investigator assessment. 
• DOR.  
• CBR (response of sCR, CR, VGPR, PR, or minimal response) by IRC and investigator 
assessment. 
• Duration of clinical benefit. 
• DCR (CBR + stable disease [SD]) by IRC and investigator assessment. 
• Duration of disease control.  
• PFS (time from the date of first dose until the sooner of the date of PD, defined by IMWG 
criteria [(Appendix F)] or the date of death due to any cause by IRC and investigator 
assessment. 
• TTP by IRC and investigator assessment. 
• OS (date from first dose to the date of death due to any cause). 
• Rate of MRD negative status at a sensitivity of 10-5 in patients achieving CR. 
• Duration of MRD negativity at a sensitivity of 10-5 in patients achieving CR. 
• AEs, SAEs, laboratory assessments, supportive care use. 
• Eastern Cooperative Oncology Group (ECOG) status. 
• ADA incidence and characteristics (eg, titer and specificity) and NAb. 
• Length of hospital stay, types of hospital stay, and other healthcare resource utilization data 
as defined in Section 9.3.13.  
• No worsening of disease symptoms (includes bone aches or pain, back pain, hip pain, arm or 
shoulder pain, chest pain, and pain increasing with activity) from baseline at 12 weeks across 
doses of modakafusp alfa as measured by the patient-reported outcome (PRO) instrument 
European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple 
Myeloma Module (EORTC QLQ-MY20). 
• Summary statistics by dose level and cycle day for the following PK parameters in Chinese 
patients with intensive PK schedule: Cmax, AUC∞, AUClast, λz, tmax, CL, Vss, and t1/2z. 
 

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5.4.3.3 
Part 3 Exploratory Endpoints 
• CD38 expression on MM cells and other immune cells within the bone marrow and its 
correlation with clinical outcome. 
• Evaluation of somatic mutations and polymorphisms and their associations with response 
and/or acquired resistance.  
• Evaluation of anti-interferon antibodies at baseline and correlation with response. 
• Rate of MRD negative status at a sensitivity of 10-6 in patients achieving CR. 
• Duration of MRD negativity (10-6) in patients who achieve MRD negative status at CR.  
• Evaluation of generic HRQOL/health status as measured by the EQ-5D-5L instrument. 
6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a multicenter, open-label, phase 1/2 study designed to determine the safety and 
tolerability of modakafusp alfa as a single agent and in combination with dexamethasone in 
patients with relapsed/refractory MM. The study will be conducted in 3 parts.  
Part 1 Dose Escalation: Single-agent modakafusp alfa with 1 or more schedules of 
administration. 
Part 2 Dose Expansion: At least 1 cohort of modakafusp alfa combined with dexamethasone 
using the dose and schedule determined in Part 1. 
Treatment cycle duration is 28 days (21 days for Schedule C). For Parts 1 and 2, modakafusp 
alfa with or without dexamethasone will be administered for up to 12 cycles or until disease 
progression, unacceptable toxicity, or any other discontinuation criterion is met (Section 9.4). 
Patients with demonstrated clinical benefit may continue treatment beyond 12 cycles with the 
agreement of the sponsor. 
Part 3 Dose Extension: Single-agent modakafusp alfa with 1:1 randomization to receive 
modakafusp alfa 120 or 240 mg. Patients will be stratified by their cytogenetics risk (high risk 
[del17, t(4;14) and/or t(14;16)] vs standard risk) and myeloma type (IgA vs other). Cytogenetic 
results from samples taken within 5 weeks prior to first dose are acceptable for stratification. All 
patients should also have a sample from screening sent for central analysis. If a previous result is 
not available and the patient is known to have high-risk disease [ie, del17, t(4;14) and/or 
t(14;16)] from prior cytogenetic testing, regardless of timing, they should be stratified as high 
risk for the purpose of enrollment. 
For Part 3, treatment can continue until any criterion described in Section 9.4 is met. Response 
assessments in Part 3 will be made on the basis of central laboratory data. 
Patient participation includes a screening phase, a treatment phase, and a follow-up phase 
(Section 9.3). The screening phase will be up to 21 days before Cycle 1 Day 1 (C1D1). Please 

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refer to the guidance in the Site Operations Manual if a patient needs to be rescreened. The 
follow-up phase begins once a patient discontinues study treatment and completes the 
end-of-treatment (EOT) visit; study follow-up continues until the study ends or the patient 
completes OS follow-up (Section 9.5). The total duration of patient participation is described in 
Section 6.3.  
Part 1 Dose Escalation  
The primary objective of Part 1 of the study was to determine the safety and tolerability of one or 
more schedules of single-agent modakafusp alfa in patients with RRMM.  
Part 1 followed a 3 + 3 dose escalation design to evaluate up to 4 different schedules of 
administration of modakafusp alfa with the objective of determining, with one or more 
schedules, either an MTD based on the observation of DLTs, or an OBD.  
Four single-agent schedules were evaluated during Part 1:  
• Schedule A (initial): Modakafusp alfa infusion is given at weekly intervals in a 28-day cycle 
for 2 cycles followed by 1 infusion every 2 weeks (twice per cycle) in Cycles 3 to 6, and 
once every 4 weeks from Cycle 7 until treatment discontinuation.  
• Schedule B: Modakafusp alfa infusions will be administered on a 28-day (4-week) cycle 
once every 2 weeks until treatment discontinuation criterion is met. 
• Schedule C: Modakafusp alfa infusions will be administered on a 21-day (3-week) cycle 
once every 3 weeks until treatment discontinuation criterion is met. 
• Schedule D: Modakafusp alfa infusions will be administered on a 28-day (4-week) cycle 
once every 4 weeks until treatment discontinuation criterion is met. 
The overall study schematic is displayed in Figure 6.a. 
Part 2 Dose Expansion 
The primary objective of Part 2 of the study is to provide a preliminary evaluation of the clinical 
activity of one or more schedules of modakafusp alfa given as a single agent in patients with 
RRMM. Additional cohort(s) of modakafusp alfa (using the same dose used in a single-agent 
cohort) in combination with dexamethasone will be implemented, with the selected schedule(s) 
to be determined once the modakafusp alfa MTD or OBD is established. Treatment allocation 
will be randomly assigned. Dexamethasone will be given as a once weekly oral dose of 40 mg. 
Patients over 75 years of age will receive a reduced dose of dexamethasone (20 mg, same 
schedule). The aim of this approach is to obtain preliminary information on the effect of standard 
doses of dexamethasone on modakafusp alfa safety, efficacy, and pharmacodynamic endpoints. 
Preliminary activity of modakafusp alfa as a single agent and in combination with 
dexamethasone will be evaluated by measuring the confirmed ORR (PR or better) according to 
IMWG Uniform Response Criteria (Appendix F). The efficacy of modakafusp alfa will further 
assessed by assessing DOR, PFS, OS, and time to response.  

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Figure 6.a 
Overall Study Schematic Diagram  
Treatment Cycle – Schedule A: 28-day Cycles; Q1W Dosing a 
C1 
C2 
C3 
C4 
C5 
C6 
C7 C8 C9 C10 C11 C12 C13 
D1 D8 D15 D22 D1 D8 D15 D22 D1 D15 D1 D15 D1 D15 D1 D15 D1 D1 D1 D1 
D1 
D1 
D1 
 
Treatment Cycle – Schedule B: 28-day Cycles; Q2W Dosing a 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 
D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 D1 D15 
 
Treatment Cycle – Schedule C: 21-day Cycles; Q3W Dosing a 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 
C14 
C15 
C16 
C17 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
 
Treatment Cycle – Schedule D: 28-day Cycles; Q4W Dosing a 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
D1 
C: cycle; D: day; Q1W: once every week; Q2W: once every 2 weeks; Q3W: once every 3 weeks; Q4W: once every 
4 weeks. 
Cycle = 4 weeks for Schedules A, B and D; 3 weeks for Schedule C. 
In Part 3, Schedule D Q4W dosing will be followed by one cohort receiving 120 mg and one cohort receiving 
240 mg to determine the optimal dose.  
Dose modification guidelines are detailed in Section 8.4, study completion guidelines are detailed in Section 9.4, 
treatment discontinuation guidelines are detailed in Section 9.4.1, and study withdrawal is detailed in Section 9.4.2. 
Dose escalation:  
Schedule A = 0.001, 0.01, 0.1, 0.75, 1.5, 3, 6, 9, 14 mg/kg. Intermediate dose levels are permissible with agreement 
between investigators and sponsor.  
Schedule B, C and D = opening of the first cohort and starting dose level will be decided by the investigators and 
sponsor. For each of these levels, the starting dose will not be above the highest dose previously tested with a more 
intensive schedule. 
a In Part 2, only, at least one cohort(s) will combine modakafusp alfa with dexamethasone in parallel with a Part 2 
single-agent cohort using the same modakafusp alfa schedule. Dexamethasone is administered once weekly (starting 
on C1D1) at 40 mg (20 mg for patients >75 years of age) until a discontinuation criterion is met. 
 
Part 3 Dose Extension 
Part 3 will determine the confirmed ORR per IRC assessment, evaluate other efficacy endpoints, 
assess MRD negativity in patients achieving CR, further characterize the safety, tolerability, and 
immunogenicity of modakafusp alfa therapy, collect PK data, and assess healthcare resource 
utilization. 
The modakafusp alfa doses of 1.5 and 3 mg/kg Q4W will be translated into 2 fixed doses of 
120 and 240 mg based on the median bodyweight of approximately 80 kg (from Parts 1 and 2 of 
Study TAK-573-1501) for the Part 3 evaluation. 
Two interim analyses for futility are planned for the study when approximately 15 and 
48 patients of the planned 118 patients per arm are enrolled and treated for at least 3 cycles or 
have discontinued treatment prematurely (Figure 6.b).  

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The sponsor will only proceed with enrolling additional patients into a treatment arm where the 
futility boundary is not crossed; more specifically:  
Scenario 1: If the futility boundary is not crossed in one arm (eg, the 120 mg arm) but is crossed 
in the second treatment arm (eg, the 240 mg arm), patient enrollment will continue only in the 
arm that did not cross the futility boundary (eg, the 120 mg arm). 
Scenario 2: If the futility boundary is not crossed in the 120 mg treatment arm and is not crossed 
in the 240 mg treatment arm, patient enrollment will continue for both arms to identify the 
optimal dose, defined as having the more favorable risk-benefit profile based on the totality of 
data from both arms and Parts 1 and 2. 
Scenario 3: If the futility boundary is crossed in the 120 mg treatment arm and is crossed in the 
240 mg treatment arm, the study will be terminated. 
In addition, the sponsor may decide to discontinue 1 arm if there is early detection of an 
unfavorable risk-benefit profile based on the interim data analysis data. 
Study procedures and assessments, with their time points, are shown in Appendix A, 
Appendix B, and Appendix C.  
Part 3 China Continuation Cohort  
After global patient enrollment is completed in Part 3, enrollment will continue for the China 
continuation cohort until about 15% of the total sample size is reached at the selected dose(s) 
(eg, 18 patients based on 118 patients treated at the selected dose[s]). 

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Figure 6.b 
Part 3 Study Schematic 
 
 
PD: progressive disease; Q4W: once every 4 weeks. 
Dosing is Q4W in both cohorts.  
 

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6.2 
Number of Patients 
For Part 1, the number of evaluable patients is planned to be 36 to 51.  
For Part 2, a total of approximately 25 patients will be enrolled in each expansion cohort. The 
planned expansion cohorts include 3 modakafusp alfa single-agent cohorts plus at least one 
combination cohort of modakafusp alfa with dexamethasone using the same dose and schedule 
of modakafusp alfa used in a single-agent expansion cohort (approximately 100 patients).  
For Part 3, approximately 236 patients (118 per dose cohort) will be enrolled.  
After global patient enrollment is completed in Part 3, enrollment will continue for the China 
continuation cohort until about 15% of the total sample size is reached at the selected dose(s) 
(eg, 18 patients based on 118 patients treated at the selected dose[s]).  
Details on the definition of evaluable patients and sample size are given in Section 13.0. 
The study is planned to be conducted globally at approximately 100 investigational centers.  
6.3 
Duration of Study 
6.3.1 
Duration of an Individual Patient’s Study Participation 
Patients may receive modakafusp alfa until they experience PD, unacceptable toxicity, or any 
other discontinuation criterion is met (Section 9.4). In Parts 1 and 2, the maximum scheduled 
duration of treatment will be 1 year; however, patients with clinical benefit can continue 
treatment beyond 1 year with explicit sponsor approval. Patients in the modakafusp alfa plus 
dexamethasone cohort can continue receiving single-agent modakafusp alfa if the investigator 
considers that there are clinical reasons (for example safety) supporting the removal of 
dexamethasone from the treatment. 
Patients may be treated in Part 3 until progression or other discontinuation criteria are met. If the 
investigator considers that treatment after PD is in the patient’s best interest, it can be approved 
after consultation with the sponsor. 
Patients will be evaluated 30 days (EOT visit) after the last dose of modakafusp alfa or right 
before the start of subsequent systemic anticancer therapy to permit the detection of any delayed 
TEAEs. 
Patient participation includes up to 21 days of screening, 1 year of treatment (Parts 1 and 2) or 
until disease progression (Part 3), and 1 month posttreatment follow-up (EOT visit). Patients 
who discontinue for reasons other than PD will continue PFS follow-up every 4 weeks from the 
EOT visit until the occurrence of PD, death, the start of subsequent systemic antineoplastic 
therapy, study termination (Section 9.4), or until 6 months after the discontinuation of study 
treatment, whichever occurs first. OS follow-up continues every 12 weeks from the EOT visit 
until death, study termination, or patient withdrawal. 

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6.3.2 
End of Study/Study Completion Definition and Planned Reporting 
The final analysis for the clinical study report will be conducted after all patients enrolled in the 
study have completed OS follow-up, have withdrawn from the study, or have transitioned to 
posttrial access (Section 6.3.5).  
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures 
Refer to Table 6.a for disclosure information for all primary and secondary endpoints. 
Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
Part 1 
 
 
Primary: Percentage of patients with 
TEAEs 
TEAEs, DLTs, SAEs, Grade 3 TEAEs, 
dose modification, discontinuations, and 
clinically significant laboratory values and 
vital signs.  
Up to ~90 months.  
Secondary: DLT-like TEAEs 
TEAEs meeting DLT definition that occur 
after phase 1 Cycle 1) frequencies and 
other TEAEs occurring over the course of 
extended treatment with modakafusp alfa, 
including information about dose 
modification, treatment discontinuation, 
and clinically significant laboratory values 
and vital signs.  
Up to ~90 months.  
Secondary: Summary PK statistics 
See Section 9.3.11. 
Up to ~90 months.  
Secondary: ORR, sCR, CR, VGPR, 
and PR 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: CBR and DCR 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: PFS 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: Duration of response, time 
to response 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: Anti–modakafusp alfa 
antibody incidence and characteristics, 
NAb  
See Section 13.1.7. 
Up to ~90 months.  
Part 2 Expansion 
 
 
Primary: ORR  
See Section 9.3.10. 
Up to ~90 months.  
Primary: DOR, time to response  
 
Up to ~90 months.  
Primary: PFS 
See Section 9.3.10. 
Up to ~90 months.  
Primary: OS 
See Section 9.3.10. 
Up to ~90 months.  
Primary: Time to response 
See Section 9.3.10. 
Up to ~90 months.  

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Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
Secondary: DLT-like TEAEs  
TEAEs meeting DLT definition that occur 
after Part 1 Cycle 1 and TEAEs occurring 
over the course of extended treatment with 
modakafusp alfa including information 
about dose modification, treatment 
discontinuation, clinically significant 
laboratory values, and vital signs. 
Up to ~90 months.  
Secondary: Summary PK statistics 
See Section 9.3.11.2. 
Up to ~90 months.  
Part 3 Extension  
Primary: ORR as assessed by the IRC  
See Section 9.3.10. 
Up to ~90 months.  
Secondary: ORR as assessed by the 
investigator 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: CBR, DCR, DOR by IRC 
and investigator assessment 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: PFS, TTP by IRC and 
investigator assessment  
See Section 9.3.10. 
Up to ~90 months.  
Secondary: Duration of clinical benefit 
and disease control  
See Section 9.3.10. 
Up to ~90 months.  
Secondary: OS 
See Section 9.3.10. 
Up to ~90 months.  
Secondary: Summary PK statistics in 
Chinese patients 
See Section 9.3.11.2. 
Up to ~90 months. 
Secondary: Antimodakafusp alfa 
antibody incidence and characteristics 
and NAb 
See Section 9.3.11.5. 
Up to ~90 months. 
Secondary: Rate and duration of MRD 
negativity in patients achieving CR 
See Section 9.3.11.3. 
Up to ~90 months.  
Secondary: AEs, SAEs, laboratory 
assessments, supportive care use 
See Section 9.3.9. 
Up to ~90 months.  
Secondary: HRU measures 
See Section 9.3.13. 
Up to ~90 months.  
Secondary: HRQOL measures 
See Section 9.3.12. 
 
AE: adverse event; CBR: clinical benefit rate; CR: complete response; DCR: duration of complete response; 
DLT: dose-limiting toxicity; DOR: duration of response; ECOG: Eastern Cooperative Oncology Group; HRQOL: 
health-related quality of life; HRU: health care resource utilization; IRC: independent review committee; MRD: 
minimal residual disease; NAb: neutralizing antibody; ORR: objective response rate; OS: overall survival; PFS: 
progression-free survival; PK: pharmacokinetic(s); SAE: serious adverse event; sCR: stringent complete 
response; TEAE: treatment-emergent adverse event; TTP: time to progression; VGPR: very good partial 
response. 
 
6.3.4 
Total Study Duration 
Patients will be followed for 30 days after the last dose of modakafusp alfa or right before the 
start of subsequent anticancer therapy, whichever occurs first, to permit the detection of any 

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delayed TEAEs. All patients, including those patients no longer on treatment, will be assessed 
for PFS and survival. Patients who discontinue the study treatment for any reason other than PD 
will be followed for PFS every 4 weeks from the EOT visit until PD, start of new systemic 
anticancer treatment, death, withdrawal of consent for further follow-up, study termination, or 
until 6 months after the discontinuation of study treatment, whichever occurs first. Patients will 
be followed for OS every 12 weeks from the EOT visit until death, study termination, or patient 
withdrawal. 
Information on any subsequent anticancer therapies will be collected during the PFS/survival 
follow-up period. For patients who achieve CR but discontinue study treatment while still in 
remission, PFS information based upon available local data for Parts 1 and 2 and central data for 
Part 3 will also be collected during the PFS/survival follow-up period. 
It is anticipated that this study will last for approximately 90 months.  
6.3.5 
Posttrial Access 
At the end or termination of the study (Section 6.3.2), ongoing patients may continue to receive 
modakafusp alfa in an extension phase of this study or will be given the opportunity to enroll in a 
separate open-label rollover study, a single patient Investigational New Drug (IND), or other 
regulated access to continue receiving modakafusp alfa if, in the opinion of the investigator and 
confirmed by the sponsor, they have experienced a clinically important benefit from modakafusp 
alfa received in the study, have no alternative therapeutic option, and would be harmed without 
continued access.  
6.3.5.1 
Duration of Posttrial Access 
Continued access to modakafusp alfa for participants will be terminated for those individuals 
who no longer benefit from modakafusp alfa (eg, they have completed the recommended course 
of therapy or their disease has resolved), the benefit-risk no longer favors the individual, if 
modakafusp alfa becomes available either commercially or via another access mechanism, or 
when an alternative appropriate therapy becomes available. Posttrial access may be terminated in 
a country or geographical region where marketing authorization has been rejected, the 
development of modakafusp alfa has been suspended or stopped by the sponsor, or the 
modakafusp alfa can no longer be supplied. 
6.4 
Randomization in Phase 2 Part 3 Extension 
Patients will be randomized in a 1:1 ratio to receive modakafusp alfa fixed doses of 120 mg or 
240 mg Q4W. Patients will be stratified by the following 2 factors, each having 2 levels:  
1. Cytogenetics risk (high risk [defined as 17p-, t(4;14) and/or t(14;16)] vs standard risk). 
2. Myeloma type (IgA vs other).  
Randomization procedures should be performed following complete eligibility assessments and 
prior to the initiation of assigned treatment. This study is unblinded; patients, investigators, and 
the sponsor will know the identity of each patient’s study treatment. 

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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
For Parts 1 and 2: 
Each patient must meet all the following inclusion criteria to be enrolled in the study.  
1. MM defined by the IMWG criteria with evidence of disease progression and: 
a) Is in need of additional myeloma therapy as determined by the investigator. 
b) Has previously received at least 3 lines of myeloma therapy (eg, containing an IMiD, a 
PI, an alkylating agent, and/or an anti-CD38 as single agents or in combination).  
c) Is either refractory to, or intolerant of, at least 1 PI and at least 1 IMiD (see NOTE 
below).  
For Part 3: 
Each patient must meet all the following inclusion criteria to be enrolled in the study.  
1. MM defined by the IMWG criteria with evidence of disease progression and: 
a) Is in need of additional myeloma therapy as determined by the investigator. 
b) Has previously received at least 3 lines of myeloma therapy.  
c) Is refractory to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide 
excluded]), at least 1 PI (ie, bortezomib, ixazomib, or carfilzomib), and refractory to at 
least 1 anti-CD38 antibody (ie, daratumumab or isatuximab) and who have demonstrated 
disease progression during or after the last therapy (see *NOTE below). Patients who 
were primary refractory to all prior therapies, meaning they never achieved at least a MR 
with any previous treatment line, are not eligible. 
*NOTE: Refractory is defined as ˂25% reduction in M-protein or progression of disease 
during treatment or within 60 days after cessation of treatment. 
A line of therapy is defined as 1 or more cycles of a planned treatment program. This may 
consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well 
as a sequence of treatments administered in a planned manner. A new line of therapy starts 
when a planned course of therapy is modified to include other treatment agents (alone or in 
combination) as a result of disease progression, relapse, or toxicity. A new line of therapy 
also starts when a planned period of observation off therapy is interrupted by a need for 
additional treatment for the disease (Rajkumar et al. 2011). 
2. Aged 18 years or older. 
3. For patients in Parts 2 and 3 only: Measurable disease defined as one of the following: 
a) Serum M-protein ≥500 mg/dL (≥5 g/L). 
b) Urine M-protein ≥200 mg/24 hours. 

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c) Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) 
provided serum FLC ratio is abnormal. 
4. During Part 1 only, patients not meeting the above criteria for measurable disease should, at 
least, have measurable bone marrow plasmacytosis (≥10%) and/or plasmacytoma (≥1 cm in 
diameter) detected by physical examination or imaging. 
5. ECOG performance status of ≤2.  
6. Patient has adequate organ function as determined by the following laboratory values. 
Absolute neutrophil count a 
≥1000/mm3 (≥1.0×109/L)  
Platelets a 
≥75,000/mm3 (≥75×109/L)  
Hemoglobin 
≥75 g/L 
Creatinine clearance 
≥30 mL/min (Cockcroft-Gault) 
Total serum bilirubin 
≤2.0×ULN; an exception for patients with Gilbert’s syndrome 
may be granted after discussion with the sponsor. 
Liver transaminases (ALT/AST) 
≤3.0×ULN 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of the normal range. 
a Without ongoing growth factor or transfusion support for at least 1 week before Day 1. 
7. Female patients who: 
• Are postmenopausal for at least 2 years before the screening visit, OR 
• Are surgically sterile, OR 
• If they are of childbearing potential: 
– Agree to practice 1 highly effective method of contraception and 1 additional 
effective (barrier) method at the same time, from the time of signing the informed 
consent through 7 days after the last dose of study drug, OR 
– Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject, from the time of signing the informed consent through 7 days 
after the last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.) 
– Agree not to donate an egg or eggs (ova) during the study and for 7 days after the last 
dose of study drug. 
8. Male patients, even if surgically sterilized (ie, status post vasectomy), who: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and through 7 days after the last dose of study drug, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 

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postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.) 
• Agree not to donate sperm during the study and for 7 days after the last dose of study 
drug. 
9. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care. 
10. The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period and must be willing to 
return to the investigational center for the follow-up procedures and assessments specified in 
this protocol.  
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study; 
(exclusions specific to Part 3 appear at end of list): 
1. Patient has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and 
skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, 
smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia 
or IgM myeloma, or lymphoplasmacytic lymphoma. 
2. Patients who have received autologous SCT 60 days before first infusion of modakafusp alfa 
or patients who have received allogeneic SCT 6 months before first infusion.  
3. Graft-versus-host disease that is active or requires ongoing systemic immunosuppression.  
4. Part 1: Until the MTD/OBD is defined, patients who have received daratumumab (or other 
investigational anti-CD38 antibody) for at least 5 months (steady state) require a 90-day 
wash-out period before receiving modakafusp alfa. For patients who have received less than 
5 months of daratumumab or who have received another anti-CD38 monoclonal antibody, 
the necessary wash-out period needs to be discussed and approved by the sponsor. Once the 
MTD/OBD has been confirmed, these patients can be enrolled in the trial (Parts 2 and 3). 
Parts 2 and 3: No washout from daratumumab or isatuximab is required.  
5. Patient has not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≤1 or baseline, except for 
sensory or motor neuropathy which should have recovered to Grade ≤2 or baseline. 

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6. Patient has received the final dose of any of the following treatments/procedures within the 
specified minimum intervals before the first dose of modakafusp alfa.  
Chemotherapy, including proteasome inhibitors and IMiDs 
14 days 
Antibody therapy (except anti-CD38 antibody as presented in exclusion 
criterion #4) 
21 days 
Corticosteroid therapy for myeloma 
7 days 
Radiation therapy for localized bone lesions 
7 days 
Major surgery 
21 days 
IMiD: immunomodulatory imide drug. 
7. Patient has congestive heart failure (New York Heart Association Grade ≥II), cardiac 
myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina 
pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or 
clinically significant uncontrolled hypertension. 
8. Patient has a history of acute myocardial infarction within 5 months from enrollment or has 
electrocardiogram (ECG) abnormalities during screening that are deemed medically relevant 
by the investigator. 
9. Patient has QT interval corrected by the Fridericia method (QTcF) >480 msec (Grade ≥2). 
10. Patient has a concurrent illness that would preclude study conduct and assessment including, 
but not limited to, uncontrolled medical conditions, uncontrolled and active infection 
(considered opportunistic, life-threatening, or clinically significant), uncontrolled risk of 
bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive 
pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), 
alcoholic liver disease, or primary biliary cirrhosis. 
11. Patient has a chronic condition requiring the use of systemic corticosteroids >10 mg/day of 
prednisone or equivalent. 
12. Patient has clinical signs of central nervous system involvement of MM. 
13. Female patients who are lactating and breastfeeding or have a positive urine or serum 
pregnancy test during the screening period or a positive urine or serum pregnancy test on 
Day 1 before first dose of study drug if applicable. 
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol. 
15. Patient has a known history of human immunodeficiency virus. 
16. Parts 1 and 2: Known chronic hepatitis C and/or positive serology (unless due to vaccination 
or passive immunization due to Ig therapy) for chronic hepatitis B.  
Japan Safety Lead-In and Part 3: Known chronic hepatitis C and/or positive serology for 
chronic hepatitis B (unless due to vaccination or passive immunization due to Ig therapy), 
or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Seropositive for hepatitis B 
(defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with 

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resolved infection (that is, participants who are HBsAg negative but positive for antibodies 
to hepatitis B core antigen and/or antibodies to hepatitis B surface antigen [anti-HBs]) must 
be screened using real-time polymerase chain reaction (PCR) measurement of HBV DNA 
levels. Those who are PCR positive will be excluded. Seropositive for hepatitis C (anti-
HCV antibody positive or HCV-RNA quantitation positive). EXCEPTIONS: Participants 
with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only 
serologic marker) AND a known history of prior HBV vaccination do not need to be tested 
for HBV DNA by PCR; participants with hepatitis C who are seropositive but with a 
sustained virologic response (defined as absence of viremia at least 12 weeks after 
completion of antiviral therapy). 
17. Patient has a history of severe allergic or anaphylactic reactions to recombinant proteins or 
excipients used in modakafusp alfa formulation. 
18. The patient is currently participating in another antimyeloma therapeutic clinical study. 
19. Previous treatment with modakafusp alfa. 
Part 3: In addition to the above criteria, patients must not have plasma cell leukemia or have had 
primary refractory MM, current central nervous system involvement of MM, myelodysplastic 
syndrome, myeloproliferative syndrome, or have had a second malignancy within the previous 
3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate 
cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, 
or other malignancy for which the patient is not on active anticancer therapy. 
8.0 
STUDY DRUG 
8.1 
Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or subinvestigator(s). A starting dose of 0.001 mg/kg (1 g/kg) 
has been selected for this FIH study of modakafusp alfa. 
Investigational sites will refer to the IB and Pharmacy Manual for the preparation of each dose. 
Premedications are detailed in Section 8.6.1, and additional precautions and restrictions are 
described in Section 8.7. 
If a patient presents with an IRR at any dose level, the duration of the infusion may be extended 
per the investigator’s discretion. Total time from modakafusp alfa dosing solution preparation 
until end of the infusion must not exceed 7 hours. Infusion and pharmacy staff are advised to be 
prepared accordingly for either a planned, extended infusion time or for potential infusion 
interruptions. See Pharmacy Manual for additional guidance. 
More information about the management of IRRs is located in Section 8.6.2 and Section 8.7.1.1. 
Parts 1 and 2: The initial dose should be based on a patient’s weight at screening and only 
adjusted for a ≥10% change in body weight.  

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Modakafusp alfa doses <6 mg/kg will be administered over 1 hour (±10 minutes). Modakafusp 
alfa doses ≥6 mg/kg will be administered over >2 hours (±10 minutes). Any decrease in infusion 
duration must be discussed with and agreed upon by the sponsor. 
Part 3: The 2 doses of 1.5 mg/kg and 3 mg/kg Q4W will be translated into 2 fixed doses of 
120 and 240 mg based on the median bodyweight of approximately 80 kg (from Parts 1 and 2 of 
Study TAK-573-1501) for the Part 3 evaluation. 
Modakafusp alfa doses of 120 and 240 mg will be administered over 1 hour (±10 minutes).  
8.1.1 
Administration of Dexamethasone in Modakafusp Alfa Plus Dexamethasone 
Cohort(s) 
Dexamethasone will be added to the selected MTD/OBD of one or more schedule(s) as 
additional cohort(s). Dexamethasone will be given as a once weekly oral dose of 40 mg. Patients 
over 75 years of age will receive a reduced dose of dexamethasone (20 mg, same schedule).  
Each dose of dexamethasone should be taken at approximately the same time relative to the 
modakafusp alfa infusion when applicable and should be taken with food or liquid (ie, milk) to 
avoid stomach irritation, according to the local label/practice. If a dose of dexamethasone is 
missed, the dose should be taken as soon as the patient remembers as long as the next scheduled 
dose is 72 hours or more away. If the patient vomits after taking a dose, the patient should not 
repeat the dose but should resume dosing at the time of the next scheduled dose. Patient 
recollection of the dexamethasone doses taken at home should be recorded in the electronic case 
report form (eCRF).  
8.2 
Definitions of DLT 
Toxicity will be evaluated according to the NCI CTCAE, Version 5.0.  
Nonhematologic TEAEs of NCI CTCAE Grade ≥3 clearly unrelated to the underlying disease 
and occurring during the first cycle will be considered DLTs (see Section 10.2 for relatedness 
guidance), with the following exceptions: 
• Asymptomatic laboratory changes (other than renal and hepatic laboratory values, and 
Grade 4 lipase/amylase) that can be successfully supplemented (reversion of Grade 4 events 
to Grade ≤2, reversion of Grade 3 events to Grade ≤1 or baseline) within 72 hours. 
• Grade 3 nausea/vomiting that can be managed subsequently with antiemetics (Grade 3 
nausea or vomiting that persists beyond 48 hours with or without appropriate medical 
intervention will be considered a DLT). 
• Grade 3 fatigue lasting less than 72 hours. 
• Grade 3 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
that resolves to Grade ≤1 or baseline within 7 days. 
• Grade 3 IRR that responds to symptomatic treatment, without recurrence of Grade 3 
symptoms. 

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The following hematologic TEAEs Grade ≥3 clearly unrelated to the underlying disease and 
occurring during the first cycle will be considered DLTs: 
• Grade ≥3 hemolysis. 
• Grade 4 neutropenia lasting more than 7 consecutive days. 
• Grade 4 thrombocytopenia lasting more than 14 consecutive days. 
• Grade 3 thrombocytopenia with clinically significant bleeding. 
• Any other Grade ≥4 hematologic toxicity with the exception of Grade 4 lymphopenia. 
An incomplete recovery from treatment-related toxicity causing a >2-week delay in the next 
scheduled infusion before the initiation of Cycle 2 will be considered a DLT. 
In Part 1, DLTs are events meeting the criteria above that occur before Cycle 2 Day 1 
administration. Related TEAEs meeting DLT definitions occurring in later cycles or in Phase 2 
(DLT-like events) will determine the suitability of the MTD/OBD dose for future studies.  
Dose and schedule modifications for toxicity are described in Section 8.4. 
Intrapatient dose escalation will be permitted only when patients in the next dose level cohort 
have completed assessments for Cycle 1 and a decision has been made that this dose level does 
not exceed the MTD. Patients eligible for intrapatient escalation can also be changed to a 
different schedule once the conditions described above are met (for example, a Schedule A 
patient receiving Q4W treatment from Cycle 7 onwards could be moved to the last cleared dose 
level with a different schedule). 
8.3 
Part 1 Dose Escalation Rules  
Part 1 of the study followed a 3 + 3 dose escalation design to evaluate once-weekly (Schedule A) 
administration of modakafusp alfa for DLTs and to determine the MTD/OBD for further 
assessment in phase 2. A starting dose of 0.001 mg/kg was selected for Schedule A on the basis 
of a MABEL calculation (Section 4.6.1).  
Patients were enrolled in cohorts of 3 and assessed for DLTs over a 28-day period (21 days for 
Schedule C) as detailed in Figure 8.a.   
During Part 1, patients who missed one or more scheduled Cycle 1 doses of modakafusp alfa for 
reasons other than a DLT were to be replaced. 
Details regarding the management of dose escalation decisions can be found in the Cohort 
Management Plan.  
For the FIH evaluation of modakafusp alfa, a threshold of fatal AEs related to modakafusp alfa 
of 6% is proposed. Any rate of fatal events related to modakafusp alfa clearly in excess of this 
will result in the stopping of the trial. For the 30 patients expected to be treated at MTD/OBD 
between phase 1 and phase 2 with one specific dose and schedule, this means that the cohort will 
be stopped if 3 fatal AEs related to modakafusp alfa occur, or if 2 fatal AEs related to 
modakafusp alfa occur during the recruitment of the first 12 patients in each cohort. 

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The trial will also be stopped if the rate of modakafusp alfa–related Grade 4 events in any 
nonhematologic System Organ Class (SOC) exceeds 10% (with the exception of Grade 4 
asymptomatic laboratory abnormalities). The trial will also be stopped if events meeting the 
criteria of a DLT occur with an incidence of greater than 40% at any point. The stop will result in 
an immediate halt in enrollment and may also necessitate the halting of treatment of ongoing 
patients, depending on the nature and severity of the safety risk. A final decision to terminate the 
study will be made only after a full review of the safety data by the sponsor’s safety management 
team.  
Figure 8.a is a diagrammatical representation of the dose escalation scheme. 
Figure 8.a 
Dose Escalation Scheme 
 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose.  
 
8.4 
Dose Modification Guidelines 
Dose modification guidelines for toxicities are described below for modakafusp alfa on the basis 
of the type and severity of AEs and causality determination by investigators. Further clarification 
can be obtained in consultation with the sponsor clinician (or designee).  
8.4.1 
Part 1 Dose Escalation 
Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 
influenced decisions regarding dose escalation, expansion of a dose level, or evaluation of 
intermediate dose levels. Dose modifications were not permitted during Cycle 1 of therapy 

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unless the patient experiences a DLT. DLTs are defined in Section 8.2. Patients were to be 
evaluated at least weekly for possible toxicities that may have occurred after the previous 
dose(s). Toxicities are to be assessed according to the NCI CTCAE, Version 5.  
If multiple toxicities were noted, the dose adjustments and/or delays were to be made according 
to the AE with the highest toxicity grade, and the same dose modification guidelines were to 
apply to subsequent cycles unless otherwise noted.  
8.4.2 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
Treatment with modakafusp alfa will use a cycle length of 28 days (21 days for Schedule C). For 
a new cycle of treatment to begin, the patient must meet the following criteria: 
• Absolute neutrophil count must be ≥1000/mm3. Granulocyte-colony stimulating factor 
(G-CSF) can be used to reach this level.  
• Platelet count must be ≥50,000/mm3. 
For therapy to resume, toxicity considered to be related to treatment with modakafusp alfa must 
have resolved to Grade ≤1 or baseline (Grade 2 for platelets), or to a level considered acceptable 
by the physician. If the patient fails to meet the above-cited criteria for retreatment, initiation of 
the next cycle of treatment should be delayed for 1 week. At the end of that week, the patient 
should be re-evaluated to determine whether the criteria for retreatment criteria have been met. If 
modakafusp alfa cannot be administered as scheduled, the patient can continue taking the weekly 
dexamethasone doses unless the investigator considers that it is in the patient’s best interest to 
also hold dexamethasone. 
If there is a delay of a subsequent cycle longer than 2 weeks because of a related AE, the patient 
may be withdrawn from treatment unless there is clinical benefit as assessed by the investigator, 
with agreement by the sponsor. Modakafusp alfa dosing may be continued at the previously 
established safe dose level or below. 
For modakafusp alfa infusions within the same cycle (Schedules A and B [once every 2 weeks 
(Q2W)]), the decision to hold treatment is left to investigator discretion based on clinical and 
analytical data and based on the toxicity that the patient presented with previous infusions in the 
same cycle. The investigator should differentiate from acute toxicity (eg, an IRR) from which the 
patient has recovered at the time of the next infusion or subacute toxicity (eg, neutropenia) that 
might worsen with another infusion if it is not in a clear recovery path. If the dose cannot be 
administered on the scheduled day, the patient can be reviewed at the investigator’s discretion in 
the following 48 hours. If modakafusp alfa cannot be administered within a cycle in this 48-hour 
window, the dose will be missed and the patient scheduled for the next administration per the 
schedule of events (SOE). 
8.4.3 
Criteria for Treatment Interruption and Dose Reductions 
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients experiencing AEs attributed to modakafusp 
alfa may continue study treatment with the same dose, may have modakafusp alfa treatment held, 

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dose reduced, discontinued, or may be permanently discontinued from the study. Patients who 
have study drug held because of treatment-related or possibly related AEs may resume study 
drug treatment after resolution of the AE at the same dose level or at a reduced dose, depending 
on the nature and severity of the AE and whether it is the first occurrence or is recurrent unless 
otherwise specified in the protocol. 
Table 8.a provides general dose modification recommendations for Parts 1 and 2, Table 8.b and 
Table 8.c provide dose modification guidelines for Part 3, and Table 8.e provides dose 
modification recommendations for bleeding TEAEs to mitigate the risk of fatal hemorrhagic 
events. When the dose of modakafusp alfa is withheld on the basis of these criteria, clinical and 
laboratory re-evaluation should be repeated at least weekly or more frequently, depending on the 
nature of the toxicity observed, until the toxicity resolves to Grade ≤1 or baseline. If there are 
transient laboratory abnormalities that, based on investigator assessment, are not clinically 
significant or drug related, continuation of therapy without dose modification is permissible upon 
discussion with the sponsor. See details for managing specific AEs in Section 8.7.1. 
When a dose reduction occurs, the modakafusp alfa dose will be reduced to the next lower dose 
that has been established as a safe dose during dose escalation. For Parts 1 and 2, if the initial 
dose adjustment does not provide sufficient relief, the dose of modakafusp alfa can be further 
reduced if the treating physician considers that the patient is receiving benefit. In general, after a 
dose is reduced, it should not be re-escalated even if there is minimal or no toxicity with the 
reduced dose. However, if further evaluation reveals that the AE that led to the dose reduction 
was not study drug related, the dose may be re-escalated to the original dose level. For Parts 1 
and 2, up to 2 dose level reductions of modakafusp alfa because of AE are generally 
recommended. 
The dose of modakafusp alfa will not be reduced for an individual patient during Cycle 1 unless 
a DLT has been declared and it is still possible for the patient to receive treatment within the 
remaining dosing period scheduled. In this case, the patient can complete Cycle 1 at a reduced 
dose level. 

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8.4.3.1 
Parts 1 and 2 
Table 8.a 
Parts 1 and 2 Dose Modification Recommendations for Modakafusp Alfa 
Toxicities 
This table does not include guidance for management of bleeding TEAEs and IRRs. Refer to 
Table 8.e for the management of bleeding TEAEs and Table 8.g and Table 8.h for the 
management of IRRs. 
Criteria 
Action 
Grade 1 AEs 
No dose reductions or interruptions. 
Grade 2 AEs 
Treat according to local practice. Whether to hold treatment or to 
continue it at the same or a reduced dose (Table 8.d) is at the discretion of 
the investigator. 
Patients experiencing Grade 2 AEs considered related to study treatment 
that are not easily managed or corrected and are not tolerable to the 
patient, or AEs that are not acceptable in the investigator’s judgment, 
should have study treatment interrupted until the AE resolves to Grade ≤1 
or baseline and then restarted at the same dose or, depending on the 
toxicity, at the previous safe dose level or below. 
Grade 3, Grade 4 (not 
life-threatening), and Grade 4 
asymptomatic laboratory AEs 
Hold modakafusp alfa until resolution to Grade ≤1 or baseline, and then 
resume treatment at either the same dose or a reduced dose level at the 
discretion of the investigator. 
Grade 4 (life-threatening) AEs 
Consider permanently withdrawing the patient from the study, except 
when the investigator determines that the patient is receiving clinical 
benefit and has discussed this with the sponsor. Treatment may be 
restarted at a reduced dose level or below when toxicity recovers to 
Grade ≤1 or baseline. 
AEs of all grades 
If treatment has been held for >14 consecutive days without resolution of 
the toxicity (to baseline or Grade ≤1), consider permanently discontinuing 
study treatment unless there is clinical benefit for the patient as assessed 
by the investigator and with sponsor’s approval. Treatment can be 
resumed at a reduced dose level after resolution of AEs to Grade ≤1 or 
baseline. 
AE: adverse event; IRR: infusion-related reaction; TEAE: treatment-emergent adverse event. 
This table does not include guidance for the management of bleeding TEAEs, which is found in Table 8.e or for 
the management of IRRs, which is found in Table 8.g, Table 8.h, Section 8.7.1.1.1, and Section 8.7.1.1.2. 
 
8.4.3.2 
Part 3 
Part 3 dose modification recommendations for hematologic and nonhematologic toxicities are 
detailed in Table 8.b and Table 8.c, respectively, and Part 3 dose reduction levels are found in 
Table 8.d. 

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Table 8.b 
Part 3 Dose Modification Recommendations for Modakafusp Alfa 
Hematological Toxicities 
This table does not include guidance for management of bleeding TEAEs and IRRs. Refer to 
Table 8.e for the management of bleeding TEAEs and Table 8.g and Table 8.h for the 
management of IRRs. 
Criteria 
Action 
Grade 1 and 2 AEs 
No dose reductions or interruptions. 
Grade 3 and 4 AEs 
 
Hold modakafusp alfa next infusion until resolution to Grade ≤2 then 
resume treatment. 
Consider growth factors and/or transfusion according to local practice. 
If the next cycle of modakafusp alfa is delayed for >28 days, study 
treatment should be discontinued unless the investigator considers that the 
patient will receive benefit continuing in the study. 
Dose reduction can be considered.  
AE: adverse event; IRR: infusion-related reaction; TEAE: treatment-emergent adverse event. 
This table does not include guidance for the management of bleeding TEAEs, which is found in Table 8.e or for 
the management of IRRs, which is found in Table 8.g, Table 8.h, Section 8.7.1.1.1, and Section 8.7.1.1.2. 
 
Table 8.c 
Part 3 Dose Modification Recommendations for Modakafusp Alfa Non 
Hematological Toxicities 
This table does not include guidance for management of bleeding TEAEs and IRRs. Refer to 
Table 8.e for the management of bleeding TEAEs and Table 8.g and Table 8.h for the 
management of IRRs. 
Criteria 
Action 
Grade 1 and 2 AEs 
No dose reductions or interruptions. Treat according to local practice. 
Grade 3 AEs and Asymptomatic 
Grade 4 laboratory AEs 
  
Hold modakafusp alfa next infusion until resolution to Grade ≤1 or 
baseline, and then resume treatment. 
1st occurrence: Resume treatment at either the same dose or reduced dose 
at the discretion of the investigator. 
Subsequent occurrence: Reduce modakafusp alfa by 1 dose level.  
If treatment has been held for >28 consecutive days without resolution of 
the toxicity (to baseline or Grade ≤1), consider permanently 
discontinuing study treatment unless there is clinical benefit for the 
patient as assessed by the investigator and with sponsor’s approval. 
Grade 4 AEs (except asymptomatic 
Grade 4 laboratory AEs) 
Permanently withdraw the patient from the study, except when the 
investigator determines that the patient is receiving clinical benefit and 
has discussed this with the sponsor.  
AE: adverse event; IRR: infusion-related reaction; TEAE: treatment-emergent adverse event. 
This table does not include guidance for the management of bleeding TEAEs, which is found in Table 8.e or for 
the management of IRRs, which is found in Table 8.g, Table 8.h, Section 8.7.1.1.1, and Section 8.7.1.1.2. 
 

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Potential dose modifications in Part 3 are to be discussed with the sponsor before 
implementation. 
Table 8.d 
Part 3 Dose Reduction Levels 
 
120 mg 
240 mg 
1st dose level reduction 
80 mg 
160 mg 
2nd dose level reduction 
Discontinue treatment 
120 mg 
3rd dose level reduction 
NA 
Discontinue treatment 
NA: not applicable. 
 
8.4.3.3 
Parts 1, 2, and 3 
Table 8.e provides dose modification recommendations for bleeding TEAEs in Parts 1, 2, and 3 
to mitigate the risk of fatal hemorrhagic events. 
Table 8.e 
Parts 1, 2, and 3 Dose Modification Recommendations for Modakafusp 
Alfa Bleeding TEAEs 
This table does not include guidance for management of IRRs. Refer to Table 8.g and Table 8.h 
for the management of IRRs. 
Criteria 
Action 
Grade 1 and 2 
No dose reductions or interruptions. Treat according to local practice. 
Grade 3 without associated Grade 4 
thrombocytopenia 
Hold next infusion of modakafusp alfa until resolution to Grade ≤1 or 
baseline, and then resume treatment. 
Subsequent occurrence: Discontinue modakafusp alfa. 
Grade 3 with associated Grade 4 
thrombocytopenia 
Discontinue modakafusp alfa. 
Grade 4 
Discontinue modakafusp alfa. 
IRR: infusion-related reaction; TEAE: treatment-emergent adverse event. 
This table does not include guidance for the management of IRRs, which is found in Table 8.g, Table 8.h, 
Section 8.7.1.1.1, and Section 8.7.1.1.2. 
 
8.4.4 
Criteria for Discontinuing Modakafusp Alfa  
Potential discontinuations of modakafusp alfa should be discussed with the sponsor or contract 
research organization (CRO) before implementation. 
Modakafusp alfa should be discontinued in patients experiencing an AE in Cycle 1 meeting 
criteria for a DLT for which the investigator considers that retreatment of the patient could be 
dangerous. 
If the next cycle of modakafusp alfa is delayed for >14 days (>28 days for Part 3) because of 
modakafusp alfa–related toxicities, study treatment should be discontinued unless the 
investigator considers that the patient will receive benefit continuing in the study. Patients will 

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be evaluated 30 days (EOT visit) after the last dose of modakafusp alfa or right before the start of 
subsequent systemic anticancer therapy to permit the detection of any delayed TEAEs.  
8.4.5 
Dexamethasone Dose Modification 
The decision and management of dexamethasone modifications will be according to 
investigator’s discretion. Dose modifications should be recorded in the eCRF. 
8.5 
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
• Radiation therapy for disease under study. Local radiotherapy for bone pain is permitted after 
agreement with the sponsor and once PD is ruled out. 
• Any investigational agent other than modakafusp alfa, including agents that are commercially 
available for indications other than MM that are under investigation for the treatment of MM. 
• Concomitant chronic corticosteroid administration of >10 mg of prednisone or equivalent 
unless given as treatment or prophylaxis for IRRs, as premedication for administration of 
certain blood products or for exacerbations of respiratory tract disorders, acute pain 
management, suspected or confirmed immune-mediated thrombocytopenia, or if tumor flare 
is suspected.  
8.6 
Permitted Concomitant Medications and Procedures 
8.6.1 
Premedication 
As of Amendment 06, based on the experience with infusion reactions in patients not receiving 
premedications, it is strongly recommended that all patients receive premedication, 
including corticosteroids, before modakafusp alfa dosing. Any decision to stop 
premedications must be discussed with and agreed upon by the sponsor.  
Before each injection of modakafusp alfa at doses up to and including 3 mg/kg and for patients 
receiving a fixed dose in Part 3, patients should receive the following premedications (all or in 
part) per investigator discretion: 
• Corticosteroid IV or orally (PO) (methylprednisolone 100 mg, dexamethasone 20 mg, or 
equivalent) 60 minutes to 2 hours before treatment; if a patient experiences no significant 
IRR, the dose of methylprednisolone may be decreased to 50 mg (or dexamethasone to 
10 mg) after visit 4. Intermediate- or long-lasting steroids of equivalent dose can be 
substituted.  
• 650 to 1000 mg acetaminophen PO 60 minutes to 2 hours before treatment. 
• 25 to 50 mg diphenhydramine or equivalent PO approximately 12 hours before and again 
approximately 1 hour before Cycle 1 treatment; for all subsequent infusions, approximately 
1 hour before.  

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Montelukast (10 mg PO) may be given to patients who are intolerant to diphenhydramine or for 
whom diphenhydramine is ineffective.  
Patients who are receiving a modakafusp alfa dose of 6 mg/kg or higher must be premedicated 
with dexamethasone, acetaminophen, diphenhydramine, and montelukast, and it is recommended 
that the dose will be administered over >2 hours (±10 minutes). Any decrease in infusion 
duration must be discussed with and agreed upon by the sponsor.  
8.6.2 
Postinfusion Medication  
Patients may receive 20 to 25 mg prednisone or 4 mg of dexamethasone PO or equivalent on the 
first and second days after all full-dose infusions. Other concomitant medications can be 
administered per institutional protocols.  
During the infusion and for 2 hours postdose, the patient should be continually monitored by 
medically qualified staff with access to emergency medical equipment and medications to 
manage infusion reactions.  
8.6.3 
Other Permitted Concomitant Medications and Procedures 
All necessary supportive care consistent with optimal patient care will be available to patients as 
necessary. All blood products and concomitant medications will be recorded in the eCRFs as 
specified in the SOEs (Appendix A). 
The following medications and procedures are permitted while the patient is receiving the study 
drug: 
• Myeloid growth factors (eg, granulocyte colony stimulating factor, granulocyte macrophage-
colony stimulating factor) and erythropoietin are permitted. Their use should follow the 
product label, published guidelines, and institutional practice. During Cycle 1, G-CSF is 
allowed for Grade 4 neutropenia. In addition, G-CSF is allowed to accelerate the recovery of 
neutropenia to enable the start of new cycle (Section 8.4.2). 
• Patients should be transfused with red blood cells and platelets as clinically indicated. 
Transfusions must be recorded in the concomitant procedure pages of the eCRF. Platelet 
transfusion should not be applied only for the purpose of meeting the treatment criterion of 
platelet count to start a new cycle. 
• Concomitant treatment with bisphosphonates will be encouraged for all patients with 
evidence of lytic destruction of bone or with osteopenia, according to the American Society 
of Clinical Oncology Clinical Practice Guidelines or institutional practice in accordance with 
the product label, unless specifically contraindicated. If bisphosphonate therapy was not 
started before the study start, it should be initiated as soon as clinically indicated.  
• Topical or inhaled steroids (eg, for the treatment of asthma) are permitted. 
• Systemic steroids for acute management of pain, suspected or confirmed immune-mediated 
thrombocytopenia or other disease or treatment-related complications are permitted. 

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• Plasmapheresis. 
• IV immunoglobulins (IVIG) usage is acceptable for prolonged Grade 4 transfusion-
dependent thrombocytopenia or other investigator criteria if it is considered that there is an 
underlying autoimmune mechanism.  
• Thrombopoietin agonists are also allowed for thrombocytopenia management at the 
investigator’s discretion.  
8.7 
Precautions and Restrictions  
Modakafusp alfa has been shown to interfere with serological testing due to binding to CD38 on 
RBCs, which results in positive direct and indirect antiglobulin tests. Modakafusp alfa–mediated 
interference in both the direct and indirect antiglobulin tests was observed at clinically relevant 
concentrations of modakafusp alfa. The duration of modakafusp alfa–mediated positive direct 
and indirect antiglobulin tests have not yet been evaluated. The determination of a patient’s ABO 
and Rh blood type are not affected by the presence of modakafusp alfa. Notify blood transfusion 
centers of this interference with serological testing and inform blood banks that a patient has 
received modakafusp alfa. Type and screen patients before starting modakafusp alfa if this was 
not performed previously. 
Fluid deficit should be corrected before initiation of treatment and during treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal function 
given the reported NSAID-induced renal failure in patients with decreased renal function. 
Patients should not drive, operate dangerous tools or machinery, or engage in any other 
potentially hazardous activity that requires full alertness and coordination if they experience 
sedation while enrolled in this study. 
Patients are to be instructed to limit the use of alcohol while enrolled in this study. 
It is not known what effects modakafusp alfa has on human pregnancy or development of the 
embryo or fetus; therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female 
patients of reproductive age and male patients should use effective methods of contraception 
through defined periods during and after study treatment as specified below. 
Female patients must meet one of the following: 
• Postmenopausal for at least 2 years before the screening visit, OR 
• Surgically sterile, OR 
• If they are of childbearing potential:  
– Agree to practice 1 highly effective method (Table 8.f) and 1 additional effective (barrier) 
method of contraception at the same time, from the time of signing of the informed 
consent form (ICF) through 7 days after the last dose of study drug (whichever is longer), 
OR  

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– Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.) 
– Agree not to donate an egg or eggs (ova) during the study and for 7 days after the last 
dose of study drug. 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following: 
• Agree to practice effective barrier contraception (Table 8.f) during the entire study treatment 
period and through 7 days after the last dose of study drug, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
• Agree not to donate sperm during the study and for 7 days after the last dose of study drug. 
Table 8.f 
Highly Effective Methods of Contraception 
Highly effective methods 
Additional effective (barrier) methods 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation 
 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
 
Male or female condom with or without spermicide 
(female and male condoms should not be used 
together) 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation 
• 
Oral 
• 
Injectable 
• 
Implantable 
 
Intrauterine device (IUD) 
 
Cap, diaphragm, or sponge with spermicide 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
 Sexual abstinence  

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8.7.1 
Management of Specific Adverse Reactions 
8.7.1.1 
Handling of IRRs 
An IRR is a reaction that develops during or shortly after administration of a drug. Signs and 
symptoms may include pruritus, urticaria, fever, rigors/chills, diaphoresis, bronchospasms, and 
cardiovascular collapse. In this study, IRRs are designated as AESIs. 
It is strongly recommended that all patients receive premedication, including 
corticosteroids, before modakafusp alfa dosing.  
Patients who are receiving a modakafusp alfa dose of 6 mg/kg or higher must be premedicated 
with dexamethasone, acetaminophen, diphenhydramine, and montelukast. 
Modakafusp alfa doses <6 mg/kg will be administered over 1 hour (±10 minutes). Modakafusp 
alfa doses ≥6 mg kg will be administered over 2 hours (±10 minutes). Any decrease in infusion 
duration must be discussed with and agreed upon by the sponsor. 
If a patient presents with an IRR at any dose level, the duration of the infusion may be extended 
per investigator’s discretion. Total time from modakafusp alfa dosing solution preparation until 
end of infusion must not exceed 7 hours. Infusion and pharmacy staff are advised to be prepared 
accordingly for either a planned, extended infusion time or for potential infusion interruptions. 
See the IB and Pharmacy Manual for additional guidance. 
Patients should be carefully observed during modakafusp alfa infusions. Trained trial staff at the 
clinic should be prepared to intervene in case of any IRRs, and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilators and medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at bedside. 
In case of an IRR, serum samples should be taken for central evaluation of immunogenicity and 
circulating biomarkers (as detailed in the SOEs).  
Patients will be advised to promptly report signs and symptoms that may indicate IRRs, 
including fever, chills, dizziness, nausea, vomiting, flushing, cough, headache, and rash during or 
soon after end of infusion. 
If the patient continues on treatment, premedication and postinfusion medication should be 
considered for future modakafusp alfa administrations per Sections 8.6.1 and 8.6.2. 
All IRRs, including the signs and symptoms, will be reported in the eCRF per completion 
guidelines.  
Serious AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner. 
8.7.1.1.1 
Grade 1 and 2 IRRs 
The recommendations for managing Grade 1 and Grade 2 IRRs are presented in Table 8.g. 

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Table 8.g 
Recommendations for Managing Grade 1 and Grade 2 IRRs 
IRR 
Action 
Grade 1 or 2 
The infusion should be paused. When the patient’s condition is stable, 
infusion may be restarted at the investigator’s discretion. 
Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion. Consider premedication and postmedication 
before restarting the infusion and for future modakafusp alfa 
administrations. 
Grade 2 event of laryngeal edema, or 
Grade 2 event of bronchospasm that 
does not respond to systemic therapy.  
Patient must be withdrawn from treatment if the event does not resolve 
within 6 hours from onset. 
IRR: infusion-related reaction. 
 
8.7.1.1.2 
Grade 3 or Higher IRRs 
The recommendations for managing Grade 3 IRRs are presented in Table 8.h. 
Table 8.h 
Recommendations for Managing Grade 3 IRRs 
IRR 
Action 
Any Grade 4 event 
Patient must be withdrawn from treatment. 
Grade 3 bronchospasm or laryngeal edema 
Patient must be withdrawn from treatment. 
Grade 3 event other than bronchospasm or laryngeal 
edema 
Infusion must be stopped, and the patient must be 
observed carefully until resolution of the IRR. 
If the intensity of the IRR remains at Grade 3 after 2 
hours: 
Patient must be withdrawn from treatment. 
If the intensity of the IRR decreases to Grades 1 or 2: 
Infusion may be restarted at the investigator’s 
discretion. Administer corticosteroids, acetaminophen, 
and antihistamines per Sections 8.6.1 and 8.6.2 before 
restarting infusion. Within 2 hours upon restart, the 
infusion rate should be half of that employed before the 
interruption. Subsequently, the infusion rate may be 
increased at the investigator’s discretion. 
If the intensity of the IRR returns to Grade 3: 
The procedure described above may be repeated after 
restart of the infusion at the investigator’s discretion. 
If the intensity of the IRR increases to Grade 3 for a 
third time: 
Patient must be withdrawn from treatment. 
IRR: infusion-related reaction.  
 
8.7.1.2 
Handling of Low Platelet Counts 
Treatment decisions will be based on patient platelet counts assessed before any transfusion. 
Low platelet counts (Grade 4) should cause scheduled infusions to be postponed or to be 

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permanently discontinued. Please see Table 8.e for dose modifications for bleeding TEAEs for 
Parts 1, 2, and 3. If at any time the platelet count is less than 10×109/L the patient should be 
withdrawn from modakafusp alfa treatment unless clinical benefit is observed and the 
investigator considers that thrombocytopenia can be managed, including with dose 
modifications. The investigator can consider the usage of corticosteroids, IVIG, or 
thrombopoietin agonists in selected cases depending on severity, duration, transfusion 
requirements, and additional risk factors for bleeding and based on the suspected underlying 
mechanism. Platelet transfusion and daily monitoring of platelet counts are recommended.  
8.8 
Prophylaxis Against Risk of Infection 
Patients may be at an increased risk of infection, including reactivation of herpes zoster and 
herpes simplex viruses. Prophylactic antiviral therapy such as acyclovir or valacyclovir should 
be initiated as clinically indicated.  
8.9 
Blinding and Unblinding 
This is an open-label study.  
8.10 
Description of Investigational Agents 
Modakafusp alfa is a humanized anti-CD38, IgG4, mAb fused to attenuated IFN-α 2b. 
Additional details can be found in the modakafusp alfa IB.  
8.11 
Preparation, Reconstitution, and Dispensation 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever the solution and container permit. 
Modakafusp alfa is an anticancer drug; as with other potentially toxic compounds, caution should 
be exercised when handling modakafusp alfa. 
Dexamethasone will be procured by the site from commercial sources. Additional details are 
provided in the package insert. 
8.12 
Packaging and Labeling 
Supplies of modakafusp alfa will be labeled according to the current International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements.  
Dexamethasone will be site-sourced from commercial supply with commercial packaging and 
labeling. 
Modakafusp alfa is supplied as a single-use stoppered glass vial with an aluminum flip-off seal, 
providing 10 mg/mL of modakafusp alfa. 

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8.13 
Storage, Handling, and Accountability 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all modakafusp alfa received and that any discrepancies are reported and resolved 
as outlined in the Pharmacy Manual. 
Modakafusp alfa should be stored in the original container as specified on the label (frozen 
at -20°C for frozen liquid or 2°C to 8°C for lyophilized formulation) and protected from light 
until it is used. Modakafusp alfa remains suitable for use until the expiration date printed on the 
primary container or carton if stored as directed. Modakafusp alfa should be thawed and 
equilibrated to room temperature or reconstituted as directed prior to administration. 
Thawing, reconstitution, and dilution procedures for modakafusp alfa vials are provided in the IB 
and Pharmacy Manual.  
Each modakafusp alfa shipment will include a packing slip listing the contents of the shipment, 
and any applicable forms. 
Only patients enrolled in the study may receive modakafusp alfa, and only authorized staff at the 
investigational center may supply or administer modakafusp alfa. All modakafusp alfa must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions or appropriate instructions with access limited to 
the investigator and authorized staff at the investigational center. 
The investigator is responsible for ensuring that deliveries of modakafusp alfa and other study 
materials from the sponsor are correctly received, recorded, and handled, and stored safely and 
properly in accordance with the Code of Federal Regulations (CFR) or national and local 
regulations, and used in accordance with this protocol. 
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for modakafusp alfa accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
A record of modakafusp alfa accountability (ie, modakafusp alfa and other study materials 
received, used, retained, returned, or destroyed) must be prepared and signed by the principal 
investigator or designee, with an account given for any discrepancies. Empty, partially used, and 
unused modakafusp alfa will be disposed of, retained, or returned to the sponsor or designee. 
Further guidance and information are provided in the Pharmacy Manual. 
9.0 
STUDY CONDUCT 
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines. 
9.1 
Study Personnel and Organizations 
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 

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the CRO team may be found in the Study Operations Manual. A full list of investigators is 
available in the sponsor’s investigator database. 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB/independent ethics committee (IEC).  
9.3 
Study Procedures 
Refer to Appendix A, Appendix B, and Appendix C for timing of assessments. Additional details 
are provided as necessary in the sections that follow. 
Sites will make every effort to see patients in the clinic to complete all study-specified 
assessments as outlined in the SOE (Appendix A).  
In unavoidable circumstances, such as the coronavirus disease 2019 (COVID-19) public health 
emergency, exceptions can be made for alternative methods for conducting patient visits and 
performing laboratory and imaging assessments as detailed below. Remote visits and 
telemedicine must comply with national and local laws and regulations. Such instances will be 
documented in the study records and eCRF, if applicable, and the sponsor will be informed.  
Tests and procedures should be performed on schedule, but, unless otherwise specified, 
occasional changes are allowable within a 4-day window for holidays, vacations, and other 
administrative reasons or a longer window after discussion with the Takeda study clinician or 
designee. 
9.3.1 
Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care. 
Informed Consent Procedure: If necessary, informed consent from a potential or current trial 
participant may be obtained via electronic informed consent (eIC) capabilities or an electronic 
face-to-face consent interview if these individuals are unable to travel to the site. 
9.3.2 
Patient Demographics 
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening. 
9.3.3 
Medical History 
During the screening period, a complete medical history will be compiled for each patient. This 
includes initial diagnosis date and MM staging at initial diagnosis using International Staging 
System and Salmon-Durie stage. Known cytogenetic alterations should be collected, as well as 
prior treatment regimens, with each treatment duration (start and stop dates), and the best 
response obtained with each of them. Refractoriness to previous treatments should be collected 

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following IMWG criteria. In addition, concomitant medications will be recorded as specified in 
Section 9.3.8. 
9.3.4 
Physical Examination 
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A). 
If an investigator considers it safe and appropriate for a subject to miss a protocol-specified 
physical examination for COVID-19-related reasons, the study site physician or other qualified 
site staff will speak directly with the subject by telephone or other medium (eg, a 
computer-based video communication) to assess subject safety and overall clinical status with a 
plan for in-person evaluation if signs and symptoms warrant. Such instances will be documented 
in the study records and eCRF if applicable, and the sponsor will be informed. 
9.3.5 
Patient Height 
Height will be measured during the screening visit only.  
9.3.6 
Patient Weight 
Weight will be measured at the times specified in Appendix A. Initial dose should only be 
adjusted for a ≥10% change in body weight in Parts 1 and 2 (Section 8.1). 
9.3.7 
ECOG Performance Status 
ECOG performance status as defined in Appendix G will be evaluated at the times specified in 
Appendix A. 
9.3.8 
Concomitant Medications and Procedures 
Any prior or concomitant medication a patient has had from signing of the ICF through 
30 (+10) days after the last dose of modakafusp alfa or the start of subsequent systemic 
anticancer therapy, whichever occurs first, will be recorded on the eCRF. Trade name and 
international nonproprietary name (if available), indication, and start and end dates of the 
administered medication will be recorded. Medications used by the patient and therapeutic 
procedures (including any transfusion) completed by the patient will be recorded in the eCRF. 
See Section 8.5 and Section 8.6 for medications and therapies that are prohibited or allowed 
during the study. 
9.3.9 
Safety Evaluations 
9.3.9.1 
Vital Signs 
Vital signs include temperature, pulse, respiratory rate, and oxygen saturation. They include also 
supine or seated measurements of diastolic and systolic blood pressure (after 3 to 5 minutes in 
this position; all measurements should be performed in the same initial position), heart rate, and 
body temperature. They will be measured at the times specified in Appendix A. Blood pressure 

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will be measured every 30 minutes (±5 minutes) during the first 4 infusions, after the end of the 
infusion, and at any moment if the patient complains of symptoms consistent with IRR. If the 
patient experiences hypotension (with or without symptoms), intensive blood pressure 
monitoring according to local practice should be instituted. The patient cannot be released from 
the site until blood pressure has returned to Grade 1 or baseline for at least 1 hour. Patients must 
be observed for at least 2 hours after the end of every modakafusp alfa infusion.  
Any vital sign value that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the eCRF as an AE and monitored as described in 
Section 10.2.  
9.3.9.2 
Pregnancy Testing 
A participant of childbearing potential is defined as a participant with a uterus and ovary(ies) 
who: (1) has not undergone a hysterectomy or bilateral oophorectomy or, (2) has not been 
naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 
24 consecutive months). 
1) Screening/baseline: Participants of childbearing potential must have 2 negative pregnancy 
tests before starting study drug. 
• 
A urine or serum pregnancy test will be required during screening (within 10 to 14 days 
before start of study drug); this test must be negative. 
• 
A urine or serum pregnancy test must be performed at baseline (within 24 hours before 
the start of study drug). The results from these tests must be available and negative before 
the first dose of study drug is administered. 
2) On-treatment: During the study, participants of childbearing potential must have a negative 
urine or serum pregnancy test result within 72 hours before dosing on Day 1 of each cycle during 
treatment prior to dosing. If a menstrual period is delayed, absence of pregnancy in participants 
of childbearing potential must be confirmed by a negative urine or serum pregnancy test. 
• 
Pregnancy tests may also be repeated during the study as per request of IRB or if required 
by local regulations. 
3) EOT: A urine or serum pregnancy test is required at EOT in participants of childbearing 
potential. 
9.3.9.3 
TEAEs 
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as 
specified in the SOEs (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of TEAEs and SAEs. 

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9.3.9.4 
ECGs 
A 12-lead ECG will be administered at the time points specified in the SOEs (Appendix A). A 
qualified person will interpret the ECG. In Parts 1 and 2, triplicate ECGs will be read centrally, 
and single ECGs will be read locally. When the timing of triplicate and single (safety) ECGs 
coincide, the site can use the triplicate ECG collection for safety evaluation. 
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered a TEAE, recorded on the source documentation and in the 
eCRF, and monitored as described in Section 10.2. 
In Parts 1 and 2, triplicate ECGs for initial heart rate-corrected QT interval evaluation will be 
recorded and electronically stored at prespecified time points. These time points correspond with 
PK draws. Please refer to the PK Sampling Schedules (Appendix C). 
The ECG measurements should be completed before the PK/ pharmacodynamic blood draw. It is 
recommended that patients refrain from eating or limit themselves to bland food for 1 hour 
before dosing and until completion of the scheduled ECG measurements (4 hours after dosing).  
In Part 3, all patients will have single ECGs collected and read locally at screening, at the end of 
the infusion (+30 minutes), or in accordance with the SOEs in Appendix A. 
9.3.9.5 
Clinical Laboratory Evaluations 
Parts 1 and 2: Clinical laboratory evaluations will be performed either locally or centrally as 
indicated in each section.  
Part 3: Clinical laboratory evaluations will be performed by a central laboratory. For dosing 
decisions, local hematology and chemistry laboratory results may be used; however, samples 
must also be sent to central laboratories. 
In extenuating circumstances, such as during the COVID-19 public health emergency, 
laboratories closer to a patient's home may be utilized for local clinical laboratory assessments 
provided that pertinent laboratory information, including normal reference ranges, are provided 
to the sponsor or designee. 
Central laboratory assessments must still be obtained at the site as needed and sent to 
sponsor-designated laboratories. Handling of central clinical laboratory blood samples is outlined 
in the Laboratory Manual.  
Not all collections are applicable to all cohorts or patients within a cohort. Additionally, 
collection of samples for exploratory biomarkers are dependent upon local guidelines and 
regulations (including feasibility of sample export), as well as IRB/IEC approval.  
9.3.9.6 
Clinical Chemistry, Hematology, and Urinalysis 
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the SOEs (Appendix A). They will be performed locally only for Parts 1 and 2.  

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Central laboratory analysis is required for Part 3. Local hematology and chemistry 
laboratory results may be used for dosing decisions; however, samples must still be sent to the 
central laboratory as well. Hematology and chemistry panels may be collected up to 3 days 
before the day of dosing. Local laboratory evaluations may be done more frequently at the 
investigator’s discretion (ie, for acute management of TEAEs) and if they are the basis for dose 
modification or other clinical intervention, the results must be recorded in the CRF.  
Table 9.a 
Clinical Chemistry and Hematology Tests 
Hematology  
Chemistry  
Hematocrit 
Hemoglobin 
Leukocytes with differential c  
Neutrophils (ANC) 
Platelet (count) 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Bicarbonate (HCO3-) or carbon 
dioxide (CO2) 
Creatinine 
Standard C-reactive protein 
Chloride 
Glucose (nonfasting) 
Lactate dehydrogenase  
Magnesium 
Phosphate 
Potassium 
Sodium 
Urate 
Other 
Antiplatelet antibody testing a, b 
Thyroid function tests (TSH, free or 
total T3, and free or total T4) a 
PT/INR, aPTT, fibrinogen, D-Dimer  a, d 
ANC: absolute neutrophil count; aPTT: activated partial thromboplastin time; INR: international normalized 
ratio; PT: prothrombin time; TSH: thyroid stimulating hormone.  
a Analyzed locally.  
b Only applicable for Parts 1 and 2. 
c Differential to include basophils, eosinophils, lymphocytes, monocytes, and neutrophils. 
d To be collected if clinically significant bleeding is observed. 
 
Table 9.b 
Clinical Urinalysis Tests 
Urinalysis 
Bilirubin 
Glucose 
Ketones  
Leukocytes 
Nitrite  
Occult blood 
pH  
Protein 
Specific gravity 
Turbidity and color 
Urobilinogen 
Microscopic analysis (only if macroscopic 
parameters abnormal; Part 3 only) 
 
If creatinine clearance is to be estimated, the Cockcroft-Gault formula will be employed as 
follows:  
Estimated creatinine clearance 
= [(140 −Age) • Mass (kg) ] / [72 • serum creatinine (mg/dL)]  
For female patients, the result of the formula above should be multiplied by 0.85.  

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9.3.9.7 
2-Microglobulin 
A blood sample will be collected at screening for serum 2-microglobulin testing. For Parts 1 and 
2 results will be analyzed locally. Central laboratory analysis is required for Part 3. 
9.3.10 
Disease Assessment 
Patients will be assessed for disease response according to the European Group for Blood and 
Marrow Transplant criteria, modified and updated by the IMWG criteria (Appendix F).  
For Parts 1 and 2, response assessments will be made on the basis of local laboratory data. For 
Part 3, response assessments will be made on the basis of central laboratory data.  
Assessments should occur every cycle during treatment and every 4 weeks during the 
PFS/survival follow up period until disease progression (see SOEs). If the start of a cycle is 
delayed, serum M-protein and serum FLCs are to be collected for central laboratory analysis if 
not previously sent within the preceding 10 days. If a patient has collected a 24-hour urine 
sample and brought it to a visit, the sample should be sent for central laboratory analysis of urine 
M-protein even if not on Day 1 of a cycle. 
Serum and urine response assessments will be performed as indicated in the SOEs (Appendix A). 
Imaging tests for qualifying patients (see Sections 9.3.10.1 and 9.3.10.2) are to be performed 
every other cycle beginning with Cycle 3 only for patients with extramedullary disease at 
screening or when there is a clinical suspicion of extramedullary progression. In extenuating 
circumstances, such as during the COVID-19 public health emergency, patients may use an 
alternative site for imaging with prior notification to the sponsor or designee. 
CR should be confirmed follow up assessments (by local laboratories for Parts 1 and 2 and by 
central laboratories for Part 3) of serum protein electrophoresis (SPEP), urine protein 
electrophoresis (UPEP), immunofixation of blood and urine, and serum FLCs as outlined in the 
SOEs (Appendix A). One bone marrow assessment (locally evaluated for Parts 1, 2 and 3) is 
required to document CR; no second bone marrow confirmation is needed.  
Please note that to determine a response of sCR, bone marrow immunohistochemistry or 
immunofluorescence for the : ratio, as well as serum FLC assay, should be performed for all 
patients suspected to be in CR to meet this response category’s requirements. 
For Parts 1 and 2, PD may be confirmed per standard clinical practice at the site. Local 
laboratories may be used to confirm PD. For Part 3, PD must be confirmed based on central 
laboratories. 
The following disease assessments will be performed as indicated in the SOEs (Appendix A).   
For Part 3, imaging assessments to summarize status of known lesions will be collected and 
should be based on available imaging at each respective time point. 

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9.3.10.1 Extramedullary Disease Imaging 
Imaging will be evaluated locally for all patients. For patients with previously documented 
extramedullary disease or with suspicion of extramedullary progression, a positron emission 
tomography-computed tomography (PET-CT) scan, computed tomography (CT) scan, or 
magnetic resonance imaging (MRI) scan will be performed at screening (if the patient has 
adequate image test performed within 5 weeks of the planned first dose of study drug, they can 
be used as baseline and do not need to be repeated as part of screening) as needed for evaluation 
of disease. If extramedullary disease is documented at screening, a repeat PET-CT scan, CT 
scan, or MRI scan should be performed every other cycle beginning with Cycle 3.  
All follow-up scans should use the same imaging modality as used at screening. 
For Part 3, imaging to assess extramedullary disease is required for all patients at screening by 
PET-CT, MRI, or CT. Imaging performed within 5 weeks of the planned first dose of study drug 
can be used as baseline evaluations and does not need to be repeated as part of screening. If 
extramedullary disease is documented at screening, repeat imaging using the same modality 
every 3 cycles until a plateau or complete response is reached, or as clinically indicated, and then 
at suspected progression (Hillengass et al. 2019). Imaging tests for patients with extramedullary 
disease should be performed if new symptoms suggest PD.  
For Part 3, imaging assessments to summarize status of known lesions will be collected and 
should be based on available imaging at each respective time point. 
9.3.10.2 Bone Imaging 
Imaging will be evaluated locally for all patients. A complete skeletal survey, using plain x-ray 
or low-dose total body CT scan, will be performed at screening (if the patient has adequate 
image test performed within 5 weeks of the planned first dose of study drug, they can be used as 
baseline and do not need to be repeated as part of screening). If there are symptoms or signs that 
suggest increased or new bone lesions, the skeletal survey or plain film of symptomatic sites may 
be repeated any time during the study and at the EOT visit. A PET-CT may be done at screening 
in place of a skeletal survey provided that the same modality for assessment is used throughout 
the study. 
Patients with a normal skeletal survey at baseline do not need to repeat the test periodically 
unless bone progressive disease is clinically suspected. 
Radiographs will be analyzed locally and reports maintained with the patient record for retrieval 
during monitoring visits. 
For Part 3, imaging to assess bone disease is required for all patients at screening. Imaging 
performed within 5 weeks of the planned first dose of study drug can be used as baseline 
evaluations and does not need to be repeated as part of screening. Low-dose whole-body CT is 
recommended over conventional skeletal survey for the evaluation of multiple myeloma bone 
disease. Conventional skeletal survey can be used for the diagnosis of multiple myeloma when 
whole-body CT or other novel imaging methods are not available. Additional assessments for 

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bone disease can be done at the discretion of the investigator (ie, for suspected increased or new 
bone lesions PD). The same modality for assessment should be used throughout the study.  
For Part 3, imaging assessments to summarize status of known lesions will be collected and 
should be based on available imaging at each respective time point. 
9.3.10.3 Quantification of Immunoglobulins 
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained as specified in 
Appendix A. For the rare patient with known IgD or IgE MM, the quantitative test for that 
antibody will be followed at the same time points throughout the treatment period and PFS 
follow-up period as quantitative Igs (in addition to quantitative IgM, IgG, and IgA). Analysis of 
Ig will be performed locally for Parts 1 and 2. Central laboratory collection is required for 
Part 3.  
9.3.10.4 Quantification of M-Protein in Serum and Urine 
A blood and 24-hour urine sample will be obtained as specified in the SOE (Appendix A). Urine 
collection and testing will be repeated at the times specified only for patients with a baseline 
urine M-protein of ≥200 mg/24 hours in Parts 1 and 2. Urine collection and testing (centrally) 
will be repeated at each cycle in Part 3. 
M-protein in serum and urine will be quantified by SPEP and UPEP. These samples will be 
tested locally for Parts 1 and 2. Central laboratory collection is required for Part 3. 
9.3.10.5 Serum FLC Assay 
Blood samples will be obtained as specified in Appendix A for the serum FLC assay (including 
quantification of  and  chains and the : ratio). Samples must be obtained at the time of 
suspected CR. Blood samples will be analyzed locally for Parts 1 and 2. Central laboratory 
collection is required for Part 3. 
9.3.10.6 Immunofixation of Serum and Urine 
Serum and urine samples will be obtained as specified in the SOE (Appendix A) at screening and 
to confirm CR. Only for Parts 1 and 2, immunofixation of serum and/or urine may be omitted at 
screening if a previous local laboratory report for the serum and/or urine protein electrophoresis 
states that the observed monoclonal spike is consistent with one previously characterized by 
immunofixation and specifies the heavy chain and light chain previously identified. 
Immunofixation testing will be performed in the local laboratory for Parts 1 and 2. Central 
laboratory collection is required for Part 3. 
9.3.10.7 Interference Assay 
For Part 3 only: 
IgG mAbs given recently as prior therapy can interfere with assays used to monitor endogenous 
M-protein. The SPEP and serum immunofixation can be positive due to mAb. This interference 

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can impact the determination of CR and of disease progression in some patients with IgG 
myeloma protein. 
Therefore, in patients with persistent VGPR by IMWG criteria where mAb interference is 
suspected or whenever the SPEP values reach ≤0.2 g/dL for 2 consecutive disease evaluations 
during a period of time when the mAb could be circulating at detectable levels, a CR should be 
suspected triggering the need for interference testing on the M-protein sample at the central 
laboratory. Currently, if the interference test results are positive, the assay is considered positive 
for endogenous protein, and thus there is still disease present. If the interference test result is 
negative, the assay is considered negative for endogenous protein, and thus the remaining protein 
is likely the mAb. This is communicated back to the sites, and the sites can proceed to perform a 
confirmatory BMA evaluation for possible CR if not already performed earlier. 
9.3.10.8 Bone Marrow Aspiration 
Bone marrow samples will be analyzed locally as detailed in Appendix B (Parts 1 and 2) and in 
Appendix A for Part 3. 
Bone marrow morphology is not required for Part 3.  
9.3.10.8.1 
Bone Marrow Central Laboratory Evaluations 
A standard BMA and biopsy drawn prior to consent is acceptable for local analyses provided it is 
collected within 5 weeks of the first dose. However, this sample is not acceptable for central 
laboratory biomarker and MRD assessments; therefore, a fresh BMA is required at screening for 
central analyses.  
If CR is suspected based on laboratory values, a BMA and biopsy are required to locally confirm 
CR (Appendix F) as per routine clinical practice. At the time of this procedure, one sample must 
be collected for MRD assessment and frozen in accordance with the procedures outlined in the 
Laboratory Manual. Central MRD assessments should be done every 6 months for patients 
continuing in CR. 
Part 3: BMA collections for central MRD and cytogenetic evaluations are required at screening. 
In addition to the BMA for MRD collected at suspected CR, BMAs will be collected every 
6 months following the collection of the suspected CR MRD sample for further evaluation of 
MRD. An optional BMA collection at the time of progression is requested for those patients who 
had previously responded to treatment in order to gain insight into resistance mechanisms. 
Screening MRD samples will be obtained in China based on acceptability of method chosen. 

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9.3.10.8.2 
Bone Marrow Local Laboratory Evaluations 
9.3.10.8.2.1 
Disease Assessment 
A BMA will be obtained at screening for disease assessment and at any time during treatment to 
assess CR or to investigate suspected PD if it is in accordance with standard local practice. This 
evaluation will be performed locally. Clonality for sCR should be established by showing κλ 
light-chain restriction on ﬂow cytometry, immunohistochemistry, or immunoﬂuorescence in 
bone marrow (Appendix A and Appendix B). 
9.3.10.8.2.2 
Cytogenetics 
For Parts 1 and 2 cytogenetic evaluation will be analyzed locally, according to local standards, if 
the site has the capability to perform analysis. These analyses should be performed at screening 
using fluorescence in situ hybridization and/or conventional cytogenetics (karyotype).  
In Part 3, cytogenetic results from samples taken within 5 weeks before the first dose are 
acceptable for stratification. All patients should also have a sample from screening sent for 
central analysis. If a previous result is not available and the patient is known to have high-risk 
disease [ie, del17, t(4;14) and/or t(14;16) from prior cytogenetic testing, regardless of timing], 
they should be stratified as high risk for the purpose of enrollment.  
9.3.10.8.2.3 
Bone Marrow Morphology 
A BMA or biopsy will be obtained for local pathology review from a subset of patients at 
screening, and at the time of on-treatment BMA collections to assess plasma cell count and 
morphology of bone marrow precursor cells with special attention to megakaryocytes. The 
sponsor will communicate to the sites when a sufficient number of evaluable samples have been 
obtained to stop the collection. 
Bone morphology will not be assessed in Part 3.  
9.3.11 
PK, Immunogenicity, Biomarker, and Pharmacodynamic Samples 
9.3.11.1 Primary Specimen Collection for PK, Immunology, and Biomarker Assessments 
Blood samples will be collected via venipuncture or indwelling catheter at the time points 
detailed in the SOE (Appendix C) for serum concentration measurements of modakafusp alfa 
and biomarker assessments. Bone marrow biopsy and aspirate collections are detailed in 
Appendix B for Parts 1 and 2 and found within the SOE (Appendix A) for Part 3. The primary 
specimen collection schema is presented in Table 9.c. 
If necessary, serum samples collected for PK assessments may also be used for exploration of 
pharmacodynamic biomarkers. These serum PK samples may only be used for this purpose after 
final PK analysis has been completed.  
Details on sample handling, storage, shipment, and analysis are provided in the Laboratory 
Manual.  

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Table 9.c 
Primary Specimen Collection 
Specimen Name in 
Schedule of Events 
Primary 
Specimen 
Primary 
Specimen 
Derivative 1 
Primary 
Specimen 
Derivative 2 
Description of 
Intended Use 
Parts 1 and 2 
Sample 
Collection 
Part 3 Sample 
Collection a 
Fresh bone marrow 
aspirate sample for 
pharmacodynamics 
Bone 
marrow 
aspirate 
BMMC Cell 
Pellet 
N/A 
CD38 
immunoprofiling 
Mandatory at 
screening and 
2 postdose 
time points. 
Optional at 
PD after 
response.a 
N/A 
BMA Cell 
Pellet 
DNA 
T-cell and B-cell 
receptor 
sequencing 
Fresh bone marrow 
aspirate sample for 
RNA 
Bone 
marrow 
aspirate 
RNA 
N/A 
Pharmacodynamic 
measurements 
(RNA-seq) 
Mandatory at 
Screening and 
2 postdose 
time points. 
Optional at 
PD after 
response.b 
N/A 
Fresh bone marrow 
aspirate sample for 
MRD 
Bone 
marrow 
aspirate 
DNA 
N/A 
Biomarker 
measurements 
Mandatory at 
screening and 
suspected 
CR.c 
Mandatory at 
screening, 
suspected CR, 
and every 6 
months after 
suspected CR. c  
Fresh Bone Marrow 
Aspirate for 
cytogenetics 
Bone 
marrow 
aspirate 
Plasma 
N/A 
Biomarker 
measurements 
N/A 
Mandatory at 
screening 
CD138+ 
cryopreserve
d cells 
DNA and 
RNA 
Cytogenetics and 
biomarker 
measurements 
CD138- 
Cryopreserve
d cells 
DNA and 
RNA 
Biomarker 
measurements 
Fresh Bone Marrow 
Aspirate 
Bone 
marrow 
aspirate 
Plasma 
N/A 
 
Biomarker 
measurements 
N/A 
Optional at 
progression 
after response 
CD138+ 
cryopreserve
d cells 
DNA and 
RNA 
Biomarker 
measurements 
CD138- 
Cryopreserve
d cells 
DNA and 
RNA 
Biomarker 
measurements 
Blood sample for 
flow cytometry 
(immunoprofiling) d 
Blood 
PBMC 
N/A 
Pharmacodynamic 
measurements 
(immunoprofiling) 
Mandatory 
N/A 
Blood sample for 
flow cytometry 
(CD38 occupancy) d 
Blood 
PBMC 
N/A 
Pharmacodynamic 
measurements 
(CD38 occupancy) 
Mandatory 
N/A 

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Table 9.c 
Primary Specimen Collection 
Specimen Name in 
Schedule of Events 
Primary 
Specimen 
Primary 
Specimen 
Derivative 1 
Primary 
Specimen 
Derivative 2 
Description of 
Intended Use 
Parts 1 and 2 
Sample 
Collection 
Part 3 Sample 
Collection a 
Blood sample for 
TBNK assay (local 
analysis if available) 
Blood 
PBMC 
N/A 
Pharmacodynamic 
measurements 
Mandatory 
N/A 
Serum sample for 
circulating 
biomarkers 
Serum 
N/A 
N/A 
Biomarker 
measurements 
Mandatory 
Mandatory 
Serum sample for 
immunogenicity 
(ADA and NAb) 
Serum 
N/A 
N/A 
Immunogenicity 
measurements 
(ADA and NAb) 
Mandatory 
Mandatory 
Blood sample for 
DNA 
Blood 
DNA 
N/A 
Pharmacogenetic 
measurements 
Mandatory 
N/A 
Buccal epithelial cell 
sample for DNA 
Buccal 
epithelial 
cells 
DNA 
N/A 
Pharmacogenetic 
measurements 
N/A 
Mandatory 
Plasma sample for 
ctDNA 
Plasma 
DNA 
N/A 
Biomarker 
measurements 
N/A 
Mandatory 
Blood sample for 
receptor sequencing 
Blood 
DNA 
N/A 
Pharmacodynamic 
measurements 
Mandatory 
Mandatory 
Blood sample for 
RNA 
Blood 
RNA 
N/A 
Pharmacodynamic 
measurements 
Mandatory 
Mandatory 
Serum sample for 
modakafusp alfa PK 
analysis 
Serum 
N/A 
N/A 
PK measurements 
(drug 
concentrations) 
Mandatory 
Mandatory 
ADA: antidrug antibody; BMA: bone marrow aspirate; BMMC: bone marrow mononuclear cells; CR: complete 
response; ctDNA: circulating tumor DNA; CxDx: Cycle x Day x; MM: multiple myeloma; MRD: minimal residual 
disease; N/A: not applicable; NAb: neutralizing antibodies; PBMC: peripheral blood mononuclear cells; PD: 
progressive disease; PK: pharmacokinetics; PR: partial response; TBNK: T-lymphocyte, B-lymphocyte, and natural 
killer cells.  
a Not all collections are applicable to all cohorts or patients within a cohort.  
b See Appendix B for details.  
c Screening MRD samples will be obtained in China based on acceptability of method chosen.  
d Not all collections are applicable to all cohorts or patients within a cohort. 
 
9.3.11.2 PK Measurements 
Details regarding the preparation, handling, and shipping of the PK samples are provided in the 
Laboratory Manual. Serum samples for PK will be collected at the time points specified in 
Appendix C.  
The timing but not the total number of samples may be modified during the study on the basis of 
emerging PK data if a change in sampling scheme is considered necessary to better characterize 
the PK of modakafusp alfa. 

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9.3.11.3 Biomarkers and Pharmacodynamic Measurements 
In this study, several biomarkers will be assessed to test for correlation with safety and, if 
possible, with efficacy. These biomarkers will be used to identify potential pharmacodynamic 
activity and patients who have a higher probability of response or of adverse reactions to 
modakafusp alfa. The biomarker sample analyses will be performed if or when required.  
Collection of samples for exploratory biomarkers are dependent upon local guidelines and 
regulations (including feasibility of sample or data export), as well as IRB/IEC approval. 
Because new techniques continue to be developed, the method and laboratory that will be 
recommended for the biomarker analysis cannot always be anticipated, but will be, if required by 
local guidelines and regulations.  
For this purpose, blood samples and BMA samples will be collected as detailed in Appendix A 
and Appendix B.  
9.3.11.3.1 
Biomarker Measurements 
Serum samples will be collected to evaluate circulating biomarkers at baseline and changes in 
them upon treatment. These biomarkers will be used to identify potential pharmacodynamic 
activity and patients who have a higher probability of response or of adverse reactions to 
modakafusp alfa. The biomarker sample analyses will be performed if or when required.  
In case of an infusion reaction, blood collection should be performed for central evaluation of 
circulating biomarkers (see Section 8.7.1.1). 
9.3.11.3.2 
Pharmacodynamic Measurements 
9.3.11.3.2.1 
Fresh BMA Samples for Pharmacodynamics (Parts 1 and 2 Only) 
BMA samples will be collected for analyzing CD38 expression on the surface of MM cells, 
immunoprofiling and molecular analysis. These BMA samples should be collected at the time 
points specified in Appendix B (screening and 2 postdose time points based on the schedule for 
which the subject is enrolled). These evaluations will be performed at a central laboratory. 
An optional aspirate and biopsy for pharmacodynamic analysis may also be collected at the time 
of disease progression only if the patient had previously responded to study drug and consents to 
this procedure. This sample may be collected at the time of PD confirmation, at the EOT visit or 
prior to starting a new therapy and will be sent directly to the central laboratory for analysis. 
9.3.11.3.2.2 
Fresh BMA for Cytogenetics/Fresh BMA (Part 3 Only) 
During the screening period for Part 3, an additional sample of bone marrow (fresh BMA for 
cytogenetics) will be collected to centrally analyze cytogenetic abnormalities, CD38 expression 
on the surface of MM and immune cells, immunoprofiling, molecular analysis, and plasma 
biomarkers. For patients who have had a response to modakafusp alfa treatment, an optional 
BMA sample (fresh BMA) may be collected at the time of progression to gain insight into 
potential resistance mechanisms. These evaluations will be performed at a central laboratory. 

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9.3.11.3.2.3 
Fresh BMA Samples for MRD 
BMA samples will be collected for MRD analysis. These BMA samples should be collected at 
the time points specified in Appendix B for Parts 1 and 2 and Appendix A for Part 3 (for Parts 1 
and 2: screening and suspected CR; Part 3: screening, suspected CR, and every 6 months after 
the suspected CR MRD sample was drawn). Screening MRD samples will be obtained in China 
based on acceptability of method chosen. These evaluations will be performed at a central 
laboratory. 
9.3.11.3.2.4 
Fresh BMA Samples for RNA (Parts 1 and 2 Only) 
BMA samples for RNA should be collected at the time points specified in Appendix B 
(screening, 2 postdose time points based on the patient’s treatment schedule, and an optional 
sample at PD following response to treatment). The RNA will be sequenced for assessment of 
gene expression changes linked to pharmacodynamic activity. These evaluations will be 
performed at a central laboratory. 
9.3.11.3.2.5 
Blood Sample for Flow Cytometry 
Blood samples for receptor occupancy and density (Parts 1 and 2 only) and for immunoprofiling 
will be collected for profiling of immune cells before, during, and at the end of treatment. These 
blood samples will be analyzed for the presence and changes of immune cells by flow cytometry 
or mass cytometry, including but not limited to B and T lymphocytes, monocytes, NK cells, etc; 
and CD38 occupancy in PBMC at baseline and at multiple time points after modakafusp alfa 
infusion (Parts 1 and 2 only). Within Parts 1 and 2, lymphocyte subpopulations will be quantified 
in peripheral blood using the locally available T-lymphocyte, B-lymphocyte, natural killer cells 
(TBNK) panel at the time points indicated in the SOE (Appendix A).  
9.3.11.3.2.6 
Blood Sample for RNA 
Blood samples for RNA will be collected at the time points specified in the SOE (Appendix A), 
unless local regulations prohibit testing, for sequencing to monitor gene expression changes as a 
pharmacodynamic effect of modakafusp alfa administration and for associations with response 
and/or resistance. Sample analysis will be performed at a central laboratory.  
9.3.11.3.2.7 
Blood Sample for Receptor Sequencing 
To monitor for induction of an adaptive immune response, blood samples will be collected to 
sequence T-cell and B-cell receptors before, during, and at the end of treatment. Sample analysis 
will be performed at a central laboratory. 
9.3.11.4 DNA Measurements 
In this study, a blood sample (Parts 1 and 2) or buccal epithelial cells (Part 3) will be collected 
from each patient (unless local regulations prohibit testing) for a potential pharmacogenetic 
assessment. The pharmacogenetic assessment would evaluate polymorphisms in mechanism and 
pathway-related genes including type I IFN inborne errors, STAT2, and IFN lambda 4 and the 

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relationship to response. Data from these samples will be used as a positive control for tumor 
DNA sequencing for identification of somatic alterations.  
Additionally, in Part 3, a plasma sample for circulating tumor DNA will also be collected unless 
prohibited by country regulations. These samples will be analyzed in a central laboratory.  
9.3.11.5 Immunogenicity Measurements   
Serum samples for the assessment of ADA will be collected at the time points specified in the 
SOEs (Appendix A) as outlined in the Laboratory Manual. Samples must be collected before 
study drug is administered on a dosing day, and it is strongly suggested that samples be obtained 
at unscheduled visits for a patient who experiences Grade ≥2 hypersensitivity/IRR  
(Section 8.7.1). All ADA samples will be first analyzed in a screening assay. Positively screened 
samples will be further analyzed in a confirmatory assay. Confirmed positive ADA samples will 
be further characterized for their titer, binding domain specificity characterization, and 
neutralizing capacity (NAb).  
In case of an IRR, blood should be collected for central evaluation of immunogenicity (see 
Section 8.7.1.1). 
9.3.12 
PRO Assessments  
For patients with advanced and life-threatening diseases such as cancer, reducing symptom 
burden and preserving their HRQOL are among the most important therapeutic goals. To inform 
the PRO instrument selection and endpoint design, patient-focused qualitative research was 
conducted to help identify the most relevant PRO concepts (particularly the core symptoms of 
MM) in MM. A targeted literature review on both the PRO concepts and instruments was 
performed to better understand core concepts most relevant to this patient population and 
treatment modality and to ensure the alignment with the guidance from key stakeholders. 
Healthcare providers and patient organizations were consulted/interviewed to explore the clinical 
perspective on treatment and observed patient experience, respectively. Engagement with MM 
patients, including RRMM patients, was conducted to gather patient symptoms, patient-reported 
symptomatic AEs, functioning, and HRQOL impact experience. Results from these research 
activities were then triangulated to select the most appropriate patient-relevant instruments and 
patient-derived endpoints for this study. 
In Part 3 of this study, patient-reported symptoms and HRQOL/health status will be evaluated 
using the EORTC QLQ-MY20 and the EQ-5D-5L, respectively. These measures were superior 
to others identified in terms of overall use in MM clinical studies, regulatory precedence, and 
content coverage that was confirmed by clinical experts and patient interviews. All 
questionnaires have evidence of reliability and validity within the specific context of use and are 
instruments regularly employed in clinical research. 
During the Part 3 Extension, the EORTC QLQ-MY20 and the EQ-5D-5L will be administered 
electronically per the SOEs (Appendix A) to all randomized patients. Paper versions of the 
questionnaire are not permitted. The PRO assessments will be collected regularly during 
treatment, and at the EOT visit. All PROs should be administered on Day 8 of each cycle, except 

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for Cycle 1 when the EORTC QLQ-MY20 should be administered on Day 1 and 8 (ie, C1D1 and 
C1D8) and the EQ-5D-5L on Day 1 (ie, C1D1). On C1D1, PROs may be completed within a +1-
day window; on all other days, PROs may be completed within a ±2-day window.  
On days when PROs are administered during clinic visits (Appendix A), the EORTC 
QLQ-MY20 and EQ-5D-5L should be completed by patients when they arrive for their 
scheduled visits, before any clinical measurements, assessments, evaluations, or procedures are 
performed. The patient should be given sufficient space and time to complete the questionnaires. 
The patient should complete the questionnaires on their own without any assistance or 
interpretation from site staff. The questionnaires will be administered to patients in their local 
language, using the version provided by the sponsor.  
During the Part 3 Extension, the PRO assessments will be collected regularly during treatment 
and at the EOT visit. On days when PRO assessments are not completed at the clinic (ie, Day 8 
of each cycle starting with Cycle 3), site staff should remind each patient at every cycle to 
complete their PRO questionnaires. Site staff should regularly remind patients to contact their 
health care provider for any concerning signs or symptoms and inform patients that their 
responses to the PRO measures will not be shared with site staff or members of their health care 
team. 
Although PRO measures may assist in the overall understanding of a therapy’s safety and 
tolerability, PRO data without clinical interpretation are not considered safety data, and there is 
no expectation that PRO data will be reported to the Food and Drug Administration (FDA) 
directly as safety data in cancer trials (Kim et al. 2018). 
9.3.12.1 EORTC QLQ-MY20 
The EORTC QLQ-MY20 has 20 items across 4 subscales: 2 functional subscales (body image 
and future perspective) and 2 symptoms scales (disease symptoms and side effects of treatment) 
(Appendix A). On each of the 20 items, respondents will indicate the extent to which (not at all, 
a little, quite a bit, very much) they have experienced symptoms or problems “during the past 
week.” 
The QLQ-MY20 raw scores are converted into scale scores ranging from 0 to 100. For functional 
subscales, higher scores represent better health. For symptom subscales, higher scores represent 
worse symptoms/problems. All items in this questionnaire have a recall period of 1 week. For 
items with missing responses, the response will be managed as per the scoring manual. 
9.3.12.2 EQ-5D-5L 
The EQ-5D-5L is a self-administered preference-based measure of HRQOL/health status suitable 
for calculating quality-adjusted life years to inform economic evaluations. EQ-5D-5L includes 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each 
with 5 response levels (no problems, slight problems, moderate problems, severe problems, and 
extreme problems). Patients are asked to indicate their health state “today” by selecting the most 
appropriate level of severity on each of the 5 dimensions. Patient responses to the 5 dimensions 
of the EQ-5D-5L represent the patient’s health state. As part of this instrument, there is also a 

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visual analogue scale used by respondents to rate their health "today" on a scale from best (100) 
to worst health imaginable (0). 
9.3.13 
Healthcare Resource Utilization  
Healthcare resource utilization, including hospitalizations and outpatient visits, will be evaluated 
as a secondary endpoint. Healthcare resource utilization, including information related to 
hospitalization or outpatient clinics, will be collected from all patients, regardless of the reason 
for the medical care encounter on Day 1 of each cycle and at EOT per the SOE (Appendix A). 
Examples of data to be collected include the length of hospital stay, types of hospital stay 
(eg, intensive care unit), types of outpatient visits (eg, emergency room visit), and reasons for 
hospitalization and outpatient visits. 
9.4 
Completion of Study Treatment (for Individual Patients) 
Patients in Parts 1 and 2 may receive modakafusp alfa for up to 1 year; however, patients with 
clinical benefit can continue treatment beyond 1 year with explicit sponsor approval. Patients in 
Part 3 may continue treatment until disease progression. 
Patients will be considered to have completed study treatment if they discontinue study drug for 
any reason outlined in this section. 
Investigators are expected to evaluate the impact to the safety of the study participants and site 
personnel for subjects to continue. In evaluating such requests, the sponsor will give the highest 
priority to the safety and welfare of the subjects. Subjects must be willing and able to continue 
taking study medication and remain compliant with the protocol. 
9.4.1 
Discontinuation of Treatment with Study Drug and Patient Replacement 
Study drug must be permanently discontinued for patients meeting any of the following criteria: 
• Patient experiences an AE or other medical condition that indicates to the investigator that 
continued participation is not in the best interest of the patient.  
Treatment with study drug may also be discontinued for any of the following reasons: 
• AE. 
• Complete 1 year of treatment (unless exception is granted by the sponsor) in Parts 1 and 2 
only.  
• Protocol deviation (after discussion with sponsor). 
• Progressive disease (if the investigator considers that treatment after PD is in the patient’s 
best interest, it can be approved after consultation with the sponsor).  
• Symptomatic deterioration.  
• Unsatisfactory therapeutic response.  

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• Study terminated by sponsor. 
• Withdrawal by subject. 
• Female patient has confirmed pregnancy. 
• Lost to follow-up. 
• Other. 
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF. 
In Part 1, patients who miss 1 or more modakafusp alfa infusions during Cycle 1 for reasons 
other than a DLT will be replaced. In Part 2 and Part 3, patients who receive 1 or more infusions 
of study drug will not be replaced. 
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment assessments as 
outlined in the SOE (Appendix A) until PD or withdrawal of consent.  
9.4.2 
Withdrawal of Patients From Study 
A patient must be withdrawn from the study for any of the following reasons: 
• Lost to follow-up. 
• Study terminated by sponsor. 
• Withdrawal by subject. 
• Completed study.  
• Transfer of patient to a long-term safety study, single-patient investigational new drug 
application, or similar program. 
• Death.  
• Other. 
9.5 
Posttreatment Follow-up Assessments  
Patients in Parts 1 and 2 may receive modakafusp alfa for up to 1 year; however, patients with 
clinical benefit can continue treatment beyond 1 year with explicit sponsor approval. Patients in 
Part 3 may continue treatment until PD.   
The PFS visits should occur every 4 weeks from the EOT visit until the occurrence of 
progression, death, the start of subsequent systemic antineoplastic therapy, study termination 
(Section 9.4), or until 6 months after the discontinuation of study treatment, whichever occurs 
first. OS follow-up continues every 12 weeks from the EOT visit until death, study termination, 
or patient withdrawal. For all patients who received study therapy and then receive subsequent 
anticancer therapy, next lines of therapy will be recorded, including dates of initiation and 
termination, regardless of whether it is initiated before or after PD. Information about disease 

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response/status should also be recorded. Imaging tests for patients with extramedullary disease 
should be performed every 12 weeks or if new symptoms suggest PD. 
See the SOE (Appendix A) for appropriate assessments during follow-up. 
NOTE: Treatment-related SAEs must be reported to the Global Pharmacovigilance department 
or designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs. 
9.6 
Study Compliance 
Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). The appropriate study personnel will maintain records of study 
drug receipt and dispensing. 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation. 
10.1.2 
AE Definition 
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
10.1.3 
Adverse Events of Special Interest  
An adverse events of special interest (AESI), serious or nonserious, is an AE of scientific and 
medical concern specific to the product or program, for which ongoing monitoring and rapid 
communication by the investigator to Takeda sponsor is appropriate. Such events may require 
further investigation in order to characterize and understand them. In modakafusp alfa studies, 
IRRs are designated as AESIs. Instructions regarding how and when AESIs should be reported to 
Takeda are provided in Section 10.2. 

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10.1.4 
SAE Definition 
SAE means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.) 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. 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; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE v 5.0 . Clarification should be made between an SAE and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are not synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache). 
This is not the same as serious, which is based on patient/event outcome or action criteria 
described above and is usually associated with events that pose a threat to a patient’s life or 
ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious. For example, a white blood cell count of 1000/mm3 to less than 2000/mm3 is considered 
Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations. 
10.2 
Procedures for Recording and Reporting AEs and SAEs 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 

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considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as 1 comprehensive event. 
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must 
be reported (see Section 10.3 for the period of observation) by the investigator to the Takeda 
Global Pharmacovigilance department or designee (contact information provided below). For 
Parts 1 and 2, this should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event. The SAE Form, created specifically by Takeda, will be provided to each clinical 
study site. A sample of the SAE Form may be found in the Study Operations Manual. Follow-up 
information on the SAE or serious pretreatment event may be requested by Takeda. SAE report 
information must be consistent with the data provided on the eCRF. For Part 3, SAEs should be 
reported by completing the corresponding SAE eCRF in the electronic data capture (EDC) 
system which will automatically notify the Takeda Global Pharmacovigilance department or 
designee (contact information provided below). 
SAE Reporting Contact Information 
Cognizant Worldwide 
1-202-315-3560 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned). 
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the 
event and the causality of the event in relation to study procedures. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 5.0. The criteria are provided in the Study Operations Manual. 
Relationship of the event to study drug administration (ie, its causality) will be determined by 
the investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?” 
10.2.1 
Monitoring and Reporting IRRs 
An IRR is a type of reaction that develops during or shortly after administration of a drug. Signs 
and symptoms and management guidelines are detailed in Section 8.7.1. In modakafusp alfa 
studies, IRRs are designated as AESIs. When reporting IRRs in the eCRF, the signs and 
symptoms should be recorded and should be marked as an IRR.  
Serious AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner 
irrespective of the event’s causal relationship.  

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Further, patients will be advised to promptly report signs and symptoms that may indicate IRRs, 
including fever, chills, dizziness, nausea, vomiting, flushing, cough, headache, and rash during or 
soon after end of infusion. 
10.3 
Monitoring of AEs and Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
• AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug or the start of subsequent anticancer therapy, 
whichever occurs first, and recorded in the eCRFs.  
• SAEs: 
– Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to first dose of study 
drug and will also be recorded in the eCRF.  
– Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
30 days after administration of the last dose of study drug, even if the patient starts 
nonprotocol therapy, and recorded in the eCRF. After this period, only related SAEs must 
be reported to the Takeda Global Pharmacovigilance department or designee. SAEs 
should be monitored until they are resolved or are clearly determined to be caused by a 
patient’s stable or chronic condition or intercurrent illness(es). 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor must also be contacted immediately by faxing a completed Pregnancy Form to the 
Takeda Global Pharmacovigilance department or designee (see Section 10.2). The pregnancy 
must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via email address 
provided below. 

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A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. If a 
potential medication error situation (including overdose) is deemed related to a product quality 
complaint, then this too should be immediately reported via the email address provided below. 
Product 
E-mail 
modakafusp alfa 
ctmcomplaint@takeda.com  
 
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, 
an SAE form should be completed and sent to Cognizant (refer to Section 10.2). 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited 
report within 7 days for fatal and life-threatening events and 15 days for other serious events, 
unless otherwise required by national regulations. The sponsor will also prepare an expedited 
report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider 
changes in the investigational medicinal product’s administration or in the overall conduct of the 
trial. The investigational site also will forward a copy of all expedited reports to his or her IRB or 
IEC in accordance with national regulations.  
11.0 
STUDY-SPECIFIC COMMITTEES 
Study specific committees are detailed in Section 3.3.  
12.0 
DATA HANDLING AND RECORDKEEPING  
The full details of procedures for data handling will be documented in the Data Management 
Plan. If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be 
coded using the World Health Organization Drug Dictionary. 
12.1 
eCRFs  
Completed eCRFs are required for each subject who signs an ICF. 
The sponsor or its designee will supply investigative sites with access to eCRFs and arrange to 
train appropriate site staff in the use of the eCRF. These forms are used to transmit the 
information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English. 

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After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.  
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. ePROs and 
therefore PRO data are not included in the eCRF and should not be reviewed by the principal 
investigator. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the 
investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator should contact and receive written approval from the sponsor before disposing 
of any such documents. 

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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized before database lock. The SAP 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.  
For the phase 2 Part 3 extension cohorts, the primary analysis of the primary endpoint will be 
performed when enrolled patients have had the opportunity to be assessed for response for at 
least 6 months after modakafusp alfa administration. Additional details of analyses will be 
provided in the SAP. 
13.1.1 
Analysis Sets 
Full analysis set: The full analysis set will include all patients who receive at least 1 dose, even 
an incomplete dose, of modakafusp alfa, in the Part 3 extension cohorts. The full analysis set will 
be used for efficacy analysis. 
Safety analysis set: The safety analysis set will include all enrolled patients who receive at least 
1 dose, even an incomplete dose, of modakafusp alfa. The safety analysis set will be used for 
safety analysis. 
Response-evaluable analysis set: The subset of the safety analysis set of patients treated at the 
MTD/OBD from the Part 2 dose expansion cohorts with measurable disease at baseline and at 
least 1 posttreatment efficacy evaluation. The response-evaluable analysis set will be used in the 
futility analysis of the Part 2 expansion.  
PK analysis set: The PK analysis set will include those patients from the safety analysis set who 
have sufficient data to calculate at least 1 PK parameter for modakafusp alfa.  
Immunogenicity-evaluable analysis set: Analysis will be based on available data from patients 
with a baseline assessment and at least 1 post-baseline immunogenicity assessment. 
PRO analysis set: The PRO analysis set includes all patients with a baseline and at least one 
postbaseline measurement of any PRO. The analyses of PROs will be based on the PRO analysis 
set. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history, prior medications, 
and therapies, will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number, mean, standard deviation, median, minimum, and maximum) will 
be provided. For categorical variables, patient counts and percentages will be provided. 
Categories for missing data will be presented if necessary. 

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13.1.3 
Efficacy Analysis 
Part 2 
For the Part 2 expansion cohorts, the efficacy of modakafusp alfa will be evaluated by measuring 
the confirmed ORR defined as the proportion of patients who achieved a confirmed PR or better 
during study, duration of response, best overall response, CBR, DCR, TTP and PFS as defined 
by the IMWG Uniform Response Criteria (Appendix F). When appropriate, data from patients in 
the expansion cohorts will be summarized together with data from patients in the dose escalation 
phase. 
For each cohort, the investigator-assessed best overall response and confirmed response (sCR, 
CR, VGPR, PR, MR, SD, or PD according to IMWG) for each patient who received at least 
1 dose of study medication will be listed, and the exact 2-sided 95% CIs for the investigator-
assessed confirmed ORR will be calculated based on the binomial distribution. Duration of 
response (in responders), PFS, and OS will be analyzed by using the Kaplan-Meier method. 
Descriptive statistics will be used to summarize the time to response in responders. All patients 
receiving at least 1 dose of modakafusp alfa will be considered evaluable for efficacy. 
Part 3 
The primary analysis for all efficacy endpoints in Part 3 extension cohorts will be based on the 
full analysis set. No formal statistical analysis will be performed to compare the 2 treatment 
arms.  
The primary analysis of the primary endpoint ORR will be based on the responses assessed by 
the IRC. The number and percentage of patients with different response status will be presented. 
The ORR by IRC and the corresponding 95% exact CI will also be provided. Patients with 
unknown or missing response status will be treated as nonresponders, ie, these participants will 
be included in the denominator when calculating percentages of response.  
Analysis of secondary endpoints will include the investigator-assessed ORR, DOR, CBR, 
duration of clinical benefit, DCR, duration of disease control, PFS, TTP, and OS as defined in 
Section 5.4.3. The investigator-assessed ORR, the IRC-assessed and investigator-assessed CBR 
and DCR will also be reported in the same approach as the primary endpoint. For all the time-to-
event endpoints, the median time to event with 95% CI will be estimated by the Kaplan-Meier 
method. A Kaplan-Meier survival curve will be generated. The number and percentage of 
patients who had the event or were censored will also be reported.  
Descriptive subgroup analyses of the primary endpoint by key baseline prognostic factors may 
be performed if data permit. 
13.1.4 
PK Analysis  
PK parameters will be estimated using noncompartmental methods with Phoenix WinNonlin. 
The PK parameters will be estimated from the concentration-time profiles for the PK population. 
The following PK parameters will be determined in Parts 1 and 2, and in Chinese patients with 
the intensive PK schedule in Part 3, as permitted by data: 

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• Cmax. 
• tmax. 
• AUC∞. 
• AUClast. 
• λz. 
• t1/2z. 
• CL. 
• Vss. 
• Accumulation ratio based on AUCτ (area under the concentration-time curve during a dosing 
interval).  
PK parameters will be summarized using descriptive statistics. Individual modakafusp alfa 
concentration-time data and individual PK parameters will be presented in listings and tabulated 
using summary statistics by dose cohort. Individual and mean concentration-time profiles will be 
plotted by dose cohort. 
The PK data collected in this study are intended to contribute to future population PK analyses of 
modakafusp alfa. These population PK analyses may include data collected in other modakafusp 
alfa clinical studies. The analysis plan for the population PK analysis will be separately defined, 
and the results of these analyses will be reported separately. 
13.1.5 
Biomarker and Pharmacodynamic Analysis  
During the clinical development of modakafusp alfa, several biomarkers will be assessed to test 
for their correlation with safety and, if possible, with efficacy. Markers that will be studied are 
markers linked either to the drug itself or to the treated disease. Markers of immune system 
activation (neopterin and others) will be summarized using descriptive statistics. Individual data 
will be listed. Summaries will be provided separately for each study phase and by dose, as 
applicable. 
13.1.6 
PRO Analyses 
The PRO analysis will be based on the EORTC QLQ-MY20 subscale scores. The actual value 
and change from baseline of the EORTC QLQ-MY20 subscale scores will be summarized using 
descriptive statistics overall and by dose over time. The difference between baseline scores and 
scores over may be also explored using linear mixed models. EQ-5D-5L will be assessed using 
descriptive statistics over time.  
The percentage of missing items for all questionnaires at each cycle will be described, as well as 
the number and percentages of patients with evaluable questionnaire (ie, questionnaire with at 
least 1 nonmissing item). PRO compliance and PRO completion over time will be calculated at 
the questionnaire level for the QLQ-MY20 at each cycle from baseline to provide context for the 
interpretation of PRO results. Rate of PRO score completion will be calculated as follows: 
(number of participants with the PRO score available at the visit) / (number of participants for 

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whom a PRO score is expected at the visit). Rate of available PRO scores over time will be 
calculated as follows: (number of participants with the PRO score available at the visit) / (total 
number of participants in the PRO analysis population). The PRO analysis population includes 
all patients with a baseline and at least 1 postbaseline measurement of any PRO. 
13.1.7 
Immunogenicity Analyses  
The proportion of subjects with positive ADA (incidence, titer, and domain specificity) and NAb 
during the study will be summarized. The effect of immunogenicity on PK, pharmacodynamics, 
safety, and efficacy will be examined, if possible. 
Analysis will be based on available data from patients with a baseline assessment and at least 
1 post-baseline immunogenicity assessment (immunogenicity-evaluable analysis set). Summaries 
will be provided separately for each study phase and by dose, as applicable. All analyses will be 
descriptive and exploratory in nature.  
13.1.8 
Safety Analysis 
The safety and tolerability of modakafusp alfa will be assessed by the recording of TEAEs (using 
NCI CTCAE, Version 5.0), vital signs, physical examination, chemistry, hematology, urinalysis, 
ECG, and concomitant medications. 
TEAEs will be summarized using the safety analysis set and will be coded using the MedDRA. 
Data will be summarized using preferred terms and the primary SOC. 
All patients receiving at least 1 dose of modakafusp alfa will be considered evaluable for the 
safety analysis. The AE incidence rates and the frequency of occurrence of overall toxicity, 
categorized by toxicity grades (severity), will be presented. Listings of laboratory test results and 
vital signs will be generated. Descriptive statistics summarizing the changes in laboratory tests 
over time will be reported. 
13.2 
Interim Analyses and Criteria for Early Termination 
13.2.1 
Part 2 Dose Expansion 
A futility analysis will be conducted when 10 response-evaluable patients in a Part 2 arm have 
been followed for at least 3 cycles or have already responded or withdrawn. An arm with a 
posterior probability of success (PPOS) (ie, having 11 or more responders out of 25 patients) of 
<15% (ie, 3 or fewer responders in 10 patients) will stop enrollment for futility. Unless all 
25 patients have already been enrolled, another futility analysis with the same decision rule 
based on PPOS will be conducted when 15 response-evaluable patients in a Part 2 arm have been 
followed for at least 3 cycles or have already responded or withdrawn. If there are 5 or fewer 
responders in 15 patients, enrollment will stop for futility. 

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13.2.2 
Part 3 Extension 
13.2.2.1 Part 3 Futility Stopping Rules  
Two interim analyses for futility are planned for the Part 3 extension cohorts when 
approximately 15 and 48 patients of the planned 118 patients per arm are enrolled and treated for 
at least 3 cycles or have discontinued treatment prematurely. The futility stopping boundary will 
be determined based on the predictive probability of success at the primary analysis, using a 
Bayesian efficacy monitoring approach (Lee and Liu 2008). The treatment arm will be dropped 
for futility if the predictive probability of success at the primary analysis is found to be <10% 
based on the data from the interim analysis. Various prior distributions for the ORR are used for 
each treatment arm due to different prior efficacy information at different dose levels collected in 
Parts 1 and 2 of the study. To reflect the prior efficacy information for the 120 mg arm (40% 
ORR) collected in Parts 1 and 2, a weakly informative prior of Beta (1.2, 1.8) is used. However, 
because of comparatively limited efficacy data available at the 3 mg/kg (240 mg) dose, a 
noninformative prior of Beta (0.5, 0.5) is used. Based on these prior distributions, Table 13.a 
shows the stopping rules used for the treatment arms of 240 mg and 120 mg at each interim 
futility analysis. The details of the operating characteristics of the futility stopping rules are 
described in Appendix H. 
There is no plan to stop for efficacy based on the interim analysis data. 
Table 13.a 
Stopping Boundaries for 240 and 120 mg Arms at Each Interim Futility 
Analyses  
 
Number of 
patients enrolled 
and followed up 
for 3 months 
Recommend terminating the corresponding 
treatment arm due to lack of efficacy when 
number of responders is: 
240 mg Arm 
120 mg Arm 
1st Interim Futility Analysis 
15 
≤2 
≤1 
2nd Interim Futility Analysis 
48 
≤10 
≤10 
 
13.2.2.2 Part 3 Continuous Safety Monitoring Plan and Stopping Rules 
In the Part 3 extension cohorts, an IDMC will review accumulating safety, tolerability, and 
efficacy data. Grade ≥4 nonhematologic treatment-related TEAEs, as well as treatment-related 
deaths, will be continuously monitored at the following time points using a Bayesian toxicity 
monitoring approach based on posterior probability (Table 13.b). 

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Table 13.b 
Safety Monitoring Time Points Based on Bayesian Stopping Rules  
 
Time Point 
1st DMC Safety review 
20 patients have been treated (10 patients in each arm). 
2nd DMC Safety review (first futility analysis) 
15 patients in each arm treated for at least 3 cycles or 
discontinued treatment prematurely. 
3rd DMC Safety review (second futility analysis) 
48 patients in each arm treated for at least 3 cycles or 
discontinued treatment prematurely. 
DMC: Data Monitoring Committee. 
 
The stopping rules will be determined based on the posterior probability of the unacceptable 
toxicity event rate >25%, and the unacceptable treatment-related death rate >5%. If there is at 
least an 80% probability that the true toxicity event (Grade ≥4 nonhematologic treatment-related 
TEAEs) rate is greater than 25% given the observed toxicity data, the enrollment will be paused 
until the IDMC reviews the data to avoid putting more patients at risk. 
Similarly, if there is at least an 80% probability that the true treatment-related death rate is 
greater than 5% given the observed death data, the enrollment will be paused until the IDMC 
reviews the data. Details of the Bayesian toxicity monitoring plan and the operating 
characteristics can be found in Appendix I. 
If the trial is stopped or paused for unacceptable toxicity or death, the regulatory agencies and 
investigators will be informed. 
13.3 
Determination of Sample Size 
Part 1 of the study will follow a standard 3 + 3 dose escalation design. Under this design, the 
probability of dose escalation according to the true DLT rate is as follows: 
True DLT rate 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
Probability of escalating 
97% 
91% 
71% 
49% 
31% 
17% 
8% 
3% 
DLT: dose-limiting toxicity.  
The probability of not observing a DLT in a sample size of 6 patients according to the true DLT 
rate is as follows: 
True DLT rate 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
Probability of no toxicity 
74% 
53% 
26% 
12% 
4.7% 
1.6% 
0.4% 
<0.1% 
DLT: dose-limiting toxicity.  
Patients will be considered evaluable in Part 1 for MTD/OBD assessment provided they have not 
missed any of their infusions of modakafusp alfa in Cycle 1 and have not had a DLT. Patients 
who are not considered evaluable as defined above will be replaced.  

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Part 2 Expansion 
The study will enroll up to 25 patients in each arm to further characterize safety of the 
OBD/MTD and obtain preliminary clinical efficacy data. An OBD/MTD dose will be considered 
clinically relevant if at least 11 out of 25 response evaluable patients have a confirmed PR or 
better. With a vague beta prior with shape parameters 0.428 and 1 for ORR (ie, mean of 30%), 
11 responders out of 25 gives a greater than 90% posterior probability of true ORR being greater 
than 30%. The design has reasonable operating characteristics. With a true ORR of 30%, the 
probability of declaring success is 7%. In contrast, with a true ORR of 50%, the probability of 
declaring success is 70%. 
Part 3 Extension  
The primary objective of Part 3 of the study is to determine the confirmed ORR, including PR, 
VGPR, CR, and sCR assessed according to the IMWG criteria (Appendix F) to modakafusp alfa 
in patients with MM previously treated with ≥3 lines and with evidence of disease progression 
who are refractory to, or intolerant of, a PI, an IMiD, and an anti-CD38 mAb (triple 
refractory).The sample size was determined to claim that the true ORR is greater than the 
threshold response rate of 20% within each treatment arm. A total sample size of approximately 
236 enrolled patients (118 patients per arm) will allow the study to have over 90% power to rule 
out an uninteresting response rate of 20% if the true rate is 35% with a 1-sided alpha of 0.025. 
The purpose of the China continuation cohort is to allow continued evaluation of efficacy and 
any emerging safety signals in Chinese patients enrolled in China. After global patient 
enrollment is completed in Part 3, enrollment will continue for the China continuation cohort 
until about 15% of the total sample size is reached at the selected dose(s) (eg, 18 patients based 
on 118 patients treated at the selected dose[s]). 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. If monitors are not allowed to perform on-site visits for data 
verification due to exceptional circumstances (eg, COVID-19), remote electronic medical 
records access visits may be conducted (where allowed by local laws and regulations). Source 
documents will be reviewed for verification of data recorded on the eCRFs. Source documents 
are defined as original documents, data, and records. The investigator and institution guarantee 
access to source documents by the sponsor or its designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 

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14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment.  
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the US FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor should 
be notified immediately. The investigator and institution guarantee access for quality assurance 
auditors to all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix D. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 

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direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study specific screening activity). The IRB 
or IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will 
ship drug once the sponsor has confirmed the adequacy of site regulatory documentation and, 
when applicable, the sponsor has received permission from competent authority to begin the 
trial. Until the site receives notification, no protocol activities, including screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports, and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent are 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 

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applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor prior to use. 
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering the study. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and date the ICF and subject authorization (if 
applicable) at the time of consent and prior to subject entering the study; however, the Sponsor 
may allow a designee of the investigator to sign to the extent permitted by applicable law. 
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject. 
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF. 
15.3 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, the US FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and 

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the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication  
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
15.4.2 
Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov, 
clinicaltrialsregister.eu, or other publicly accessible websites on or before start of study, as 
defined in Takeda Policy/Standard. Takeda contact information, along with investigator’s city, 
state (for America’s investigators), country, and recruiting status will be registered and available 
for public viewing.  
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods callers requesting trial information. Once subjects receive 
investigator contact information, they may call the site requesting enrollment into the trial. The 
investigative sites are encouraged to handle the trial inquiries according to their established 

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subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.  
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site.  
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov, clinicaltrialsregister.eu, or 
other publicly accessible websites (including the Takeda corporate site) and registries, as 
required by Takeda Policy/Standard, applicable laws and/or regulations.  
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 

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16.0 
REFERENCES 
2015. DARZALEX (daratumumab) [prescribing information]. USPI, Janssen Biotech, Inc. 
Alexanian, R., Dimopoulos, M. A., Delasalle, K. and Barlogie, B. 1992. Primary dexamethasone 
treatment of multiple myeloma. Blood, 80(4), 887-90. 
Arbour, K., Mezquita, L., Long, N., Rizvi, H., Auclin, E., Ni, A., et al. 2018. Deleterious effect 
of baseline steroids on efficacy of PD-(L)1 blockade in patients with NSCLC. Abstract 
No. 9003. J Clin Oncol, 36(no. 15_suppl). 
Bai, S., Jorga, K., Xin, Y., Jin, D., Zheng, Y., Damico-Beyer, L. A., et al. 2012. A guide to 
rational dosing of monoclonal antibodies. Clin Pharmacokinet, 51(2), 119-35. 
Bauvois, B., Durant, L., Laboureau, J., Barthelemy, E., Rouillard, D., Boulla, G., et al. 1999. 
Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II. 
Journal of Interferon & Cytokine Research, 19(9), 1059-66. 
Bolognesi, A., Polito, L., Farini, V., Bortolotti, M., Tazzari, P. L., Ratta, M., et al. 2005. CD38 as 
a target of IB4 mAb carrying saporin-S6: design of an immunotoxin for ex vivo depletion 
of hematological CD38+ neoplasia. Journal of Biological Regulators & Homeostatic 
Agents, 19(3-4), 145-52. 
Chapman, M. A., Lawrence, M. S., Keats, J. J., Cibulskis, K., Sougnez, C., Schinzel, A. C., et al. 
2011. Initial genome sequencing and analysis of multiple myeloma. Nature, 471(7339), 
467-72. 
Chillemi, A., Zaccarello, G., Quarona, V., Ferracin, M., Ghimenti, C., Massaia, M., et al. 2013. 
Anti-CD38 antibody therapy: windows of opportunity yielded by the functional 
characteristics of the target molecule. Molecular Medicine, 19, 99-108. 
Coutinho, A. E. and Chapman, K. E. 2011. The anti-inflammatory and immunosuppressive 
effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell 
Endocrinol, 335(1), 2-13. 
Darzalex (daratumumab) injection 2015. Full Prescribing Information. Horsham, PA: Janssen 
Biotech, Inc. 
Deaglio, S., Aydin, S., Vaisitti, T., Bergui, L. and Malavasi, F. 2008. CD38 at the junction 
between prognostic marker and therapeutic target. Trends in Molecular Medicine, 14(5), 
210-8. 
Funaro, A., Spagnoli, G. C., Ausiello, C. M., Alessio, M., Roggero, S., Delia, D., et al. 1990. 
Involvement of the multilineage CD38 molecule in a unique pathway of cell activation 
and proliferation. Journal of Immunology, 145(8), 2390-6. 
Giles, A. J., Hutchinson, M. N. D., Sonnemann, H. M., Jung, J., Fecci, P. E., Ratnam, N. M., et 
al. 2018. Dexamethasone-induced immunosuppression: mechanisms and implications for 
immunotherapy. J Immunother Cancer, 6(1), 51. 
Goldmacher, V. S., Bourret, L. A., Levine, B. A., Rasmussen, R. A., Pourshadi, M., Lambert, J. 
M., et al. 1994. Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple 
myeloma. Blood, 84(9), 3017-25. 
Green, D. J., Orgun, N. N., Jones, J. C., Hylarides, M. D., Pagel, J. M., Hamlin, D. K., et al. 
2014. A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell 
malignancies. Cancer Research, 74(4), 1179-89. 

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Hillengass, J., Usmani, S., Rajkumar, S. V., Durie, B. G. M., Mateos, M. V., Lonial, S., et al. 
2019. International myeloma working group consensus recommendations on imaging in 
monoclonal plasma cell disorders. Lancet Oncol, 20(6), e302-e12. 
Kim, J., Singh, H., Ayalew, K., Borror, K., Campbell, M., Johnson, L. L., et al. 2018. Use of 
PRO measures to inform tolerability in oncology trials: implications for clinical review, 
IND safety reporting, and clinical site inspections. Clin Cancer Res, 24(8), 1780-4. 
Kumar, S., Paiva, B., Anderson, K. C., Durie, B., Landgren, O., Moreau, P., et al. 2016. 
International Myeloma Working Group consensus criteria for response and minimal 
residual disease assessment in multiple myeloma. Lancet Oncol, 17(8), e328-46. 
Kumar, S. K., Lee, J. H., Lahuerta, J. J., Morgan, G., Richardson, P. G., Crowley, J., et al. 2012. 
Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs 
and bortezomib: a multicenter international myeloma working group study. Leukemia, 
26(1), 149-57. 
Lee, J. J. and Liu, D. D. 2008. A predictive probability design for phase II cancer clinical trials. 
Clin Trials, 5(2), 93-106. 
Lin, P., Owens, R., Tricot, G. and Wilson, C. S. 2004. Flow cytometric immunophenotypic 
analysis of 306 cases of multiple myeloma. Am J Clin Pathol, 121(4), 482-8. 
Mould, D. R. 2015. The Pharmacokinetics of Biologics: A Primer. Dig Dis, 33 Suppl 1, 61-9. 
Nijhof, I. S., Casneuf, T., van Velzen, J., van Kessel, B., Axel, A. E., Syed, K., et al. 2016. CD38 
expression and complement inhibitors affect response and resistance to daratumumab 
therapy in myeloma. Blood, 128(7), 959-70. 
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., et al. 
1982. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol, 5(6), 649-55. 
Poh, A. 2016. Multiple Myeloma Gets Three New Drugs. Cancer Discovery, 6(1), 4. 
Rajkumar, S. V., Harousseau, J. L., Durie, B., Anderson, K. C., Dimopoulos, M., Kyle, R., et al. 
2011. Consensus recommendations for the uniform reporting of clinical trials: report of 
the International Myeloma Workshop Consensus Panel 1. Blood, 117(18), 4691-5. 
Saber, H., Gudi, R., Manning, M., Wearne, E. and Leighton, J. K. 2016. An FDA oncology 
analysis of immune activating products and first-in-human dose selection. Regul Toxicol 
Pharmacol, 81, 448-56. 
Santonocito, A. M., Consoli, U., Bagnato, S., Milone, G., Palumbo, G. A., Di Raimondo, F., et 
al. 2004. Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-
lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma 
patients. Leukemia Research, 28(5), 469-77. 
Siegel, R., Naishadham, D. and Jemal, A. 2013. Cancer statistics, 2013. CA Cancer J Clin. 
Wang, D. D., Zhang, S., Zhao, H., Men, A. Y. and Parivar, K. 2009. Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol, 
49(9), 1012-24. 
 

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neutralizing antibodies; OBD: optimal biological dose; PBMC: peripheral blood mononuclear cells; PD: progressive disease; PET-CT: positron emission 
tomography-computed tomography; PFS: progression-free survival; PK: pharmacokinetic(s); Q12wk: every 12 weeks; SAE: serious adverse event; TBNK: T-
lymphocyte, B-lymphocyte, and natural killer cells; V: visit; WB: wide beam; WBC: white blood cell. 
Note: Crosses in parentheses “(X)” indicate tests are to be performed only under certain circumstances as indicated in associated footnote(s). 
a. 
Written informed consent must be obtained before performing any protocol-specific procedure. Test results from routine clinical management are acceptable 
for screening if obtained within the specified time window. 
b. 
Height will be measured only at the screening visit. 
c. 
For all patients in the trial, 1 standard local ECG will be collected and read at screening and at the end of the infusion (+30 minutes) on the days indicated in 
these Schedule of Events. Triplicate ECGs will be obtained as described in these Schedule of Events and in Appendix C starting in Cohort 3 (0.1 mg/kg) or 
earlier if there is evidence of biological effect, read centrally. When the timing of triplicate and single (safety) ECGs coincide, the site can use the triplicate 
ECG collection for safety evaluation. When a standard single ECG is to be collected during a cycle/day that is other than on C1D1, C1D8 and C1D15, 1 
standard ECG will be collected at the end of the infusion (+30 minutes) on the days indicated in this Schedule of Events, read locally. 
d. 
Vital signs measured before starting the infusion and after the completion of the infusion. Vital signs include temperature, pulse, respiratory rate, oxygen 
saturation, and blood pressure. Blood pressure will be measured every 30 minutes (±5 minutes) during the first 4 infusions, after the end of the infusion, and 
at any moment if the patient complains of symptoms consistent with IRR.  
e. 
In case of an IRR, blood draws should be performed for central evaluation of immune markers, cytokines, and complement (see Section 8.7.1.1). The 
following samples should be collected: serum sample for circulating biomarkers (cytokines, complement, neopterin), and serum sample for immunogenicity. 
Modakafusp alfa doses <6 mg/kg will be administered over 1 hour (±10 minutes). Modakafusp alfa doses ≥6 mg/kg will be administered over 2 hours (±10 
minutes). Any decrease in infusion duration must be discussed with and agreed upon by the sponsor. If a patient presents with an IRR at any dose level, the 
duration of the infusion may be extended per investigator’s discretion. Total time from modakafusp alfa dosing solution preparation until end of infusion 
must not exceed 7 hours. Infusion and pharmacy staff are advised to be prepared accordingly for either a planned, extended infusion time or for potential 
infusion interruptions. See Pharmacy Manual for additional guidance. 
f. 
For patients with no previously documented extramedullary disease at screening, a complete skeletal survey, using plain x-ray or low-dose total body CT 
scan, will be performed at screening (if the patient has adequate imaging test(s) performed within 5 weeks of the planned first dose of study drug, they can 
be used as baseline evaluations and do not need to be repeated as part of screening). If there are symptoms or signs that suggest increased or new bone 
lesions, the skeletal survey or plain film of symptomatic sites may be repeated any time during the study and at the EOT visit. A PET-CT may be done at 
screening in place of a skeletal survey provided that the same modality for assessment is used throughout the study. Patients with normal skeletal survey at 
baseline do not need to repeat the test periodically unless bone progressive disease is clinically suspected. 
For patients with previously documented extramedullary disease or with suspicion of extramedullary progression, a PET-CT scan, CT scan, or MRI scan will 
be performed at screening (if the patient has adequate imaging test(s) performed within 5 weeks of the planned first dose of study drug, they can be used as 
baseline evaluations and do not need to be repeated as part of screening) and as needed for evaluation of disease. If extramedullary disease is documented at 
screening, then a repeat PET-CT scan, CT scan, or MRI scan should be performed every other cycle starting on Cycle 3. For posttreatment follow-up of 
patients with extramedullary disease who stop treatment for reason other than PD, PET-CT scan, CT scan, or MRI scan should be performed every 12 weeks 
or if new symptoms suggest PD. 
g. 
Chemistry will consist of albumin, ALT, alkaline phosphatase, AST, HCO3- or CO2, blood urea nitrogen, calcium, chloride, potassium, sodium, phosphate, 
creatinine, total bilirubin, LDH, urate, blood glucose (nonfasting), and standard C-reactive protein. Thyroid function tests (thyroid stimulating hormone, free 

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or total T3, and free or total T4) will also be performed. Serum β2 microglobulin levels will be measured at baseline only. It is not necessary to repeat these 
tests on C1D1 predose if the tests performed at screening are less than 4 days old. Hepatitis B serology (hepatitis B surface antigen, hepatitis B core 
antibody, hepatitis B surface antibody) and hepatitis C serology will be performed at screening. Patients with known chronic hepatitis C and/or positive 
serology (unless due to vaccination or passive immunization due to Ig therapy) for chronic hepatitis B are excluded.  
h. 
Hematology will consist of hemoglobin, hematocrit, platelet count, WBC count, and WBC differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils). It is not necessary to repeat these tests on C1D1 predose if the tests performed at screening are less than 4 days old. 
i. 
Urinalysis (dipstick) will include bilirubin, glucose, ketones, leukocytes, nitrite, occult blood, pH, protein, specific gravity, turbidity and color, and 
urobilinogen. Microscopic if clinically indicated only: bacteria, RBCs, WBCs, casts, and crystals. 
j. 
Pregnancy test (refer to Section 9.3.9.2).  
▪ 
Screening/Baseline: Participants of childbearing potential must have 2 negative pregnancy tests before starting study drug.  
o 
A urine or serum pregnancy test will be required during screening (within 10 to 14 days before start of study drug); this test must be negative. 
o 
A urine or serum pregnancy test must be performed at baseline (within 24 hours before the start of study drug). The results from these tests 
must be available and negative before the first dose of study drug is administered. 
• 
On-treatment: During the study, participants of childbearing potential must have a negative urine or serum pregnancy test result within 72 hours before 
dosing on Day 1 of each cycle during treatment prior to dosing. If a menstrual period is delayed, absence of pregnancy in participants of childbearing 
potential must be confirmed by a negative urine or serum pregnancy test. 
o 
Pregnancy tests may also be repeated during the study as per request of IRB or if required by local regulations. 
• 
EOT: A urine or serum pregnancy test is required at EOT in participants of childbearing potential. 
k. 
To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
l. 
Urine M-protein 24-hour urine sample required while on treatment and during follow-up only if urine M-protein is measurable at baseline (urine M-protein 
≥200 mg/24 hours).  
m. 
Immunofixation of serum and/or urine may be omitted at screening if a previous local laboratory report for the serum and/or urine protein electrophoresis 
states that the observed monoclonal spike is consistent with one previously characterized by immunofixation and specifies the heavy chain and light chain 
previously identified. Immunofixation in serum and urine is required for patients evaluated for CR. 
n. 
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained. For the rare patient with known IgD or IgE MM, the quantitative test for that 
antibody will be followed at the same time points throughout the treatment period and PFS follow-up period as quantitative Igs (in addition to quantitative 
IgM, IgG, and IgA). 
o. 
All responses, including PD, must be confirmed by central laboratory evaluation. If the start of a cycle is delayed, serum M-protein and serum FLCs are to 
be collected for central laboratory analysis if not previously sent within the preceding 10 days. If a patient has collected a 24-hour urine sample and brought 
it to a visit, the sample should be sent for central laboratory analysis of urine M-protein even if not on Day 1 of a cycle. 
p. 
See Appendix B for details.  
q. 
Blood samples for PK will be collected at time points specified in Appendix C. 
r. 
Immunoprofiling consists of flow cytometric analysis of T, B, and NK lymphocyte subsets, and will be analyzed centrally. 
s. 
Predose. 
t. 
Predose and at 8 hours after the start of infusion. 
u. 
Blood samples for immunogenicity (ADA and NAb) testing will be collected before the dose on indicated visits while the patient remains in treatment and, if 

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possible, at the EOT follow-up visit. In case of an infusion reaction, blood draws should be performed for central evaluation of immunogenicity (see  
Section 8.7.1.1).  
v. 
 One blood sample for DNA will be taken at either screening or C1D1 predose (when it is not possible to collect at screening, samples can be collected at the 
next visit). 
w. 
Cycle 9 Day 1 only. 
x. 
Only repeat tests in parentheses for patients terminating treatment due to PD, if they were not performed before for PD determination at the last visit, and for 
patients discontinuing due to treatment completion or CR if not performed before for CR confirmation. 
y. 
Patients who discontinue for reasons other than PD will continue PFS follow-up every 4 weeks from the EOT visit until the occurrence of PD, death, the 
start of subsequent systemic antineoplastic therapy, study termination, or until 6 months after the discontinuation of study treatment, whichever occurs first.  
z. 
End-of-treatment laboratory assessments are to be performed prior to the patient starting a new treatment or a maximum of 30 days following the last dose. 
aa. Schedule D Visits for C1D3 and C2D3 may be removed at a future time if no longer needed depending on MTD/OBD. 
bb. Dexamethasone will be added to the MTD/OBD of one or more schedule(s) as additional cohort(s). Dexamethasone will be given as a once weekly oral dose 
of 40 mg. Patients over 75 years of age will receive a reduced dose of dexamethasone (20 mg, same schedule) (refer to Section 8.1). 
cc. Antiplatelet antibodies will be collected as indicated in the Schedule of Events until the sponsor communicates to the sites that a sufficient number of 
samples have been obtained to stop the collection. 
dd. Predose and at 4 hours (± 30 minutes) after the end of infusion. 
ee. Strongly recommended for >6 mg/kg dose group only. 
ff. 
Coagulation panel (prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, D-Dimer) to be performed if clinically 
significant bleeding occurs.  

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d. 
Vital signs include temperature, pulse, respiratory rate, oxygen saturation, and blood pressure.  
e. 
For patients with no previously documented extramedullary disease at screening, a complete skeletal survey, using plain x-ray or low-dose total body CT 
scan, will be performed at screening (if the patient has adequate imaging test(s) performed within 5 weeks of the planned first dose of study drug, they can 
be used as baseline evaluations and do not need to be repeated as part of screening). If there are symptoms or signs that suggest increased or new bone 
lesions, the skeletal survey or plain film of symptomatic sites may be repeated any time during the study and at the EOT visit. A PET-CT may be done at 
screening in place of a skeletal survey provided that the same modality for assessment is used throughout the study. Patients with normal skeletal survey at 
baseline do not need to repeat the test periodically unless bone progressive disease is clinically suspected. For patients with previously documented 
extramedullary disease or with suspicion of extramedullary progression, a PET-CT scan, CT scan, or MRI scan will be performed at screening (if the patient 
has adequate imaging test(s) performed within 5 weeks of the planned first dose of study drug, they can be used as baseline evaluations and do not need to be 
repeated as part of screening) and as needed for evaluation of disease. If extramedullary disease is documented at screening, then a repeat PET-CT scan, CT 
scan, or MRI scan should be performed every other cycle starting on Cycle 3. For posttreatment follow-up of patients with extramedullary disease who stop 
treatment for reason other than PD, PET-CT scan, CT scan, or MRI scan should be performed every 12 weeks or if new symptoms suggest PD. 
f. 
Chemistry will consist of albumin, ALT, alkaline phosphatase, AST, HCO3- or CO2, blood urea nitrogen, calcium, chloride, potassium, sodium, phosphate, 
creatinine, total bilirubin, LDH, urate, blood glucose (nonfasting), and standard C-reactive protein. Serum β2 microglobulin levels will be measured at 
baseline only.  
g. 
Hematology will consist of hemoglobin, hematocrit, platelet count, WBC count, and WBC differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils). It is not necessary to repeat these tests on C1D1 predose if the tests performed at screening are less than 4 days old.  
h. 
Urinalysis (dipstick) will include bilirubin, glucose, ketones, leukocytes, nitrite, occult blood, pH, protein, specific gravity, turbidity and color, and 
urobilinogen. Microscopic if clinically indicated only: bacteria, RBCs, WBCs, casts, and crystals. 
i. 
Pregnancy test (refer to Section 9.3.9.2). A urine or serum pregnancy test is required at EOT in women of childbearing potential. If menstrual period is 
delayed, absence of pregnancy in women of childbearing potential must be confirmed by serum pregnancy test. 
j. 
Urine M-protein 24-hour urine sample required while on treatment and during follow-up only if urine M-protein is measurable at baseline (urine M-protein 
≥200 mg/24 hours). 
k. 
Immunofixation of serum and/or urine may be omitted at screening if a previous local laboratory report for the serum and/or urine protein electrophoresis 
states that the observed monoclonal spike is consistent with one previously characterized by immunofixation and specifies the heavy chain and light chain 
previously identified. Immunofixation in serum and urine is required for patients evaluated for CR. 
l. 
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained. For the rare patient with known IgD or IgE MM, the quantitative test for that 
antibody will be followed at the same time points throughout the treatment period and PFS follow-up period as quantitative Igs (in addition to quantitative 
IgM, IgG, and IgA). 
m. 
See Appendix B for details.  
n. 
Immunoprofiling consists of flow cytometric analysis of T, B, and NK lymphocyte subsets and will be analyzed centrally.  
o. 
Blood samples for immunogenicity (ADA and NAb) testing will be collected, if possible, at the EOT follow-up visit.  
p. 
Only repeat tests in parentheses for patients terminating treatment due to PD, if they were not performed before for PD determination at the last visit, and for 
patients discontinuing due to treatment completion or CR if not performed before for CR confirmation. 
q. 
Patients who discontinue for reasons other than PD will continue PFS follow-up every 4 weeks from the EOT visit until the occurrence of PD, death, the 
start of subsequent systemic antineoplastic therapy, study termination, or until 6 months after the discontinuation of study treatment, whichever occurs first.  

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r. 
End-of-treatment laboratory assessments are to be performed prior to the patient starting a new treatment or a maximum of 30 days following the last dose.  
s. 
Antiplatelet antibodies will be collected and analyzed locally until the sponsor communicates to the sites that a sufficient number of samples have been 
obtained to stop the collection. 
t. 
Coagulation panel (prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, D-Dimer) to be performed if clinically 
significant bleeding occurs.  

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positron emission tomography-computed tomography; PFS: progression-free survival; PK: pharmacokinetic(s); PRO: patient-reported outcome; q12wk: every 12 
weeks; SAE: serious adverse event; TBNK: T-lymphocyte, B-lymphocyte, and natural killer cells; V: visit; WBC: white blood cell.  
Note: Crosses in parentheses “(X)” indicate tests are to be performed only under certain circumstances as indicated in associated footnote(s). 
a. 
Written informed consent must be obtained before performing any protocol-specific procedure. Test results from routine clinical management are acceptable 
for screening if obtained within the specified time window. 
b. 
Height will be measured only at the screening visit. 
c. 
All patients will have 1 standard local ECG collected and read locally at screening and at the end of the infusion (+30 minutes) on the days indicated.  
d. 
Vital signs measured before starting the infusion and after the completion of the infusion. Vital signs include temperature, pulse, respiratory rate, oxygen 
saturation, and blood pressure. Blood pressure will be measured every 30 minutes (±5 minutes) during the first 4 infusions, after the end of the infusion, and 
at any time a patient complains of symptoms consistent with IRR.  
e. 
Clinical imaging assessments to summarize status of known lesions should be based on available imaging at each respective time point. 
f. 
In case of an IRR, the following samples should be collected: serum sample for circulating biomarkers and serum sample for immunogenicity. Any decrease 
in infusion duration must be discussed with and agreed upon by the sponsor. If a patient presents with an IRR at any dose level, the duration of the infusion 
may be extended per investigator’s discretion. Total time from modakafusp alfa dosing solution preparation until end of infusion must not exceed 7 hours. 
Infusion and pharmacy staff are advised to be prepared accordingly for either a planned, extended infusion time or for potential infusion interruptions. See 
Pharmacy Manual for additional guidance. 
g. 
Imaging to assess bone disease is required for all patients at screening. Imaging performed within 5 weeks of the planned first dose of study drug can be used 
as baseline evaluations and does not need to be repeated as part of screening. Low-dose whole-body CT is recommended over conventional skeletal survey 
for the evaluation of multiple myeloma bone disease. Conventional skeletal survey can be used for the diagnosis of multiple myeloma when whole-body CT 
or other novel imaging methods are not available. Additional assessments for bone disease can be done at the discretion of the investigator (ie, for suspected 
increased or new bone lesions PD). The same modality for assessment should be used throughout the study.  
h. 
Imaging to assess extramedullary disease is required for all patients at screening by PET-CT, MRI, or CT. Imaging performed within 5 weeks of the planned 
first dose of study drug can be used as baseline evaluations and does not need to be repeated as part of screening. If extramedullary disease is documented at 
screening, repeat imaging using the same modality every 3 cycles until a plateau or complete response is reached, or as clinically indicated, and then at 
suspected progression. Imaging tests for patients with extramedullary disease should be performed if new symptoms suggest PD. 
i. 
Local laboratory results may be used for dosing decisions; however, all samples (other than thyroid function tests) must still be sent to the central laboratory 
until the occurrence of progression, death, the start of subsequent systemic antineoplastic therapy, study termination, or until 6 months after the 
discontinuation of study treatment, whichever occurs first. Chemistry will consist of albumin, ALT, alkaline phosphatase, AST, HCO3- or CO2, blood urea 
nitrogen, calcium, chloride, magnesium, potassium, sodium, phosphate, creatinine, total bilirubin, LDH, urate, blood glucose (nonfasting), and standard C-
reactive protein and may be collected up to 3 days prior to dosing. Thyroid function tests (thyroid stimulating hormone, free or total T3, and free or total T4) 
will be performed during screening, Cycle 3, and every 3 cycles thereafter and will be analyzed locally. Serum β2 microglobulin levels will be measured at 
screening only and must be done by central laboratory (see Section 9.3.9.6 for further details on chemistry evaluations) It is not necessary to repeat these 
tests on C1D1 predose if the tests performed at screening are less than 3 days old.  
j. 
As required by country regulations, hepatitis B serology (HBsAg, hepatitis B core antibody, hepatitis B surface antibody) and hepatitis C serology will be 
performed at screening. Patients with known chronic hepatitis C and/or positive serology (unless due to vaccination or passive immunization due to Ig 
therapy) for chronic hepatitis B are excluded. Patients who are seropositive for hepatitis B (defined as a positive test for HBsAg) are excluded. Patients with 

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resolved infection (that is, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen and/or anti-HBs) must be screened 
using real-time PCR measurement of HBV DNA levels. Those who are PCR positive will be excluded. Exception: Patients with serologic findings 
suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be tested for 
HBV DNA by PCR. 
k. 
Urinalysis (dipstick) includes bilirubin, glucose, ketones, leukocytes, nitrite, occult blood, pH, protein, specific gravity, turbidity and color, and urobilinogen. 
Microscopic analysis only if clinically indicated: bacteria, RBCs, WBCs, casts, and crystals. 
l. 
Pregnancy test (refer to Section 9.3.9.2).  
Screening/baseline: Participants of childbearing potential must have 2 negative pregnancy tests before starting study drug. 
• 
A urine or serum pregnancy test will be required during screening (within 10 to 14 days before start of study drug); this test must be negative. 
• 
A urine or serum pregnancy test must be performed at baseline (within 24 hours before the start of study drug). The results from these tests must be 
available and negative before the first dose of study drug is administered. 
On-treatment: During the study, participants of childbearing potential must have a negative urine or serum pregnancy test result within 72 hours before 
dosing on Day 1 of each cycle during treatment prior to dosing.  
• 
If a menstrual period is delayed, absence of pregnancy in participants of childbearing potential must be confirmed by a negative urine or serum 
pregnancy test. 
• 
Pregnancy tests may also be repeated during the study as per request of IRB or if required by local regulations. 
 
EOT: At EOT, a urine or serum pregnancy test is required in participants of childbearing potential. 
m. 
All responses, including PD, must be confirmed by central laboratory evaluation. If the start of a cycle is delayed, serum M-protein and serum FLCs are to 
be collected for central laboratory analysis if not previously sent within the preceding 10 days. If a patient has collected a 24-hour urine sample and brought 
it to a visit, the sample should be sent for central laboratory analysis of urine M-protein even if not on Day 1 of a cycle. 
n. 
Screening levels for Part 3 must be ≥500 mg/dL. To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
o. 
Sample to be collected at any time on Day 2 of the cycle. 
p. 
Urine M-protein 24-hour urine sample required while on treatment and during follow-up. To be repeated at baseline (C1D1) if screening sample was taken 
more than 7 days before C1D1. 
q. 
Serum FLC to be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
r. 
Immunofixation in serum and urine is required for patients evaluated for CR; see Sections 9.3.10.6. To be repeated at baseline (C1D1) if screening sample 
was taken more than 7 days before C1D1. 
s. 
A blood sample for quantification of Ig (IgM, IgG, and IgA) will be obtained. For the rare patient with known IgD or IgE MM, the quantitative test for that 
antibody will be followed at the same time points throughout the treatment period and PFS follow-up period as quantitative Igs (in addition to quantitative 
IgM, IgG, and IgA) (see Section 9.3.10.3). To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1. 
t. 
For local analysis of disease assessment and cytogenetics at screening, a standard BMA drawn before consent is acceptable provided this is collected within 
5 weeks of the first dose. All patients should also have a sample from screening sent for central cytogenetic analysis (“BMA for cytogenetics”). 
u. 
Blood samples for PK will be collected at time points specified in Appendix C, Tables 9 and 10. 
v. 
All patients should have a fresh BMA sample from screening sent for central cytogenetic analysis.  
w. 
Predose.  
x. 
Coagulation panel (prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, D-Dimer) to be performed if clinically 

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significant bleeding occurs.  
y. 
Blood samples for immunogenicity (ADA/NAb) testing will be collected before the dose on indicated visits during treatment and, if possible, at the EOT 
visit. In case of an infusion reaction, blood draws should be performed for central evaluation of immunogenicity (see Section 8.7.1.1). On days when dosing 
is not required, samples may be collected at any point during the clinic visit.  
z. 
Only repeat tests in parentheses for patients terminating treatment due to PD if they were not performed before for PD determination at the last visit, and for 
patients in CR if not performed before for CR confirmation. 
aa. End-of-treatment laboratory assessments are to be performed prior to the patient starting a new treatment or a maximum of 30 days following the last dose. 
bb. Patients will have PFS follow-up every 4 weeks from the EOT visit until the occurrence of PD, death, the start of subsequent systemic antineoplastic 
therapy, study termination, or until 6 months after the discontinuation of study treatment, whichever occurs first.  
cc. OS follow-up continues every 12 weeks until death, study termination, or patient withdrawal. 
dd. Predose and at 4 hours (± 60 minutes) after the end of infusion. 
ee. All PROs should be administered D8 of each cycle, except for C1 when the EORTC QLQ-MY20 should be administered on D1 and D8 (ie, C1D1 and 
C1D8) and the EQ-5D-5L on D1 (ie, C1D1). On C1D1, PROs may be completed within a +1-day window, and on the rest of the days PROs may be 
completed within a 2-day window. On days when PROs are administered during clinic visits, the EORTC QLQ-MY20 and EQ-5D-5L should be 
administered to patients when they arrive for their scheduled visits, before any clinical measurements, assessments, evaluations, or procedures being 
performed (see Section 9.3.12). On days when PROs are not completed at the clinic (ie, Day 8 of each cycle starting with Cycle 3), site staff should remind 
each patient at every cycle to complete their PROs. Healthcare utilization data is collected on D1 of every cycle, starting at C1, and at EOT.  
ff. 
Immediately following the bone marrow aspiration/biopsy obtained for local disease assessment at screening and for confirmation of a suspected CR, BMA 
will be collected for evaluation of minimal residual disease and sent to a central laboratory for analysis. If a BMA/biopsy drawn before consent, within 5 
weeks of first dose, is used for local disease assessment at screening, the first BMA pull will be drawn for the MRD sample. Additionally, BMAs will be 
requested for MRD assessment every 6 months after suspected CR to further characterize MRD status. Screening MRD samples will be obtained in China 
based on acceptability of method chosen. 
gg. Following the collection of BMA for MRD sample at screening, an additional 3 mL pull of BMA will be collected for cytogenetic analysis and central 
evaluation of both tumor and immune fractions of bone marrow.  
hh. Sample collection not applicable to patients enrolled in China. See Sections 9.3.11.3.2.6, 9.3.11.3.2.7 and 9.3.11.4. 
ii. 
Cytogenetic results from samples taken within 5 weeks prior to first dose are acceptable for stratification. If a previous result is not available and the patient 
is known to have high-risk disease [ie, del17, t(4;14) and/or t(14;16)] from prior cytogenetic testing, regardless of timing, they should be stratified as high 
risk for the purpose of enrollment. Additionally, all patients should have a sample from screening sent for central cytogenetic analysis (“BMA for 
cytogenetics”).  
jj. 
A portion of this sample will be used for exploratory analyses. 
kk. See Section 9.3.10.7 for details regarding interference testing for patients who received an IgG MAb as recent prior therapy.  
ll. 
For patients who have had a response to modakafusp alfa treatment, a 3mL BMA collection at progression is optional. Sample to be used for central 
evaluation of both tumor and immune fractions of the bone marrow to inform potential resistance mechanisms.

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Appendix C PK Sampling Schedules 
Appendix C Table 1 Part 1 Schedule A PK Sampling: Cycle 1 
Time Points 
Cycle 1 
Day 1 a Into Day 2 
Day 4 
Day 8 
Day 15 
Day 16 
Day 18 
Day 22 a 
Triplicate 
ECG b 
PK 
PK 
PK 
Triplicate 
ECG b 
PK 
PK 
PK 
PK 
Predose (within 1 hour before infusion) 
X c 
X 
 
X 
X 
X 
 
 
X 
1 hour after start of infusion (±10 min) 
X 
X 
 
 
X 
X 
 
 
 
2 hours after start of infusion (20 min)  
X 
X 
 
 
X 
X 
 
 
 
4 hours after start of infusion (30 min) 
X d 
X 
 
X 
X d 
X 
 
 
X 
6 hours after start of infusion (30 min) 
X 
X 
 
 
X 
X 
 
 
 
8 hours after start of infusion (30 min) 
X 
X 
 
 
X 
X 
 
 
 
24 hours after start of infusion (1 hour) 
X 
X 
 
 
X 
 
X 
 
 
72 hours after start of infusion (1 hour) 
 
 
X 
 
 
 
 
X 
 
ECG: electrocardiogram; PK: pharmacokinetic. 
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood sample. The triplicate ECG measurements will be collected using sponsor provided Holter equipment and should be completed 
immediately before the corresponding PK blood draw. Triplicate ECGs for initial heart rate-corrected QT interval evaluation will be recorded and electronically 
stored during Cycle 1 at prespecified time points starting in Cohort 3 (0.1 mg/kg) or earlier if there is evidence of biological effect.  
a. 
The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of the cycle. 
b. 
Collection of triplicate ECG begins after patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs 
occurs within 3 minutes of each other and over a 10-minute window. When the timing of triplicate and single (safety) ECGs coincide, the site can use the 
triplicate ECG collection for safety evaluation. On Days 1 and 15, patients will abstain from eating food or having anything to drink except water from a 
minimum of 2 hours prior to collection of the pre-dose ECGs until after collection of the 4-hour after start of infusion ECGs. Immediately following the 4-
hour ECG and PK collection, patients will be administered a light meal, following which they will again abstain from eating until collection of the 8-hour 
ECG sample. On Day 2, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours prior to collection of the 
24-hour and 72-hour after start of infusion ECGs until after collection of the ECGs on those days. In patients unable to comply with these recommendations, 
any food intake should be limited to the smallest required portion of bland food.  
c. 
Collection of triplicate ECG must occur prior to any drug infusion. 
d. 
Collection of the triplicate ECG at 4 hours post start of infusion should be completed prior to turning off the infusion pump. 

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Appendix C Table 2 Part 1 Schedule A PK Sampling: Cycle 2 
Time Points 
Cycle 2 
Day 1 a 
Day 2 
Day 4 
Day 8 a 
Day 15 a 
Day 22 a 
Predose (within 1 hour before infusion) 
X 
 
 
X 
X 
X 
1 hour after start of infusion (±10 min) 
X 
 
 
 
 
 
2 hours after start of infusion (20 min) 
X 
 
 
 
 
 
4 hours after start of infusion (30 min) 
X 
 
 
X 
X 
X 
6 hours after start of infusion (30 min) 
X 
 
 
 
 
 
8 hours after start of infusion (30 min) 
X 
 
 
 
 
 
24 hours after start of infusion (1 hour) 
 
X 
 
 
 
 
72 hours after start of infusion (1 hour) 
 
 
X 
 
 
 
ECG: electrocardiogram; PK: pharmacokinetic. 
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood sample. 
a. 
The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of the cycle. 

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Appendix C Table 3 Part 1 Schedule A PK Sampling: Cycle 3 to Cycle 13 
Time Points 
Cycle 3 
Cycle 4 to Cycle 6 
Cycles 7-13 
Day 1 a 
Day 2 
Day 15 a 
Day 1 a 
Day 15 
Day 1 a 
Predose (within 1 hour before infusion) 
X 
 
X 
X 
X 
X 
4 hours after start of infusion (30 min) 
X 
 
X 
X 
X 
X 
24 hours after end of infusion (±1 hour) 
 
X 
 
 
 
 
ECG: electrocardiogram; PK: pharmacokinetic. 
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be 
completed before the collection of the blood sample.  
a. 
Modakafusp alfa infusion. The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of 
the cycle.  

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Appendix C Table 4 Part 1 Schedule B (Q2W) PK Sampling: Cycle 1 and Cycle 2 
 
Day 1 a 
Day 2 a 
Day 15 a 
Day 16 
Time Points 
Triplicate 
ECG b 
PK 
Triplicate 
ECG b 
PK 
PK 
PK 
Predose (within 30 min prior to start of infusion)  
X c 
X 
 
 
X 
 
End of infusion (±5 min) 
X 
X 
 
 
X 
 
1 hour after end of infusion (±10 min) 
X 
X 
 
 
X 
 
2 hours after end of infusion (20 min) 
 X  
X 
 
 
X 
 
4 hours after end of infusion (30 min) 
X 
X 
 
 
X 
 
6 hours after end of infusion (30 min) 
X 
X 
 
 
X 
 
24 hours after end of infusion (1 hour) 
 
 
X 
X 
  
X 
ECG: electrocardiogram; PK: pharmacokinetic; Q2W; every 2 weeks. 
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood sample.  
a. 
The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of the cycle. 
b. 
Collection of triplicate ECG begins after patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs occur 
within 3 minutes of each other and over a 10-minute window. When the timing of triplicate and single (safety) ECGs coincide, the site can use the triplicate 
ECG collection for safety evaluation. On Day 1, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours 
prior to collection of the predose ECGs until after collection of the 2-hour after end of infusion ECGs. Immediately following the 2-hour ECG and PK 
collection, patients will be administered a light meal, following which they will again abstain from eating until collection of the 6-hour ECG sample. On Day 
2, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours prior to collection of the ECGs until after 
collection of the ECGs on those days. In patients unable to comply with these recommendations, any food intake should be limited to the smallest required 
portion of bland food. 
c. 
Collection of triplicate ECG must occur prior to any drug infusion. 

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Appendix C Table 5 Part 1 Schedule B (Q2W) PK Sampling: Cycle 3 and Beyond 
Time Points 
Cycle 3 
Cycle 4 and Beyond 
Day 1 a 
Day 2 
Day 15 a 
Day 1 a 
Day 15 a 
Predose (within 30 min prior to start of infusion) 
X 
 
X 
X 
X 
End of infusion (+5 min) 
X 
 
X 
X 
X 
2 to 4 hours after end of infusion (±30 min) 
X 
 
X 
X 
X 
24 hours after end of infusion (±1 hour) 
 
X 
 
 
 
PK: pharmacokinetic; Q2W: every 2 weeks. 
a. 
Modakafusp alfa infusion. The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of 
the cycle.  

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Appendix C Table 6 Part 1 Schedule C (Q3W) PK Sampling: Cycle 1 and Cycle 2 
Time Points 
Cycle 1 and Cycle 2 
Day 1 into Day 2 a 
Day 3 
Day 8 a 
Day 15 a 
Triplicate  
ECG b 
PK 
Triplicate  
ECG b 
PK 
Triplicate  
ECG b 
PK 
Triplicate  
ECG b 
PK 
Predose (within 30 min prior to start of infusion)  
X c 
X 
 
 
 
 
 
 
End of infusion (±5 min) 
X 
X 
 
 
 
 
 
 
1 hour after end of infusion (±15 min) 
X 
X 
 
 
 
 
 
 
2 hours after end of infusion (±15 min) 
X  
X 
 
 
 
 
 
 
4 hours after end of infusion (±30 min) 
X 
X 
 
 
 
 
 
 
6 hours after end of infusion (±30 min) 
X 
X 
 
 
 
 
 
 
24 hours after end of infusion (±1 hour) 
X 
X 
 
 
 
 
 
 
48 hours after end of infusion (±1 hour) 
 
 
X 
X 
 
 
 
 
168 hours after end of infusion (±2 hour) 
 
 
 
 
X 
X 
 
 
336 hours after end of infusion (±4 hour) 
 
 
 
 
 
 
X 
X 
ECG: electrocardiogram; PK: pharmacokinetic; Q3W: once every 3 weeks. 
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood sample.  
a. 
The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of the cycle. 
b. 
Collection of triplicate ECG begins after patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs occur 
within 3 minutes of each other and over a 10-minute window. When the timing of triplicate and single (safety) ECGs coincide, the site can use the triplicate 
ECG collection for safety evaluation. On Day 1, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours 
prior to collection of the pre-dose ECGs until after collection of the 2-hour after end of infusion ECGs. Immediately following the 2-hour ECG and PK 
collection, patients will be administered a light meal, following which they will again abstain from eating until collection of the 6-hour ECG sample. On 
Days 2, 4, 8 and 15, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours prior to collection of the 
planned ECGs until after collection of the triplicate ECGs on those days. In patients unable to comply with these recommendations, any food intake should 
be limited to the smallest required portion of bland food. 
c. 
Collection of triplicate ECG must occur prior to any drug infusion. 
 

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Appendix C Table 7 Part 1 Schedule C (Q3W) PK Sampling: Cycle 3 and Beyond 
Timepoints 
Cycle 3 and beyond 
Day 1 a 
Predose (within 30 min prior to start of infusion) 
X 
End of infusion (+5 min) 
X 
2 to 4 hours after end of infusion (±30 min) 
X 
PK: pharmacokinetic; Q3W: once every 3 weeks. 
a. 
Modakafusp alfa infusion. The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous infusion 
visits. 

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Appendix C Table 8 Parts 1 and 2 Schedule D (Q4W) PK Sampling: Cycles 1 and 2 
Time Points 
Day 1 into Day 2 a 
Day 3 a 
Day 8 a 
Day 15 a 
Day 22 d 
Triplicate 
ECG b 
PK 
Triplicate 
ECG b 
PK 
Triplicate 
ECG b 
PK 
Triplicate 
ECG b 
PK 
PK 
Predose (within 30 min prior to start of infusion)  
X c 
X 
 
 
 
 
 
 
 
End of infusion (±5 min)  
X 
X 
 
 
 
 
 
 
 
2 hours after end of infusion (±30 min) 
X  
X 
 
 
 
 
 
 
 
4 hours after end of infusion (±30 min) 
X 
X 
 
 
 
 
 
 
 
6 hours after end of infusion (±30 min) 
X 
X 
 
 
 
 
 
 
 
24 hours after end of infusion (1 hour) 
X 
X 
 
 
 
 
 
 
 
48 hours after end of infusion (±1 hour) 
 
 
X 
X 
 
 
 
 
 
168 hours after end of infusion (2 hour) 
 
 
 
 
X 
X 
 
 
 
336 hours after end of infusion (4 hour) 
 
 
 
 
 
 
X 
X 
 
504 hours after end of infusion (± 4 hour) 
 
 
 
 
 
 
 
 
X 
ECG: electrocardiogram; PK: pharmacokinetic; Q4W: once every 4 weeks. 
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood sample.  
a. 
The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous days of the cycle. 
b. 
Collection of triplicate ECG begins after patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs occur 
within 3 minutes of each other and over a 10-minute window. When the timing of triplicate and single (safety) ECGs coincide, the site can use the triplicate 
ECG collection for safety evaluation. On Day 1, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours 
prior to collection of the predose ECGs until after collection of the 2-hour after end of infusion ECGs. Immediately following the 2-hour ECG and PK 
collection, patients will be administered a light meal, following which they will again abstain from eating until collection of the 6-hour ECG sample. On 
Days 2, 4, 8, and 15, patients will abstain from eating food or having anything to drink except water from a minimum of 2 hours prior to collection of the 
planned ECGs until after collection of the triplicate ECGs on those days. In patients unable to comply with these recommendations, any food intake should 
be limited to the smallest required portion of bland food. 
c. 
Collection of triplicate ECG must occur prior to any drug infusion.  
d. 
Strongly recommended for > 6 mg/kg dose group only. 

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Appendix C Table 9 Parts 1 and 2 Schedule D (Q4W) PK Sampling: Cycle 3 and Beyond 
Time Points 
Day 1 a 
Day 2 b 
Predose (within 30 min prior to start 
of infusion) 
X 
 
End of infusion (±10 min) 
X 
 
2 to 4 hours after end of infusion 
(30 min) 
X 
 
24 hours after the end of the 
infusion (±1 hr) 
 
X 
PK: pharmacokinetic; Q4W: every 4 weeks. 
a. 
Mofakafusp alfa infusion. The timing of the morning visits should occur at approximately the same time as the morning infusion times on previous infusion 
visits. 
b. 
Day 2 of Cycles 3, 7, and 11 only. 
 

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Appendix C Table 10 
Part 3 Extension PK Sampling: Cycles 1 and 2 a 
Timepoints 
Cycle 1 
 
 
Cycle 2 
Day 1 
Day 2 
Day 8 
Day 15 
Day 1 
Day 2 
Day 8 
Day 15 
Predose (within 30 min prior to start of infusion) 
X 
 
 
 
X  
 
 
 
End of infusion (±10 min) 
X 
 
 
 
X 
 
 
 
2 to 4 hours after end of infusion (±30 min) 
X 
 
 
 
X 
 
 
 
During the clinic visit 
 
X  
X 
X 
 
X  
X 
X 
PK: pharmacokinetic. 
a Not applicable to patients enrolled in China with intensive PK schedule (Table 11), but applicable to all other patients enrolled in China.   
 

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Appendix C Table 11 Part 3 Extension PK Sampling for Chinese Patients With Intensive PK Schedule: Cycles 1 and 2 
Time Points 
Day 1 into Day 2 a  
Day 3  
Day 8  
Day 15  
Day 22  
Predose (within 30 min prior to start of infusion)  
X 
 
 
 
 
End of infusion (±10 min)  
X 
 
 
 
 
2 hours after end of infusion (±30 min) 
X 
 
 
 
 
4 hours after end of infusion (±30 min) 
X 
 
 
 
 
6 hours after end of infusion (±30 min) 
X 
 
 
 
 
24 hours after end of infusion (1 hour) 
X 
 
 
 
 
48 hours after end of infusion (±1 hour) 
 
X 
 
 
 
168 hours after end of infusion (2 hour) 
 
 
X 
 
 
336 hours after end of infusion (4 hour) 
 
 
 
X 
 
504 hours after end of infusion (± 4 hour) 
 
 
 
 
X 
PK: pharmacokinetics. 
Note: Intensive PK samples will be collected only in up to 8 Chinese patients enrolled in China per dose upon laboratory kit 
availability.   
The timing of the morning visits should occur at approximately the same time as the morning dosing on previous dosing visits.  
a Blood sample for Day 1 predose will be collected within 30 minutes before start of any drug administration.  
 

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Appendix C Table 12 
Part 3 Extension PK Sampling: Cycle 3 and Beyond 
Time Points 
Cycle 3 and beyond 
Day 1 
Day 2 a 
EOT 
Predose (within 30 min prior to start of infusion) 
X 
 
 
End of infusion (±10 min) 
X 
 
 
2 to 4 hours after end of infusion (±30 min) 
X 
 
 
During the clinic visit 
 
X  
X 
PK: pharmacokinetic. 
a. 
Day 2 of Cycles 5 and 11 only.  

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Appendix D Responsibilities of the Investigator 
Clinical research studies Sponsored by the Sponsor are subject to ICH GCP and all the 
applicable local laws and regulations.  
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff that will assist in the protocol. 
3. If the investigator/institution retains the services of any individual or party to perform trial-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated. 
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities. 
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56, ICH, and local regulatory requirements. 
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC and issue a final report within 3 months of study completion. 
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
9. Obtain valid informed consent from each subject who participates in the study and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative. 
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued 
or that the regulatory authority has approved the marketing application. The investigator 
should contact and receive written approval from the Sponsor before disposing of any such 
documents. 

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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor.  
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours. 

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Appendix E Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
• Takeda, its affiliates, and licensing partners. 
• Business partners assisting Takeda, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication. 
• Inspections and investigations by regulatory authorities relating to the study. 
• Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above. 
 

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Appendix F IMWG Definition of MM (Kumar et al. 2016)  
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma-deﬁning events: 
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative 
disorder, specifically: 
• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of the 
normal range or >2.75 mmol/L (>11 mg/dL). 
• Renal insufficiency: creatinine clearance <40 mL per min† or serum creatinine >177 μmol/L 
(>2 mg/dL). 
• Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin 
value <100 g/L. 
• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡. 
Any one or more of the following biomarkers of malignancy: 
• Clonal bone marrow plasma cell percentage* ≥60%. 
• Involved: uninvolved serum FLC ratio§ ≥100. 
• >1 focal lesions on MRI studies. 
PET-CT, [18F]ﬂuorodeoxyglucose PET with CT. 
* Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, 
or immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. 
† Measured or estimated by validated equations. 
‡ If bone marrow has less than 10% clonal plasma cells, more than 1 bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement. 
§ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The 
involved FLC must be ≥100 mg/L. Each focal lesion must be 5 mm or more in size. 
 

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IMWG Uniform Criteria for Response  
Response 
Category  
Response Criteria 
sCR 
Complete response as defined below plus 
normal FLC ratio** and absence of clonal cells in bone marrow biopsy by 
immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after 
counting ≥100 plasma cells)†† 
CR 
Negative immunofixation of serum and urine, disappearance of any soft tissue 
plasmacytomas, and <5% plasma cells in bone marrow; in patients for whom only 
measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in 
addition to CR criteria is required; 2 consecutive assessments are needed a. 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein 
<100 mg/24 hours; in patients for whom only measurable disease is by serum FLC 
level, >90% decrease in difference between involved and uninvolved FLC levels, 
in addition to VGPR criteria, is required; 2 consecutive assessments are needed c. 
PR 
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 
≥90% or to <200 mg/24 hours. 
If the serum and urine M-protein are not measurable, 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 FLC is also not 
measurable, ≥50% reduction in bone marrow plasma cells is required in place of 
M-protein, provided the baseline percentage was ≥30%. 
In addition to the above criteria, if present at baseline, ≥50% reduction in the size 
of soft tissue plasmacytomas is also required. 
Two consecutive assessments are needed a no known evidence of progressive or 
new bone lesions if radiographic studies were performed. 
MRb 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-
protein by 50% to 89%. 
In addition to the above criteria, if present at baseline, 25% to 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 
fracture does not exclude response). 
SD c 
Does not meet the response criteria for CR (any variant), VGPR, PR, MR, or PD; 
no known evidence of progressive or new bone lesions if radiographic studies were 
performed. 
PD 
See text below. 
BM: bone marrow; CR: complete response; FLC: free light chain; MR: minimal response; ORR: objective 
response rate; PR: partial response; PD: progression of disease; RRMM: relapsed refractory multiple myeloma; 
sCR: stringent complete response; SD: stable disease; VGPR:  very good partial response.  
a Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, 
or immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. For this 

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Response 
Category  
Response Criteria 
trial 2 consecutive BM assessments are not required. 
b For RRMM only. 
c These categories do not contribute to the ORR. 
 
Before the institution of any new therapy, sCR, CR, and VGPR categories require serum and 
urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or 
neither. Radiographic studies are not required to satisfy these response requirements. Bone 
marrow assessments need not be conﬁrmed. 
PD is defined as an increase of ≥25% from lowest response value in any of the following: 
a) Serum M-protein (absolute increase must be ≥0.5 g/dL); serum M component increases 
≥1 g/dL are sufficient to deﬁne relapse if starting M component is ≥5 g/dL), and/or 
b) Urine M-protein (absolute increase must be ≥200 mg/24 hour), and/or 
c) Only in patients without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL). 
d) Only in patients without measurable serum and urine M-protein levels and without 
measurable disease by FLC levels, bone marrow plasma cell percentage (absolute 
percentage must be ≥10%). 
OR 
a) Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas. 
b) Development of hypercalcemia (corrected serum calcium >11.0 mg/dL) that can be 
attributed solely to the plasma cell proliferative disorder. 
A diagnosis of PD must be confirmed by 2 consecutive assessments. 
Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only 
in patients without measurable disease by M-protein and by FLC levels; “25% increase” refers to 
M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a 
confirmed value. 

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Appendix G ECOG Scale for Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without restriction. 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
Source: Oken MM et al, 1982(Oken et al. 1982). 
ECOG: Eastern Cooperative Oncology Group.  
 

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Appendix H Operating Characteristics of the Futility Stopping Rules  
The stopping rules used for the treatment arms of 240 mg and 120 mg at each interim futility 
analysis were chosen to have reasonable operating characteristics as displayed in this section 
(Appendix H Table 1 and Appendix H Table 2).  
Based on the proposed 2 interim futility analyses criteria (Section 13.2.2.1 Part 3 Futility 
Stopping Rules), the design operating characteristics were calculated for each of the treatment 
arms under different true ORR scenarios. 
Appendix H Table 1 displays the corresponding operating characteristics for the treatment arm of 
240 mg, including cumulative probability of terminating the arm early at each interim analysis, 
average number of patients enrolled and followed up for 3 months, average number of 
responders observed, and probability of success (PoS) at primary analysis. As there is no plan for 
efficacy claim based on any of the interim analyses, the only time to claim a positive efficacy 
conclusion (success for each arm) will be at the primary analysis. The success criterion will be a 
minimal of 33 responders among 118 treated patients, achieving the goal of lower limit of 95% 
CI above 20% uninteresting rate. 
Appendix H Table 1 Operating Characteristics for the Treatment Arm of 240 mg 
True ORR 
Cumulative probability of terminating the 
arm early at 
PoS at primary 
analysis 
Average number 
of patients 
enrolled and 
followed up for 
3 months 
Average 
number of 
observed 
responders 
1st IA for Futility 
2nd IA for futility 
10% 
82% 
99% 
0% 
21 
2 
20% 
40% 
70% 
2% 
56 
11 
30% 
13% 
19% 
64% 
101 
30 
35% 
6% 
8% 
89% 
111 
39 
40% 
3% 
3% 
97% 
115 
46 
50% 
<1% 
<1% 
100% 
118 
59 
IA: interim analysis; ORR: objective response rate; PoS: probability of success. 
 
As shown in Appendix H Table 1, when the true ORR is 20%, there is about 40% chance to 
terminate the 240 mg arm at the first interim futility analysis; about 70% chance to terminate the 
arm at either the first or second interim futility analysis; probability of success at primary 
analysis is around only 2%. When the true response rate is 35%, the cumulative probabilities of 
terminating the arm are reduced to 6% and 8% at the first and second interim futility analyses, 
the probability of success at primary analysis is 89%.  
A similar operating characteristics table was created for the treatment arm of 120 mg 
(Appendix H Table 2).  

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Appendix H Table 2 Operating Characteristics for the Treatment Arm of 120 mg 
True 
ORR 
Cumulative probability of 
terminating the arm early at 
PoS at 
primary 
analysis 
Average number of 
patients enrolled and 
followed up for 3 
months 
Average number of 
observed 
responders 
1st IA for Futility 
2nd IA for futility 
10% 
55% 
99% 
0% 
30 
3 
20% 
17% 
66% 
2% 
67 
13 
30% 
4% 
13% 
68% 
108 
32 
35% 
1% 
4% 
93% 
115 
40 
40% 
1% 
1% 
99% 
117 
47 
50% 
<1% 
<1% 
100% 
118 
59 
IA: interim analysis; ORR: objective response rate; PoS: probability of success 
 
Similarly, as shown in Appendix H Table 2, when the true ORR is 20%, there is about 17% 
chance to terminate the 120 mg arm at the first interim futility analysis; about 66% chance to 
terminate the arm at either the first or second interim futility analysis; PoS at primary analysis is 
around only 2%. When the true response rate is 35%, the cumulative probabilities of terminating 
the arm are reduced to 1% and 4% at the first and second interim futility analyses, the probability 
of success at primary analysis is about 93%.  
 

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Appendix I 
Statistical Guidance on Unacceptable Toxicity and Treatment Related Death 
The Bayesian toxicity monitoring approach based on posterior probability will be implemented 
to each DMC data review up to the second interim futility analysis to continuously monitor the 
unacceptable toxicity (particularly for Grade ≥4 nonhematologic treatment-related TEAEs) and 
treatment-related death within each treatment arm separately at various time points.  
These toxicity monitoring rules can be translated to toxicity boundaries in terms of the number of 
patients with Grade ≥4 nonhematologic treatment-related TEAEs and the number of treatment 
related death among all patients treated for each arm at each safety review. Appendix I Table 1 
illustrates the toxicity boundaries with the expected numbers of treated patients for each IDMC 
safety review based on our most recent enrollment projection. The actual toxicity boundaries will 
be recalculated based on the observed number of treated patients at each safety review using the 
same posterior probability stopping rule. 
Appendix I Table 1 Bayesian Toxicity Monitoring Boundaries for Grade ≥4 
Nonhematologic Treatment-Related TEAEs and Treatment Related- 
Deaths for Each Treatment Arm 
Number of treated 
patients per arm 
Unacceptable toxicity if the number of 
patients with Grade ≥4 nonhematologic 
treatment-related TEAEs 
Unacceptable toxicity if the number of 
patients with treatment-related death 
10 
≥4 
≥1 
35 a 
≥11 
≥3 
65 a 
≥20 
≥5 
a The expected numbers of patients treated at IA1 and IA2 based on most recent enrollment projection. 
 
Based on the toxicity boundaries presented in Appendix I Table 1, the corresponding operating 
characteristics for Grade ≥4 nonhematologic treatment-related TEAE monitoring for each 
treatment arm and the cumulative probability of early detection of unacceptable toxicity under 
different true toxicity rates with the expected number of patient treated at each safety review are 
displayed in Appendix I Table 2.  
Appendix I Table 2 Operating Characteristics for Monitoring Grade ≥4 
Nonhematologic Treatment-Related TEAEs Within Each Treatment Arm 
True 
Toxicity rate 
Cumulative probability of early detection with number of treated patients 
10 patients 
35 patients 
65 patients 
15% 
5% 
6% 
6% 
20% 
12% 
16% 
17% 
25% 
22% 
35% 
39% 
30% 
35% 
58% 
67% 
35% 
49% 
78% 
88% 
TEAE: treatment-emergent adverse event.  

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As shown in Appendix I Table 2, when the true toxicity rate is as low as 15%, there are low 
cumulative probabilities of 5% to 6% for early calls of unacceptable toxicity at each safety 
review; when the true toxicity rate is as high as 35%, there are about 49% to 88% cumulative 
probabilities of early call for unacceptable toxicity at each safety review. When the true DLT rate 
is 25% (the maximum toxicity allowed), there is about 39% cumulative probability to have an 
early call for unacceptable toxicity.  
Similar operating characteristics table was created for monitoring of treatment-related death for 
each treatment arm, shown in Appendix I Table 3.  
Appendix I Table 3 Operating Characteristics for Monitoring Treatment-Related Death 
Within Each Treatment Arm 
True 
Toxicity rate 
Cumulative probability of early detection with number of treated patients 
10 patients 
35 patients 
65 patients 
1% 
10% 
10% 
10% 
3% 
26% 
29% 
30% 
5% 
40% 
48% 
52% 
7% 
52% 
64% 
71% 
9% 
61% 
76% 
85% 
 
As shown in Appendix I Table 3, when the true treatment-related death rate is as low as 1%, 
there is about 10% cumulative probability of early call of unacceptable toxicity at each safety 
review; when the true treatment related death rate is as high as 9%, there are about 61% to 85% 
cumulative probabilities of early toxicity call at each safety review. When the true 
treatment-related death rate is 5% (the maximum toxicity allowed), there is about 52% 
cumulative probability to alarm the unacceptable toxicity early.  

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Appendix J 
Protocol History Including EUCTR Consolidation Table 
Protocol History: Amendments Harmonized with Global Protocol Amendment 9 
Date 
Amendment Number 
Region 
26 February 2024 
Amendment 10 v1 (not implemented) 
Global 
02 August 2023 
Amendment 9 
Global 
10 February 2023 
Amendment 8 CH v1 
Local China 
12 July 2022 
Amendment 8 NO v1 
Local Norway 
23 June 2022 
Amendment 8 GB v1 
Local United Kingdom 
01 March 2022 
Amendment 8 
Global 
25 October 2021 
Amendment 7 (not implemented) 
Global  
16 October 2020 
Amendment 6 
Global 
03 July 2019 
Amendment 5 
Global 
22 October 2018 
Amendment 4 
Global 
29 June 2018 
Amendment 3 
Global 
07 November 2017 
Amendment 2 
Global 
05 April 2017 
Amendment 1 
Global 
14 December 2016 
Initial protocol 
Global 
 
Protocol History: Amendments Not Harmonized with Global Protocol Amendment 9 
Country 
Date of Amendment 
Amendment Title 
France 
15 July 2022  
Amendment 8 FR v1 
France  
12 August 2022  
Amendment 8 FR v2 
Germany  
25 August 2022 
Amendment 8 DE v1 
Czech Republic  
04 November 2022 
Amendment 8 CZ v1 
Japan 
31 March 2022 
Amendment JP v1 
Japan 
12 August 2022 
Amendment JP v2 
Japan 
20 October 2022 
Amendment JP v3 
 
 

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Country Specific Requirements/Differences for the European Union 
(Consolidation of country-specific protocol differences approved in different member states 
under the Directive 2001/20/EC that will transition to the Regulation [EU] No. 536/2014) 
Summary of Changes 
Country Section 
Number 
Country Specific Language  
Country Specific Language in Tracked 
Changes against Global Protocol Language 
France 
v2 
8.1 Study Drug 
Administration 
Section 8.6.1 
Premedications  
…hospitalization is required for 
the first [infusion] of modakafusp 
alfa.  
Modakafusp alfa doses of 120 and 240 mg will 
be administered over 1 hour (±10 minutes). 
Hospitalization is required for Cycle 1 Day 1 
dose administration of modakafusp alfa. 
France 
v1 
7.2 Exclusion 
Criteria #12 
urine or 
or serum 
Female patients who are lactating and 
breastfeeding or have a positive urine or serum 
pregnancy test during the screening period or a 
positive urine or serum pregnancy test on Day 
1 before first dose of study drug if applicable.  
France 
v1 
9.3.9.2 
Pregnancy Test 
or serum 
urine or 
For women of childbearing 
potential, a urine or serum 
pregnancy test will be performed 
monthly on Day 1 of each cycle 
during treatment prior to dosing 
and at the EOT visit. 
A urine or serum pregnancy test will be used 
during screening (within 10 to 14 days prior to 
start of study drug). A urine or serum 
pregnancy test must be performed at baseline 
(within 24 hours prior to the start of study 
drug). 
For women of childbearing potential, a urine 
or serum pregnancy test will be performed 
monthly on Day 1 of each cycle during 
treatment prior to dosing and at the EOT 
visit. 
During the study, if menstrual period is 
delayed, absence of pregnancy in women of 
childbearing potential must be confirmed by 
urine or serum pregnancy test. Pregnancy tests 
may also be repeated during the study as per 
request of IRB or if required by local 
regulations.  
At end of treatment, a urine or serum 
pregnancy test is required in women of 
childbearing potential. 
France 
v1 
Appendix A  
Part 3  
Footnote l 
or serum 
urine or 
For women of childbearing 
potential, a urine or serum 
pregnancy test will be performed 
monthly on Day 1 of each cycle 
during treatment prior to dosing. 
Pregnancy test (refer to Section 9.3.9.2).  
• Screening: Women of childbearing potential 
must have 2 negative pregnancy tests prior to 
starting study drug. A urine or serum 
pregnancy test will be used during screening 
(within 10 to 14 days prior to start of study 
drug). A urine or serum pregnancy test is 
required at baseline.  

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Changes against Global Protocol Language 
• On treatment: For women of childbearing 
potential, a urine or serum pregnancy test 
will be performed monthly on Day 1 of each 
cycle during treatment prior to dosing. If 
menstrual period is delayed, absence of 
pregnancy in women of childbearing potential 
must be confirmed by serum pregnancy test.  
• A urine or serum pregnancy test is required 
at EOT in women of childbearing potential.  
France 
v1 
7.1 Inclusion 
Criteria #8 and 
#9 
see Table 8.e 
#7 
…Agree to practice 1 highly effective method 
of contraception and 1 additional effective 
(barrier) method (see Table 8.e) at the same 
time, from the time of signing the informed 
consent through 6 months after the last dose of 
study drug, OR  
 
#8… 
Male patients, even if surgically sterilized (ie, 
status postvasectomy), who:  
• Agree to practice effective barrier 
contraception (see Table 8.e) during the entire 
study treatment period and through 120 days 
after the last dose of study drug, OR  
France 
v1 
8.7 Precautions 
and 
Restrictions 
 
Table 8.e Highly Effective 
Methods of Contraception  
Highly 
Effective 
Methods  
Additional 
Effective 
(Barrier) 
Methods  
Combined 
(estrogen and 
progestogen 
containing) 
hormonal 
contraception 
associated 
with 
inhibition of 
ovulation  
• Oral  
• Intravaginal  
• Transdermal  
Male or 
female 
condom with 
or without 
spermicide 
(female and 
male 
condoms 
should not be 
used 
together)  
Table 8.e Highly Effective Methods of 
Contraception  
Highly Effective 
Methods  
Additional 
Effective (Barrier) 
Methods  
Combined (estrogen 
and progestogen 
containing) 
hormonal 
contraception 
associated with 
inhibition of 
ovulation  
• Oral  
• Intravaginal  
• Transdermal  
 
Male or female 
condom with or 
without 
spermicide 
(female and male 
condoms should 
not be used 
together)  
Progestogen-only hormonal contraception 
associated with inhibition of ovulation  
• Oral  

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Summary of Changes 
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Number 
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Changes against Global Protocol Language 
 
Progestogen-only hormonal 
contraception associated with 
inhibition of ovulation  
• Oral  
• Injectable  
• Implantable  
 
Intrauterine 
device  
Cap, 
diaphragm, 
or sponge 
with 
spermicide  
Intrauterine hormone-releasing 
system  
Bilateral tubal occlusion  
Vasectomized partner  
Sexual abstinence  
• Injectable  
• Implantable  
 
Intrauterine device  
Cap, diaphragm, 
or sponge with 
spermicide  
Intrauterine hormone-releasing system  
Bilateral tubal occlusion  
Vasectomized partner  
Sexual abstinence  
 
France 
v1 
9.3.9.4 ECGs 
before and 
In Part 3, all patients will have single ECGs 
collected and read locally at screening, before 
and at the end of the infusion (+30 minutes), or 
in accordance with Appendix A. 
Germany 2.0 STUDY 
SUMMARY 
6.1 Overview 
of Study 
Design 
7.0 STUDY 
POPULATION 
8.1 Study Drug 
Administration 
9.0 STUDY 
CONDUCT 
6.2 Number of 
Patients 
13.2 Interim 
Analyses and 
Criteria for 
Early 
Termination 
Only the Part 3 dose-extension 
portion of the study will be 
conducted in Germany. 
Only the Part 3 dose-extension portion of the 
study will be conducted in Germany. 

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Summary of Changes 
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Number 
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Changes against Global Protocol Language 
Germany 7.1 Inclusion 
Criteria #7 
or 5 half-lives, whichever is longer Patient has received the final dose of any of the 
following treatments/procedures within the 
specified minimum intervals before the first 
dose of modakafusp alfa. 
Chemotherapy, including proteasome inhibitors 
and IMiDs 14 days 
Antibody therapy (except anti-CD38 antibody 
as presented in exclusion criterion #4) 21 days 
or 5 half-lives, whichever is longer 
Corticosteroid therapy for myeloma 7 days 
Radiation therapy for localized bone lesions 7 
days 
Major surgery 21 days 
. 
Germany 7.1 Inclusion 
Criteria #8 
7 days 
Agree to practice 1 highly effective method of 
contraception and 1 additional effective 
(barrier) method at the same time, from the 
time of signing the informed consent through 6 
months7 days after the last dose of study drug, 
OR 
– Agree to practice true abstinence, when this 
is in line with the preferred and usual lifestyle 
of the subject, from the time of signing the 
informed consent through 6 
months7 days after the last dose of study drug. 
(Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], 
withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable 
methods of contraception. Female and male 
condoms should not be used together.) 
– Agree not to donate an egg or eggs (ova) 
during the study and for 6 months7 days after 
the last dose of study drug. 
Germany Inclusion 
Criteria #9 
unless 
for over a year 
7 
Male patients, even ifunless surgically 
sterilized (ie, status postvasectomy) for over a 
year, 
who: 
• Agree to practice effective barrier 
contraception during the entire study treatment 
period and through 1207 days after the last 
dose of study drug, OR 
• Agree to practice true abstinence, when this is 
in line with the preferred and usual lifestyle of 

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the subject. (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, 
postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. 
Female and male condoms should not be used 
together.) 
• Agree not to donate sperm during the study 
and for 1207 days after the last dose of study 
drug. 
Germany 7.2 Exclusion 
Criteria 
14. Infection with HIV: Screening 
for HIV infection will be 
performed, and patients who 
have a positive result will be 
excluded. 
14.  Infection with HIV: Screening for HIV 
infection will be performed, and patients 
who have a positive result will be excluded. 
Germany 7.2 Exclusion 
Criteria 
15. Screening for HBV and HCV 
infection will be performed. 
Part 3: Hepatitis B virus (HBV) or hepatitis C 
virus (HCV) infection. Screening for HBV 
and HCV infection will be performed. 
Germany Appendix A 
Part 3 SOE  
..and HBV, HCV, and HIV 
serologies)… 
HBV, HCV, and HIV serologies 
are performed at screening only 
and analyzed locally. 
Part 3 SOE Footnote i 
Local laboratory results may be used for dosing 
decisions; however, all samples (other than 
thyroid function tests and HBV, HCV, and 
HIV serologies) must still be sent to the 
central laboratory until the occurrence of 
progression, death, the start of subsequent 
systemic antineoplastic therapy, study 
termination, or until 6 months after the 
discontinuation of study treatment, whichever 
occurs first. Chemistry will consist of albumin, 
ALT, alkaline phosphatase, AST, HCO3- or 
CO2, blood urea nitrogen, calcium, chloride, 
magnesium, potassium, sodium, phosphate, 
creatinine, total bilirubin, LDH, urate, blood 
glucose (nonfasting), and standard C-reactive 
protein and may be collected up to 3 days prior 
to dosing. Thyroid function tests (TSH, T3, T4) 
will be performed during screening, Cycle 3, 
and every 3 cycles thereafter and will be 
analyzed locally. HBV, HCV, and HIV 
serologies are performed at screening only 
and analyzed locally. 
Germany 9.3.9.6 Clinical 
Chemistry, 
In  
all 
Central laboratory analysis is required forIn 
Part 3., Llocal hematology and chemistry 

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Hematology, 
and Urinalysis 
(other than thyroid function tests 
and HBV, HCV, and HIV 
serologies)  
until the occurrence of progression, 
death, the start of subsequent 
systemic antineoplastic therapy, 
study termination, or until 6 
months after the discontinuation of 
study treatment, whichever occurs 
first. 
laboratory results may be used for dosing 
decisions; however, all samples (other than 
thyroid function tests and HBV, HCV, and HIV 
serologies) must still be sent to the central 
laboratory as well until the occurrence of 
progression, death, the start of subsequent 
systemic antineoplastic therapy, study 
termination, or until 6 months after the 
discontinuation of study treatment, whichever 
occurs first.  
Germany 4.5.2 Clinical 
Safety 
must 
Premedications and treatment should must be 
provided, as described in Section 8.7.1.1. 
Germany 8.6.1 
Premedication 
5.4.1.2 Part 1 
Secondary 
Endpoints 
This amendment makes 
premedications mandatory, as 
detailed in Section 8.6.1. 
In addition, patients receiving modakafusp alfa 
doses ≥6 mg/kg are treatedwith additional 
premedication and the dose is delivered over a 
longer infusion time. This amendment makes 
premedications mandatory, as detailed in 
Section 8.6.1. 
Germany 8.7.1.1 
Handling of 
IRRs 
 
Mandatory 
IV and/or oral corticosteroids, 
methylprednisolone, 
acetaminophen, and/or 
diphenhydramine, as well as 
nonsteroidal anti-inflammatory 
drugs and H2 blockers if indicated, 
should be administered according 
to local standards and at sufficient 
time before the start of the 
modakafusp alfa infusion to allow 
the premedication drugs to exert 
their effects. Montelukast may be 
given to patients who are intolerant 
to diphenhydramine or for 
whom diphenhydramine is 
contraindicated. 
 
It is strongly recommendedmandatory that all 
patients receive premedication, including 
corticosteroids, before modakafusp alfa dosing. 
Patients who are receiving a modakafusp alfa 
dose of 6 mg/kg or higher must be 
premedicated with dexamethasone, 
acetaminophen, diphenhydramine, and 
montelukast. 
IV and/or oral corticosteroids, 
methylprednisolone, acetaminophen, and/or 
diphenhydramine, as well as nonsteroidal anti-
inflammatory drugs and H2 blockers if 
indicated, should be administered according to 
local standards and at sufficient time before 
the start of the modakafusp alfa infusion to 
allow the premedication drugs to exert their 
effects. Montelukast may be given to patients 
who are intolerant to diphenhydramine or for 
whom diphenhydramine is contraindicated. 
Modakafusp alfa doses <6 mg/kg will be 
administered over 1 hour (±10 minutes). 
Modakafusp alfa doses ≥6 mg kg will be 
administered over 2 hours (±10 minutes). Any 
decrease in infusion duration must be discussed 
with and agreed upon by the sponsor. 

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Germany Appendix A 
Schedules of 
Events, Tables 
12 and 13, Part 
3 Extension 
Schedule of 
Events. 
It is mandatory that all patients 
receive premedication, including 
corticosteroids, before modakafusp 
alfa dosing. 
Footnote f 
It is mandatory that all patients receive 
premedication, including corticosteroids, 
before modakafusp alfa dosing. In case of an 
IRR, the following samples should be 
collected: serum sample for circulating 
biomarkers and serum sample for 
immunogenicity. 
Germany 6.3.4.1 Closure 
of the Study 
(new section)  
6.3.4.1 Closure of the Study 
Study participation by individual 
sites or the entire study may be 
prematurely terminated if, in the 
opinion of the investigator or 
Takeda, there is sufficient 
reasonable cause. Written 
notification documenting the 
reason for study termination will 
be provided to the investigator or 
Takeda by the terminating party. 
Circumstances that may warrant 
termination include, but are not 
limited to: 
• Determination of unexpected, 
significant, or unacceptable risk to 
patients. 
• Failure to enter patients at an 
acceptable rate. 
• Insufficient adherence to protocol 
requirements. 
• Insufficient, incomplete, and/or 
unevaluable data. 
• Determination of efficacy based 
on an IA. 
• Plans to modify, suspend, or 
discontinue the development of the 
study drug. 
Should the study be closed 
prematurely, the site will no longer 
be able to access the EDC 
application, will not have a right to 
use the EDC application, and will 
cease using the password or access 
materials once their participation in 
the study has concluded. Any 
6.3.4.1 Closure of the Study 
Study participation by individual sites or the 
entire study may be prematurely terminated if, 
in the opinion of the investigator or Takeda, 
there is sufficient reasonable cause. Written 
notification documenting the reason for study 
termination will be provided to the investigator 
or Takeda by the terminating party. 
Circumstances that may warrant termination 
include, but are not limited to: 
• Determination of unexpected, significant, or 
unacceptable risk to patients. 
• Failure to enter patients at an acceptable rate. 
• Insufficient adherence to protocol 
requirements. 
• Insufficient, incomplete, and/or unevaluable 
data. 
• Determination of efficacy based on an IA. 
• Plans to modify, suspend, or discontinue the 
development of the study drug. 
Should the study be closed prematurely, the 
site will no longer be able to access the EDC 
application, will not have a right to use the 
EDC application, and will cease using the 
password or access materials once their 
participation in the study has concluded. Any 
devices provided to access the EDC application 
will be returned to Takeda once the site’s 
participation in the study has concluded. 
Takeda must notify the competent authorities 
and IECs of any member state where the study 
is being conducted within 15 days of premature 
study closure and provide the reasons for study 
closure. 
Within 90 days of ending the study, the sponsor 
will notify the competent authorities and the 
IECs in all member states where the study was 

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devices provided to access the 
EDC application will be returned 
to Takeda once the site’s 
participation in the study has 
concluded. 
Takeda must notify the competent 
authorities and IECs of any 
member state where the study is 
being conducted within 15 days of 
premature study closure and 
provide the reasons for study 
closure. 
Within 90 days of ending the 
study, the sponsor will notify the 
competent authorities and the IECs 
in all member states where the 
study was being carried out. 
Within 1 year of the end of the 
study, a summary of the clinical 
trial results will be submitted to the 
competent authorities and IECs in 
all member states involved in the 
study. 
being carried out. Within 1 year of the end of 
the study, a summary of the clinical trial results 
will be submitted to the competent authorities 
and IECs in all member states involved in the 
study. 
Germany 8.1.1 
Administration 
of  
Dexamethasone 
in Modakafusp 
Alfa Plus 
Dexamethasone 
Cohort(s) 
In Part 2 expansion only, 
In Part 2 expansion only, Ddexamethasone 
will be added to the selected MTD/OBD of one 
or more schedule(s) as additional cohort(s). 
Germany 8.1 Study Drug 
Administration 
Deletion only. 
Modakafusp alfa doses <6 mg/kg will be 
administered over 1 hour (±10 minutes). 
Modakafusp 
alfa doses ≥6 mg/kg will be administered over 
>2 hours (±10 minutes). Any decrease in 
infusion duration must be discussed with and 
agreed upon by the sponsor. 
Germany 8.6.1 
Premedication 
Deletion only. 
Montelukast (10 mg PO) may be given to 
patients who are intolerant to diphenhydramine 
or for whom diphenhydramine is ineffective. 
Patients who are receiving a modakafusp alfa 
dose of 6 mg/kg or higher must be 
premedicated with dexamethasone, 

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acetaminophen, diphenhydramine, and 
montelukast, and it is recommended that the 
dose will be administered over >2 hours (±10 
minutes). Any decrease in infusion duration 
must be discussed with and agreed upon by the 
sponsor. 
Germany 9.3.9.2 
Pregnancy Test 
Appendix A 
Part 3 SOE 
Participants 
or serum 
urine or  
reproductively  
During the study, participants of 
childbearing potential must have a 
negative urine or  
serum pregnancy test result within 
72 hours before dosing on Day 1 of 
each cycle. 
WomenParticipants of childbearing potential 
must have 2 negative pregnancy tests results 
prior to starting study drug. A urine or serum 
pregnancy test will be used during screening 
(within 10 to 14 days prior to start of study 
drug). A urine or serum pregnancy test must 
be performed at baseline (within 24 hours prior 
to the start of study drug). A woman 
participant of childbearing potential is a 
sexually mature reproductively female 
participant who: (1) has not undergone a 
hysterectomy or bilateral oophorectomy; or (2) 
has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 
24 consecutive months (ie, has had menses at 
any time in the preceding 24 consecutive 
months). 
During the study, participants of 
childbearing potential must have a negative 
urine or serum pregnancy test result within 
72 hours before dosing on Day 1 of each 
cycle. 
During the study, if menstrual period is 
delayed, absence of pregnancy in women 
participants of childbearing potential must be 
confirmed by serum pregnancy test. Pregnancy 
tests may also be repeated during the study as 
per request of IRB or if required by local 
regulations. 
At end of treatment, a urine or serum 
pregnancy test is required in women 
participants of childbearing potential. 
Germany Appendix C PK 
Sampling 
Schedules, 
Table 9, Parts 1 
and 2 Schedule 
D (Q4W) PK 
New table 
Appendix C Table 9 Parts 1 and 
2 Schedule D (Q4W) PK 
Sampling: Cycle 3 and Beyond 
Appendix C Table 9 Parts 1 and 2 Schedule 
D (Q4W) PK Sampling: Cycle 3 and Beyond 
Schedule D PK Sampling: Cycle 3 and 
Beyond 
Time Points 

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Sampling: 
Cycle 3 and 
Beyond 
Schedule D PK Sampling: Cycle 
3 and Beyond 
Time Points 
Cycle 3 and Beyond 
Day 1 a 
Predose (within 30 min prior to 
start of infusion) X 
End of infusion X 
2 to 4 hours after end of infusion 
(±30 min) X 
PK: pharmacokinetic; Q4W: 
every 4 weeks. 
a TAK-573 infusion. The timing 
of the morning visits should 
occur at approximately the same 
time as the morning infusion 
times on previous infusion visits. 
Cycle 3 and Beyond 
Day 1 a 
Predose (within 30 min prior to start of 
infusion) X 
End of infusion X 
2 to 4 hours after end of infusion (±30 min) 
X 
PK: pharmacokinetic; Q4W: every 4 weeks. 
a TAK-573 infusion. The timing of the 
morning visits should occur at 
approximately the same time as the morning 
infusion times on previous infusion visits. 
Czech 
Republic 
4.4.2 
Toxicology 
Studies  
Sexually immature nonhuman 
primates were used in the repeat 
dose toxicity studies, and thus no 
data on fertility are available from 
these general toxicity studies. 
Based on the development of 
antidrug antibodies (ADA) by Day 
15 in all cynomolgus monkeys, 
which was associated with 
substantial loss of exposure and 
neutralization of pharmacologic 
activity by Day 22, the duration of 
meaningful exposure is considered 
too short to conduct reproductive 
(embryo/fetal development) 
toxicity studies. In addition, since 
rodents are not a relevant species 
for modakafusp alfa, they cannot 
be used for reproductive toxicity 
testing. In accordance with 
regulatory guidelines (ICH 
Guidances S6(R1) 2011, and S9, 
2009), a weight-of-evidence 
approach is used to assess the risk 
of reproductive toxicity of 
modakafusp alfa. While there are 
no direct nonclinical data to 
support a lack of teratogenicity or 
As described in International Conference on 
Harmonisation (ICH) Guidance S6 (R1), the 
range and type of genotoxicity studies routinely 
conducted for pharmaceuticals are not 
applicable to biotechnology derived 
pharmaceuticals. ICH Guidance S9, 
Nonclinical Evaluation for Anticancer 
Pharmaceuticals, also states that genotoxicity 
studies are not considered essential to support 
clinical trials for therapeutics intended to treat 
patients with advanced cancer. Therefore, 
genotoxicity studies have not been conducted 
with modakafusp alfa. 
Sexually immature nonhuman primates 
were used in the repeat dose toxicity studies, 
and thus no data on fertility are available 
from these general toxicity studies. Based on 
the development of antidrug antibodies 
(ADA) by Day 15 in all cynomolgus 
monkeys, which was associated with 
substantial loss of exposure and 
neutralization of pharmacologic activity by 
Day 22, the duration of meaningful exposure 
is considered too short to conduct 
reproductive (embryo/fetal development) 
toxicity studies. In addition, since rodents 
are not a relevant species for modakafusp 
alfa, they cannot be used for reproductive 

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embryo-fetal lethality effects with 
modakafusp alfa, genotoxicity 
assessments are not required for 
biologics due to a lack of 
demonstrable interaction with 
DNA and accepted low risk from 
health authorities.   
Based on these considerations, 
modakafusp alfa is considered 
nongenotoxic and falls into the 
category of possible human 
teratogenicity/fetal toxicity based 
on a lack of data. United States 
(US) Food and Drug 
Administration (FDA) guidelines 
for nongenotoxic biologic 
pharmaceuticals with a potential 
for teratogenicity or embryo-fetal 
lethality recommend a 
contraception period of 5 half-lives 
after the last dose for females and 
no additional duration after the last 
dose for males. The half-life of 
modakafusp alfa is less than 24 
hours. Similarly, for therapeutics 
with these characteristics, the 
Clinical Trial Facilitation Group 
(CTFG) recommends 
contraception in females for the 
duration of systemic exposure plus 
1 month and no contraception in 
males. The lack of contraception 
requirements in males for biologics 
is due to a low likelihood of 
exposure to childbearing partners 
(lack of semen accumulation, 
limited absorption, and likely 
proteolytic degradation by 
vaginal/cervical enzymes) (Scialli 
et al. 2015).  
Based on the current lack of 
reproductive toxicity data with 
modakafusp alfa, the duration of 
contraception was extended over 
that recommended by guidance 
toxicity testing. In accordance with 
regulatory guidelines (ICH Guidances 
S6(R1) 2011, and S9, 2009), a weight-of-
evidence approach is used to assess the risk 
of reproductive toxicity of modakafusp alfa. 
While there are no direct nonclinical data to 
support a lack of teratogenicity or embryo-
fetal lethality effects with modakafusp alfa, 
genotoxicity assessments are not required 
for biologics due to a lack of demonstrable 
interaction with DNA and accepted low risk 
from health authorities.   
Based on these considerations, modakafusp 
alfa is considered nongenotoxic and falls into 
the category of possible human 
teratogenicity/fetal toxicity based on a lack 
of data. United States (US) Food and Drug 
Administration (FDA) guidelines for 
nongenotoxic biologic pharmaceuticals with 
a potential for teratogenicity or embryo-fetal 
lethality recommend a contraception period 
of 5 half-lives after the last dose for females 
and no additional duration after the last 
dose for males. The half-life of modakafusp 
alfa is less than 24 hours. Similarly, for 
therapeutics with these characteristics, the 
Clinical Trial Facilitation Group (CTFG) 
recommends contraception in females for 
the duration of systemic exposure plus 1 
month and no contraception in males. The 
lack of contraception requirements in males 
for biologics is due to a low likelihood of 
exposure to childbearing partners (lack of 
semen accumulation, limited absorption, 
and likely proteolytic degradation by 
vaginal/cervical enzymes) (Scialli et al. 
2015).  
Based on the current lack of reproductive 
toxicity data with modakafusp alfa, the 
duration of contraception was extended over 
that recommended by guidance from the 
FDA and the CTFG. The duration of 
contraception after the last dose of 
modakafusp alfa of 6 months after the last 
dose for females and 120 days after the last 

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from the FDA and the CTFG. The 
duration of contraception after the 
last dose of modakafusp alfa of 6 
months after the last dose for 
females and 120 days after the last 
dose for males is considered a very 
conservative approach.  
dose for males is considered a very 
conservative approach.  
 
Czech 
Republic 
7.1 Inclusion 
Criteria #7 
Live vaccine 
30 days 
Chemotherapy, including proteasome inhibitors 
and IMiDs 
14 days 
Antibody therapy (except anti-CD38 antibody 
as presented in exclusion criterion #4) 
21 
days  
Corticosteroid therapy for myeloma 7 days 
Radiation therapy for localized bone lesions 7 
days 
Major surgery 
21 days 
Live vaccine 
30 days 
Czech 
Republic 
8.5 Excluded 
Concomitant 
Medications 
and Procedures 
Patients may not receive a live 
vaccine during the study and 
within 90 days after completion of 
study treatment. 
Patients may not receive a live vaccine 
during the study and within 90 days after 
completion of study treatment. 
Czech 
Republic 
7.2 Exclusion 
Criteria #14 
Known history of human 
immunodeficiency virus (HIV).  
Infection with 
Screening for 
will be performed, and patients 
who have a positive result will be 
excluded. Screening for HBV and 
HCV infection will be performed. 
Patients with HBV or HCV 
infection, or who are  
are excluded  
14. 
12. Parts 1 and 2: Known chronic 
hepatitis C and/or positive serology (unless due 
to vaccination or passive immunization due to 
Ig therapy) for chronic hepatitis B. Known 
history of human immunodeficiency virus 
(HIV).  
Part 3: Hepatitis B virus (Infection with 
HBIV) or hepatitis C virus (: Screening for 
HCIV)  infection. will be performed, and 
patients who have a positive result will be 
excluded. Screening for HBV and HCV 
infection will be performed. Patients with 
HBV or HCV infection, or who are 
Sseropositive for hepatitis B (defined by a 
positive test for hepatitis B surface antigen 
[HBsAg]) are excluded. Participants with 
resolved infection (that is, participants who are 
HBsAg-negative but positive for antibodies to 
hepatitis B core antigen [anti-HBc] and/or 
antibodies to hepatitis B surface antigen [anti-

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HBs]) must be screened using real-time 
polymerase chain reaction (PCR) measurement 
of HBV DNA levels. Those who are PCR 
positive will be excluded. 
Czech 
Republic 
9.3.9.6 Clinical 
Chemistry, 
Hematology, 
and Urinalysis  
In 
all  
other than thyroid function tests 
and HBV, HCV, and HIV 
serologies) 
Central laboratory analysis is required forIn 
Part 3., Llocal hematology and chemistry 
laboratory results may be used for dosing 
decisions; however, all samples (other than 
thyroid function tests and HBV, HCV, and 
HIV serologies) must still be sent to the central 
laboratory as well.  
Czech 
Republic 
9.3.9.2 
Pregnancy Test 
Appendix A 
Part 3 SOE 
Participants 
or serum 
urine or  
reproductively  
During the study, participants of 
childbearing potential must have a 
negative urine or  
serum pregnancy test result within 
72 hours before dosing on Day 1 of 
each cycle. 
WomenParticipants of childbearing potential 
must have 2 negative pregnancy tests results 
prior to starting study drug. A urine or serum 
pregnancy test will be used during screening 
(within 10 to 14 days prior to start of study 
drug). A urine or serum pregnancy test must 
be performed at baseline (within 24 hours prior 
to the start of study drug). A woman 
participant of childbearing potential is a 
sexually mature reproductively female 
participant who: (1) has not undergone a 
hysterectomy or bilateral oophorectomy; or (2) 
has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 
24 consecutive months (ie, has had menses at 
any time in the preceding 24 consecutive 
months). 
During the study, participants of 
childbearing potential must have a negative 
urine or serum pregnancy test result within 
72 hours before dosing on Day 1 of each 
cycle. 
During the study, if menstrual period is 
delayed, absence of pregnancy in women 
participants of childbearing potential must be 
confirmed by serum pregnancy test. Pregnancy 
tests may also be repeated during the study as 
per request of IRB or if required by local 
regulations. 
At end of treatment, a urine or serum 
pregnancy test is required in women 
participants of childbearing potential. 

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Czech 
Republic 
Appendix A  
Part 3  
Footnote l 
or serum 
urine or 
For women of childbearing 
potential, a urine or serum 
pregnancy test will be performed 
monthly on Day 1 of each cycle 
during treatment prior to dosing. 
Pregnancy test (refer to Section 9.3.9.2).  
• Screening: Women of childbearing potential 
must have 2 negative pregnancy tests prior to 
starting study drug. A urine or serum 
pregnancy test will be used during screening 
(within 10 to 14 days prior to start of study 
drug). A urine or serum pregnancy test is 
required at baseline.  
• On treatment: For women of childbearing 
potential, a urine or serum pregnancy test 
will be performed monthly on Day 1 of each 
cycle during treatment prior to dosing. If 
menstrual period is delayed, absence of 
pregnancy in women of childbearing potential 
must be confirmed by serum pregnancy test.  
• A urine or serum pregnancy test is required 
at EOT in women of childbearing potential.  
Czech 
Republic 
9.4.1 
Discontinuation 
of Treatment 
With Study 
Drug and 
Patient 
Replacement 
Confirmed pregnancy in a study 
patient. 
Study drug must be permanently discontinued 
for patients meeting any of the following 
criteria: 
• 
Patient experiences an AE or other medical 
condition that indicates to the investigator 
that continued participation is not in the 
best interest of the patient.  
• 
Confirmed pregnancy in a study 
patient…. 
• 
Female patient has confirmed pregnancy. 
• 
Lost to follow up.  
Czech 
Republic 
Appendix C PK 
Sampling 
Schedules, 
Table 9, Parts 1 
and 2 Schedule 
D (Q4W) PK 
Sampling: 
Cycle 3 and 
Beyond 
New table 
Appendix C Table 9 Parts 1 and 
2 Schedule D (Q4W) PK 
Sampling: Cycle 3 and Beyond 
Schedule D PK Sampling: Cycle 
3 and Beyond 
Time Points 
Cycle 3 and Beyond 
Day 1 a 
Predose (within 30 min prior to 
start of infusion) X 
End of infusion X 
2 to 4 hours after end of infusion 
(±30 min) X 
Appendix C Table 9 Parts 1 and 2 Schedule 
D (Q4W) PK Sampling: Cycle 3 and Beyond 
Schedule D PK Sampling: Cycle 3 and 
Beyond 
Time Points 
Cycle 3 and Beyond 
Day 1 a 
Predose (within 30 min prior to start of 
infusion) X 
End of infusion X 
2 to 4 hours after end of infusion (±30 min) 
X 
PK: pharmacokinetic; Q4W: every 4 weeks. 
a TAK-573 infusion. The timing of the 

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PK: pharmacokinetic; Q4W: 
every 4 weeks. 
a TAK-573 infusion. The timing 
of the morning visits should 
occur at approximately the same 
time as the morning infusion 
times on previous infusion visits. 
morning visits should occur at 
approximately the same time as the morning 
infusion times on previous infusion visits. 
 

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Global Amendments Summary of Changes 
Protocol Amendment 10 v1 Summary of Changes (Not Implemented) 
This section describes the changes to the protocol incorporating Amendment 10 v1 (not 
implemented). The primary reasons for this amendment were to change the primary objective of 
the Part 3 Dose Extension portion of the study from IRC-assessed objective response rate (ORR) 
to investigator-assessed ORR and change the primary analysis time point to utilize an earlier data 
cutoff date due to the sponsor decision to discontinue the development of modakafusp alfa. 
In light of the decision to discontinue the development of modakafusp alfa, the sponsor has 
decided to change the primary analysis time point to utilize an earlier data cutoff date as of the 
implementation of Protocol Amendment 10 v1. Following the implementation of Protocol 
Amendment 10 v1, the majority of study assessments will be discontinued to ease the burden of 
protocol-mandated assessments on patients. Modakafusp alfa will continue to be provided for 
patients who continue to derive benefit. 
Upon implementation of Protocol Amendment 10 v1, activities will be limited to dosing of study 
drug and any modifications to administration and data collection requirements will be limited to 
the following safety assessments: all serious adverse events (SAEs) (regardless of causality, 
including all deaths), any adverse event (AE) leading to dose modification or discontinuation of 
study drug, Grade ≥3 AEs, all reports of drug exposure during pregnancy and pregnancy 
outcomes, product complaints, and medication errors (including overdose). All other study 
assessments are no longer required. Given what is already known regarding the safety profile of 
modakafusp alfa based upon all previous data collection, further collection and reporting of 
Grade ≤2 AEs is not expected to result in a change to patient management. Treating physicians 
will monitor and manage patients according to standard of care, in order to ensure overall patient 
safety. 
All central laboratory and investigator assessments of response and progression for protocol 
purposes will be discontinued. Patients will not be followed for the progression-free survival 
(PFS) or overall survival (OS) follow-up periods, as PFS and OS will no longer be collected. 
Quality of Life (QOL), pharmacokinetic (PK), immunogenicity, biomarker, and 
pharmacodynamic assessments will no longer be performed or recorded. Patients should 
otherwise be treated by the investigator according to local standard of care, including local 
laboratory assessments. Further, recording of AEs in the electronic case report form (eCRF) will 
be limited to AEs leading to dose modification or discontinuation of study drug and local 
laboratory assessments and symptom-directed physical examination data will only be recorded in 
the eCRF in the event that they are needed to evaluate an AE. See the updated Schedule of 
Events—Protocol Amendment 10 v1 and Beyond (Appendix A Table 1) for more detailed 
information. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 

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Protocol Amendment 10 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
1.  
2.0 STUDY SUMMARY 
The purpose and rationale for the 
implementation of Protocol Amendment 
10 was added. 
Clarification. 
2.  
2.0 STUDY SUMMARY 
5.3.1 Part 3 Primary 
Objective 
5.4.3.1 Part 3 Primary 
Endpoint 
6.1 Overview of Study 
Design 
Changed the Primary Objective and 
Endpoint for the Part 3 Dose Extension 
part of the study to investigator-assessed 
ORR. 
Removed independent review committee 
(IRC) assessment of objective response 
rate (ORR). 
Clinical updates. 
3.  
2.0 STUDY SUMMARY 
5.3.2 Part 3 Secondary 
Objectives 
5.4.3.2 Part 3 Secondary 
Endpoints 
5.3.3 Part 3 Exploratory 
Objectives 
5.4.3.3 Part 3 Exploratory 
Endpoints  
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol 
Amendment  10 and Beyond 
(Appendix  A  Table 1).” was added to the 
Part 3 Dose Extension Secondary and 
Exploratory Objectives and Endpoints for 
use after the implementation of Protocol 
Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:…” was added before the 
text characterizing the Part 3 Dose 
Extension Secondary and Exploratory 
Objectives and Endpoints for use prior to 
implementation of Protocol 
Amendment  10. 
Removed ORR as assessed by the 
investigator from the Part 3 Dose 
Extension Secondary Objectives and 
Endpoints because it was changed to the 
Part 3 Dose Extension Primary Objective 
and Endpoint. 
Removed IRC assessment of disease 
control rate (DCR), clinical benefit rate 
(CBR), and duration of response (DOR). 
Clinical updates. 

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Protocol Amendment 10 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
4.  
3.3 Committees in Part 3 
Dose Extension 
13.1.3 Efficacy Analysis 
The text regarding the IRC was removed 
from the protocol. 
Clinical update and 
statistical update. 
5.  
3.3.1 Independent Data 
Monitoring Committee 
“Following the implementation of Protocol 
Amendment 10, no further IDMC reviews 
of safety and efficacy data will take place 
for patients still receiving study therapy. 
The sponsor will continue to monitor 
safety endpoints as indicated in the updated 
Schedule of Events—Protocol Amendment 
10 and Beyond (Appendix A Table 1).” 
was added to the description of the 
independent data monitoring committee 
(IDMC) information for use after the 
implementation of Protocol Amendment 
10. 
Clinical update. 
6.  
4.6.1 Rationale for the Part 1 
Starting Dose of Modakafusp 
Alfa 
4.6.3 Changes to Modakafusp 
Alfa Infusion 
8.6.1 Premedication 
Previous amendments are referred to as 
“Protocol Amendment” and their 
respective number. 
Clarification. 

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Protocol Amendment 10 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
7.  
6.1 Overview of Study 
Design 
The purpose and rationale for the 
implementation of Protocol 
Amendment  10 was added. 
“Prior to Implementation of Protocol 
Amendment 10:…” was added before the 
text characterizing Overview of Study 
Design for use prior to implementation of 
Protocol Amendment 10. 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), activities 
will be limited to dosing of study drug and 
any modifications to administration and 
data collection requirements will be limited 
to ease the burden of protocol-mandated 
assessments on patients as outlined in the 
updated Schedule of Events—Protocol 
Amendment 10 and Beyond 
(Appendix  A  Table 1).” was added to the 
Part 3 Dose Extension Overview of Study 
Design for use after the implementation of 
Protocol Amendment 10. 
Clarification and clinical 
updates. 
8.  
6.3.1 Duration of an 
Individual Patient’s Study 
Participation 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), the 
majority of study assessments will be 
discontinued to ease the burden of 
protocol-mandated assessments on patients 
as outlined in the updated Schedule of 
Events—Protocol Amendment 10 and 
Beyond (Appendix A Table 1).” was added 
to the Duration of an Individual Patient’s 
Study Participation for use after the 
implementation of Protocol 
Amendment  10. 
“Prior to Implementation of Protocol 
Amendment 10:…” was added before the 
text characterizing Duration of an 
Individual Patient’s Study Participation for 
use prior to implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Protocol Amendment 10 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
9.  
6.3.2 End of Study/Study 
Completion Definition and 
Planned Reporting 
“Following the implementation of Protocol 
Amendment 10, patients will not be 
followed for the PFS or OS follow-up 
periods, as PFS and OS will no longer be 
collected as outlined in Section 1.3.” was 
added to the End of Study/Study 
Completion Definition and Planned 
Reporting for use after the implementation 
of Protocol Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:…” was added before the 
text characterizing Duration of an End of 
Study/Study Completion Definition and 
Planned Reporting for use prior to 
implementation of Protocol 
Amendment  10. 
 

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Protocol Amendment 10 v1 (Not Implemented) 
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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
10.  
6.3.3 Timeframes for Primary 
and Secondary Endpoints to 
Support Disclosures 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), the 
primary objective of the Part 3 Dose 
Extension portion of the study is 
investigator-assessed ORR and data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol 
Amendment  10 and Beyond 
(Appendix  A  Table 1).” was added to the 
Timeframes for Primary and Secondary 
Endpoints to Support Disclosures for use 
after the implementation of Protocol 
Amendment 10. 
Table 6.a was updated to remove ORR as 
assessed by the IRC as a Part 3 Dose 
Extension Primary Endpoint. 
Table 6.a was updated to indicate that ORR 
as assessed by the investigator was the 
Part 3 Dose Extension Primary Endpoint. 
“This has been updated to align with the 
primary objective of the Part 3 Dose 
Extension portion of the study utilized 
following the implementation of Protocol 
Amendment 10 (see Section 1.3).” was 
added to the Table 6.a Part 3 Dose 
Extension Primary Endpoint row. 
Clinical updates. 
11.  
6.3.4 Total Study Duration 
“Following the implementation of Protocol 
Amendment 10, patients will not be 
followed for the PFS or OS follow-up 
periods, as PFS and OS will no longer be 
collected as outlined in Section 1.3” was 
added to the Total Study Duration for use 
after the implementation of Protocol 
Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:…” was added before the 
text characterizing the Total Study 
Duration for use prior to implementation of 
Protocol Amendment 10. 
Clinical updates. 

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Protocol Amendment 10 v1 (Not Implemented) 
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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
12.  
9.0 STUDY CONDUCT 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), activities 
will be limited to dosing of study drug and 
any modifications to administration and 
data collection requirements will be limited 
to ease the burden of protocol-mandated 
assessments on patients as outlined in the 
updated Schedule of Events—Protocol 
Amendment 10 and Beyond 
(Appendix  A  Table 1).” was added to the 
description of the Study Conduct for use 
after the implementation of Protocol 
Amendment 10. 
Clarification was added that “At all time 
points,” this study will be conducted in 
compliance with the protocol, GCP, 
applicable regulatory requirements, and 
ICH guidelines. 
Clinical updates and 
clarification. 
13.  
9.3 Study Procedures 
“Following the implementation Protocol 
Amendment 10, the SOE has been 
simplified to apply to the remainder of the 
study for ease of study conduct as outlined 
in the updated Schedule of Events—
Protocol Amendment 10 and Beyond 
(Appendix A Table 1).” was added to the 
Study Procedures for use after the 
implementation of Protocol 
Amendment  10. 
“Prior to the implementation of Protocol 
Amendment 10, the SOEs utilized can be 
found in the remainder of the Tables 
presented in Appendix A, Appendix B, and 
Appendix C.” was added before the text 
characterizing the Study Procedures for use 
prior to implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Protocol Amendment 10 v1 (Not Implemented) 
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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
14.  
9.3.9 Safety Evaluations 
Added the following text: “Data collection 
requirements will be limited to the 
following safety assessments: all SAEs 
(regardless of causality, including all 
deaths), any AE leading to dose 
modification or discontinuation of study 
drug, Grade ≥3 AEs, all reports of drug 
exposure during pregnancy and pregnancy 
outcomes, product complaints, and 
medication errors (including overdose). All 
other study assessments are no longer 
required for protocol purposes.” 
Clinical update. 
15.  
9.3.4 Physical Examination 
9.3.7 ECOG Performance 
Status 
9.3.8 Concomitant 
Medications and Procedures 
9.3.9 Safety Evaluations 
9.3.9.1 Vital Signs 
9.3.9.2 Pregnancy Testing 
9.3.9.3 TEAEs 
9.3.9.4 ECGs 
9.3.9.5 Clinical Laboratory 
Evaluations 
9.3.9.6 Clinical Chemistry, 
Hematology, and Urinalysis 
9.3.9.7 2-Microglobulin  
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol 
Amendment  10 and Beyond 
(Appendix  A  Table 1).” was added to the 
relevant Study Procedure section for use 
after the implementation of Protocol 
Amendment  10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant Study 
Procedure section for use prior to 
implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Protocol Amendment 10 v1 (Not Implemented) 
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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
16.  
9.3.9.5 Clinical Laboratory 
Evaluations 
Indicated that with the implementation of 
Protocol Amendment 10: 
- “…centralized clinical laboratory 
evaluations of efficacy and safety will no 
longer be performed.” 
- “Local laboratory evaluations should be 
entered into the eCRF only if required to 
document a TEAE.” 
- “For dosing decisions, response 
assessment, and all other safety 
assessments for the patient, local 
hematology and clinical chemistry 
laboratory results should be used and do 
not need to be entered into the eCRF.” 
- “Local laboratory evaluations may be 
performed according to local standard of 
care (ie, for acute management of TEAEs), 
per the investigator’s judgment of standard 
of care.” 
Clinical updates. 
17.  
9.3.9.6 Clinical Chemistry, 
Hematology, and Urinalysis 
9.3.9.7 2-Microglobulin 
“All laboratory assessments will be done 
locally.” was added to clarify that no 
central assessments were to be performed 
with the implementation of Protocol 
Amendment 10. 
Clinical update. 

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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
18.  
9.3.10 Disease Assessment 
9.3.10.1 Extramedullary 
Disease Imaging 
9.3.10.2 Bone Imaging 
9.3.10.3 Quantification of 
Immunoglobulins 
9.3.10.4 Quantification of M-
Protein in Serum and Urine 
9.3.10.5 Serum FLC Assay 
9.3.10.6 Immunofixation of 
Serum and Urine 
9.3.10.7 Interference Assay 
9.3.10.8 Bone Marrow 
Aspiration 
9.3.10.8.1 Bone Marrow 
Central Laboratory 
Evaluations 
9.3.10.8.2.1 Disease 
Assessment 
9.3.10.8.2.2 Cytogenetics 
9.3.10.8.2.3 Bone Marrow 
Morphology 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol Amendment 
10 and Beyond (Appendix A Table 1)…” 
was added to the relevant Disease 
Assessment section for use after the 
implementation of Protocol 
Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant Disease 
Assessment section for use prior to 
implementation of Protocol 
Amendment 10. 
Clinical updates. 
19.  
9.3.10 Disease Assessment 
Indicated that with the implementation of 
Protocol Amendment 10: 
- All assessments will be done locally, and 
disease assessments will not be recorded in 
the eCRF.” 
- “Disease assessment will be performed 
and assessed by the investigator according 
to standard of care treatment.” 
Clinical updates. 

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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
20.  
9.3.11 PK, Immunogenicity, 
Biomarker, and 
Pharmacodynamic Samples 
9.3.11.1 Primary Specimen 
Collection for PK, 
Immunology, and Biomarker 
Assessments 
9.3.11.2 PK Measurements 
9.3.11.3 Biomarkers and 
Pharmacodynamic 
Measurements 
9.3.11.3.1 Biomarker 
Measurements 
9.3.11.3.2.1 Fresh BMA 
Samples for 
Pharmacodynamics (Parts 1 
and 2 Only) Fresh BMA 
Samples for 
Pharmacodynamics (Parts 1 
and 2 Only) 
9.3.11.3.2.2 Fresh BMA for 
Cytogenetics/Fresh BMA 
(Part 3 Only) 
9.3.11.3.2.3 Fresh BMA 
Samples for MRD 
9.3.11.3.2.4 Fresh BMA 
Samples for RNA (Parts 1 
and 2 Only) 
9.3.11.3.2.5 Blood Sample 
for Flow Cytometry 
9.3.11.3.2.6 Blood Sample 
for RNA 
9.3.11.3.2.7 Blood Sample 
for Receptor Sequencing 
9.3.11.4 DNA Measurements 
9.3.11.5 Immunogenicity 
Measurements 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol 
Amendment  10 and Beyond 
(Appendix  A  Table 1).” was added to the 
relevant PK, Immunogenicity, Biomarker, 
and Pharmacodynamic Samples section for 
use after the implementation of Protocol 
Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant PK, 
Immunogenicity, Biomarker, and 
Pharmacodynamic Samples section for use 
prior to implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
21.  
9.3.11 PK, Immunogenicity, 
Biomarker, and 
Pharmacodynamic Samples 
“All PK, immunogenicity, biomarker, and 
pharmacodynamic assessments will no 
longer be performed.” was added for use 
after the implementation of Protocol 
Amendment 10. 
Clinical update. 
22.  
9.3.11.1 Primary Specimen 
Collection for PK, 
Immunology, and Biomarker 
Assessments 
“As noted above, following the 
implementation of Protocol Amendment 
10, blood and serum samples for PK, 
immunogenicity, biomarker, and 
pharmacodynamic assessments will no 
longer be collected.” was added prior to the 
presentation of Table 9.c. 
Table 9.cwas updated so the caption 
indicates that the table is not applicable for 
use following the implementation of 
Protocol Amendment 10. 
Clinical updates. 
23.  
9.3.12 PRO Assessments 
9.3.12.1 EORTC QLQ-MY20 
9.3.12.2 EQ-5D-5L 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol 
Amendment  10 and Beyond 
(Appendix  A  Table 1).” was added to the 
relevant PRO Assessments section for use 
after the implementation of Protocol 
Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant PRO 
Assessments section for use prior to 
implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Protocol Amendment 10 v1 (Not Implemented) 
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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
24.  
9.3.13 Healthcare Resource 
Utilization 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol Amendment 
10 and Beyond (Appendix A Table 1).” 
was added to the relevant Healthcare 
Resource Utilization section for use after 
the implementation of Protocol 
Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant Healthcare 
Resource Utilization section for use prior 
to implementation of Protocol 
Amendment 10. 
Clinical updates. 
25.  
9.4 Completion of Study 
Treatment (for Individual 
Patients) 
9.4.1 Discontinuation of 
Treatment with Study Drug 
and Patient Replacement 
9.4.2 Withdrawal of Patients 
From Study 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), the 
majority of study assessments will be 
discontinued to ease the burden of 
protocol-mandated assessments on patients 
as outlined in the updated Schedule of 
Events—Protocol Amendment 10 and 
Beyond (Appendix A Table 1).” was added 
to the relevant Completion of Study 
Treatment (for Individual Patients) section 
for use after the implementation of 
Protocol Amendment 10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant Completion of 
Study Treatment (for Individual Patients) 
section for use prior to implementation of 
Protocol Amendment 10. 
Clinical updates. 

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Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
26.  
9.5 Posttreatment Follow-up 
Assessments 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), the 
majority of study assessments will be 
discontinued to ease the burden of 
protocol-mandated assessments on patients 
as outlined in the updated Schedule of 
Events—Protocol Amendment 10 and 
Beyond (Appendix A Table 1).” was added 
to the relevant Posttreatment Follow-up 
Assessments section for use after the 
implementation of Protocol Amendment 
10. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the relevant Posttreatment 
Follow-up Assessments section for use 
prior to implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Number 
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Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
27.  
10.2 Procedures for 
Recording and Reporting 
AEs and SAEs 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol Amendment 
10 and Beyond (Appendix A Table 1).” 
was added to the Procedures for Recording 
and Reporting AEs and SAEs section for 
use after the implementation of Protocol 
Amendment 10. 
“If the EDC is not available, then the SAE 
form should be faxed or emailed within 24 
hours after becoming aware of the event.” 
was added to the Procedures for Recording 
and Reporting AEs and SAEs section for 
use after the implementation of Protocol 
Amendment 10. 
“Please note that while the types of AEs 
recorded and reported may differ 
dependent upon the implementation of 
Protocol Amendment 10, procedures for 
reporting AEs and SAEs will remain the 
same as stipulated here in Section 10.2.” 
was added to the Procedures for Recording 
and Reporting AEs and SAEs section for 
use after the implementation of Protocol 
Amendment 10. 
Indicated that the SAE Form can be 
emailed (in addition to faxed). 
Updated the SAE Reporting Contact 
Information with the fax number for the 
United States and Canada, fax number for 
the Rest of the World, and the email 
address. 
Clinical updates and 
clarifications. 

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Change 
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Location 
Description  
Rationale 
28.  
10.2.1 Monitoring and 
Reporting IRRs 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), data 
collection will be limited to the safety 
assessments outlined in the updated 
Schedule of Events—Protocol Amendment 
10 and Beyond (Appendix A Table 1).” 
was added to the Monitoring and 
Reporting IRRs section for use after the 
implementation of Protocol Amendment 
10. 
“Please note that while the types of AEs 
recorded and reported may differ 
dependent upon the implementation of 
Protocol Amendment 10, procedures for 
reporting IRRa will remain the same as 
stipulated here in Section 10.2.1.” was 
added to the Monitoring and Reporting 
IRRs section for use after the 
implementation of Protocol 
Amendment 10. 
Clinical updates. 

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Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
29.  
10.3 Monitoring of AEs and 
Period of Observation 
“Following the implementation of Protocol 
Amendment 10 (see Section 1.3), the 
majority of study assessments will be 
discontinued to ease the burden of 
protocol-mandated assessments on patients 
as outlined in the updated Schedule of 
Events—Protocol Amendment 10 and 
Beyond (Appendix A Table 1).” was added 
to the Monitoring of AEs and Period of 
Observation section for use after the 
implementation of Protocol Amendment 
10. 
“Only SAEs (regardless of causality, 
including all deaths), any AE leading to 
dose modification or discontinuation of 
study drug, Grade ≥3 AEs, all reports of 
drug exposure during pregnancy and 
pregnancy outcomes, product complaints, 
and medication errors (including overdose) 
are to be reported.” was indicated. 
“Prior to Implementation of Protocol 
Amendment 10:” was added before the text 
characterizing the Monitoring of AEs and 
Period of Observation section for use prior 
to implementation of Protocol Amendment 
10. 
Clinical updates. 
30.  
10.4 Procedures for 
Reporting Drug Exposure 
During Pregnancy and Birth 
Events 
Indicated that the Pregnancy Form can be 
emailed (in addition to faxed). 
 
Clarification. 
31.  
13.1 Statistical and 
Analytical Plans 
Added “…or at a time determined by the 
sponsor if the study is terminated early.” to 
the description of the timing for the 
analysis of the primary endpoint. 
Statistical update. 
32.  
13.1.1 Analysis Sets 
Added “…and PRO compliance” to the 
description of the Full Analysis Set. 
Statistical update. 

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Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
33.  
13.1.3 Efficacy Analysis 
Removed ORR as assessed by the 
investigator from the Part 3 Dose 
Extension Secondary Objectives and 
Endpoints because it was changed to the 
Part 3 Dose Extension Primary Objective 
and Endpoint. 
Removed IRC assessment of disease 
control rate (DCR), clinical benefit rate 
(CBR), and duration of response (DOR). 
Statistical update. 
34.  
13.1.4 PK Analysis 
Added “…or sponsor decision” to the 
description of PK parameter determination 
in Parts 1 and 2 and in Chinese Patients 
with the intensive PK schedule in Part 3. 
Statistical update. 
35.  
13.1.6 PRO Analyses 
Removed “The difference between 
baseline scores and scores over may be 
also explored using linear mixed models.” 
Statistical update. 
36.  
13.1.8 Safety Analysis 
Removed “Listings of laboratory test 
results and vital signs will be generated.” 
Statistical update. 
37.  
14.1 Study-Site Monitoring 
Visits 
Added “Details can be found in the 
monitoring plan.” 
Changed “will be” to “may be” regarding 
source document verification of data 
recorded on the eCRFs. 
Clarification. 
38.  
Appendix A 
Schedule of 
Events 
Provided rationale for the implementation 
of the Updated Schedule of Events—
Protocol Amendment 10 and Beyond. 
Added a new schedule of events for use 
with the implementation of Protocol 
Amendment 10 (Appendix A Table 1) and 
updated all other Schedules of Events for 
use prior to the implementation of Protocol 
Amendment 10 (Appendix A Table 2 
through Appendix A Table 14). 
Updated the titles for the Schedules of 
Events (Appendix A Table 2 through 
Appendix A Table 14) to be used Prior to 
Protocol Amendment 10 with text 
indicating as such. 
Clinical updates. 

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CONFIDENTIAL 
Protocol Amendment 10 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
39.  
Appendix A Table 13 
Provided text to indicate that “The full 
Schedule of Events for the Part 3 Dose 
Extension of the study is no longer in 
effect, as of the implementation of Protocol 
Amendment 10 (see Section 1.3). 
See Appendix A Table 1 for the Schedule 
of Events to be used after the 
implementation of Protocol Amendment 
10.” for Appendix A Table 13 and 
Appendix A Table 14 
Clinical updates and 
clarifications. 
40.  
Appendix B 
Bone 
Marrow Collection and 
Assessment Schedules (Part 1 
and Part 2) 
Provided text to indicate that 
“IMPORTANT NOTE: Bone marrow 
sample collection and assessment are no 
longer required as of the implementation of 
Protocol Amendment 10. 
Refer to Section 1.3 for a description of the 
changes to study conduct as a result of the 
implementation of Protocol Amendment 
10.” 
Clinical updates and 
clarifications. 
41.  
Appendix C 
PK 
Sampling Schedules 
Provided text to indicate that 
“IMPORTANT NOTE: Pharmacokinetic 
sample collection and assessment are no 
longer required as of the implementation of 
Protocol Amendment 10. 
Refer to Section 1.3for a description of the 
changes to study conduct as a result of the 
implementation of Protocol 
Amendment 10.” 
Clinical updates and 
clarifications. 
 

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CONFIDENTIAL 
Protocol Amendment 9 Summary of Changes  
This section describes the changes to the protocol incorporating Amendment 9. The primary 
reasons for this amendment were to add the Investigational New Drug No., add neutralizing 
antibodies (NAb) as a secondary endpoint, simplify text about the study design of Part 1, clarify 
Part 3 inclusion criteria, update serious adverse event (SAE) and product complaint reporting 
procedures, and clarify hepatitis testing requirements. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
Protocol Amendment 9 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
1.  
Cover page. 
IND No. added. 
Abbreviated European Union Drug 
Regulating Authorities Clinical Trials 
(EUDRACT) number added.   
Administrative update.  
2.  
2.0 STUDY SUMMARY 
9.3.11 PK, Immunogenicity, 
Biomarker, and 
Pharmacodynamic Samples 
“Immunogenicity” was added to 
description of assessments. 
Clarification.  
3.  
2.0 STUDY SUMMARY 
6.1 Overview of Study 
Design 
6.2 Number of Patients 
13.3 Determination of 
Sample Size 
The purpose, enrollment plan, and number 
of patients for the China cohort were 
described. 
Country-specific update.  
4.  
2.0 STUDY SUMMARY 
5.3.3 Part 3 Exploratory 
Objectives 
5.4.3.3 Part 3 Exploratory 
Endpoints 
9.3.12 PRO Assessments 
13.1.6 PRO Analyses 
Appendix A Schedule of 
Events 
The description of health-related quality of 
life instrument collection as an exploratory 
objective and endpoint in Part 3 was 
clarified, including that paper PROs may 
no longer be used and the instruction to 
sites to remind patients to complete PROs 
at each cycle,  
Clarification. 
5.  
2.0 STUDY SUMMARY 
7.1 Inclusion Criteria 
Serum creatinine was removed as an 
inclusion criterion. 
Clinical update.  
6.  
2.0 STUDY SUMMARY 
6.3.1 Duration of an 
Individual Patient’s Study 
Participation 
Patients may be treated after disease 
progression if the investigator considers it 
in the best interest of the patient and with 
approval by the sponsor.  
Clinical update.  

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Protocol Amendment 9 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
7.  
6.3.2 End of Study/Study 
Completion Definition and 
Planned Reporting 
“…or have transitioned to posttrial access 
(Section 6.3.5)” was added to the end of 
study definition. 
Administrative update.  
8.  
2.0 STUDY SUMMARY 
7.1 Inclusion Criteria 
Inclusion Criterion #1 for Part 3 was 
revised to include patients with disease 
progression during or after their last 
therapy.  
Clinical update. 
9.  
2.0 STUDY SUMMARY 
5.4.1.2 Part 1 Secondary 
Endpoints 
5.2.2 Part 2 Secondary 
Objectives 
5.4.2.2  Part 2 Secondary 
Endpoints 
Table 6.a Primary and 
Secondary Endpoints for 
Disclosures 
9.3.11 PK, Immunogenicity, 
Biomarker, and 
Pharmacodynamic Samples 
9.3.11.3 Biomarkers and 
Pharmacodynamic 
Measurements 
13.1.7 Immunogenicity 
Analyses 
Appendix A Schedule of 
Events 
Evaluation of neutralizing antibodies was 
added to antidrug antibody assessments 
and endpoints in Parts 1 and 2 endpoints.  
Clinical update.  
10.  
2.0 STUDY SUMMARY 
5.3.2 Part 3 Secondary 
Objectives 
5.4.3.2 Part 3 Secondary 
Endpoints 
Table 6.a Primary and 
Secondary Endpoints for 
Disclosures 
13.1.4 PK Analysis 
Appendix C PK Sampling 
Schedules 
Intensive pharmacokinetic (PK) sampling 
endpoints for the China cohort were added 
to Part 3 Secondary Objectives and Part 3 
Secondary Endpoints, along with a 
corresponding PK table in the appendix. 
Country-specific update.  

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Protocol Amendment 9 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
11.  
4.5.2 Clinical Safety 
8.7 Precautions and 
Restrictions 
Text regarding potential interference of 
modakafusp alfa with serologic testing 
based on daratumumab characteristics was 
removed, and the potential interference of 
modakafusp alfa with serologic testing is 
described in Section 8.7. 
The potential interference 
of modakafusp alfa with 
serologic testing is now 
better understood and is 
described in Section 8.7. 
12.  
2.0 STUDY SUMMARY 
6.1 Overview of Study 
Design 
8.3 Part 1 Dose Escalation 
Rules 
8.4.1 Part 1 Dose Escalation 
Text detailing Part 1 dose escalation was 
streamlined. 
Part 1 dose escalation has 
concluded.  
13.  
6.1 Overview of Study 
Design 
8.3 Part 1 Dose Escalation 
Rules 
Sites are referred to the Site Operations 
Manual for guidance about rescreening 
patients. 
Administrative update.  
14.  
6.1 Overview of Study 
Design 
Text added stating that the sponsor may 
decide to discontinuation 1 arm if the 
interim analysis reveals an unfavorable 
risk-benefit profile.  
Clinical update.  
15.  
6.3.1 Duration of an 
Individual Patient’s Study 
Participation 
8.4.5 Criteria for 
Discontinuing Modakafusp 
Alfa 
The duration of a patient’s participation 
was clarified to include an end-of-
treatment (EOT) evaluation 30 days after 
the last modakafusp alfa dose.  
Administrative update.  
16.  
7.1 Inclusion Criteria 
7.2 Exclusion Criteria 
A table specifying restrictions on certain 
treatments and procedures before study 
enrollment was moved from inclusion to 
exclusion criteria.  
Clarification. 
17.  
7.1 Inclusion Criteria 
8.7 Precautions and 
Restrictions 
Appendix A Schedule of 
Events 
The time period for contraception use and 
egg/sperm donation was lowered to 7 days. 
Clinical update.  
18.  
7.2 Exclusion Criteria 
Appendix A Schedule of 
Events 
The exclusion criterion for hepatitis 
infection was revised, and hepatitis testing 
for the Japan safety lead-in Part 3 was 
added. 
Clinical update.  
19.  
7.2 Exclusion Criteria 
Previous treatment with modakafusp alfa 
was added as an exclusion criterion. 
Clinical update.  

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CONFIDENTIAL 
Protocol Amendment 9 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
20.  
8.12 Packaging and Labeling Description of modakafusp alfa drug 
product revised.  
Clinical update.  
21.  
8.13 Storage, Handling, and 
Accountability 
Sites are referred to the Pharmacy Manual 
regarding any discrepancies in storage 
conditions.  
Administrative update.  
22.  
8.4.4 Part 3 
8.4.5 Criteria for 
Discontinuing Modakafusp 
Alfa 
Dose modifications and potential 
discontinuation of modakafusp alfa 
treatment in Part 3 are to be discussed with 
the sponsor or CRO before 
implementation. 
Clinical update.  
23.  
8.7.1.1 Handling of IRRs 
Recommendations for managing infusion-
related reactions (IRRs) were updated. 
Clinical update.  
24.  
9.5 Posttreatment Follow-up 
Assessments 
Appendix A Schedule of 
Events 
Subsequent anticancer therapy will be 
recorded for study patients, including 
response status.  
Clinical update.  
25.  
9.3.9.1 Vital Signs 
Patients must be observed after the end of 
every modakafusp alfa infusion. 
Clinical update.  
26.  
9.3.9.2 Pregnancy Testing 
Appendix A Schedule of 
Events 
Timing and type of pregnancy tests 
required are detailed.  
Clinical update.  
27.  
9.3.9.6 Clinical Chemistry, 
Hematology, and Urinalysis 
Appendix A Schedule of 
Events 
Thyroid function tests consist of thyroid 
stimulating hormone, free or total T3, and 
free or total T4.  
Clinical update.  
28.  
9.3.9.6 Clinical Chemistry, 
Hematology, and Urinalysis 
Appendix A Schedule of 
Events 
Prothrombin time, international normalized 
ratio, activated partial thromboplastin time, 
fibrinogen, and D-dimer tests are to be 
collected if a patient exhibits significant 
bleeding.  
Clinical update. 
29.  
9.3.10 Disease Assessment 
Appendix A Schedule of 
Events 
Serum M-protein and serum free light 
chain samples are to be collected if a cycle 
is delayed. 
Clinical update.  

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Protocol Amendment 9 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
30.  
9.3.10.8.1 Bone Marrow 
Central Laboratory 
Evaluations 
9.3.11.1 Primary Specimen 
Collection for PK, 
Immunology, and Biomarker 
Assessments 
9.3.11.3.2.3 Fresh BMA 
Samples for MRD 
Appendix A Schedule of 
Events 
Screening minimal residual disease 
samples will be obtained in China based on 
the acceptability of the method chosen. 
Regulatory update.  
31.  
9.3.11.4 DNA Measurements Circulating tumor DNA is to be collected 
in Part 3 as permitted by country 
regulations. 
Regulatory update.  
32.  
9.3.13 Healthcare Resource 
Utilization  
Collection of healthcare resource 
utilization forms is required. ut PRO 
collection in Part 3 were added, and 
electronic forms must be used.  
Clinical update.  
33.  
9.4.2 Withdrawal of Patients 
From Study 
Withdrawal is required, not optional, if any 
of the criteria listed occur. 
Clinical update.  
34.  
10.2 Procedures for 
Recording and Reporting 
AEs and SAEs 
Procedures for reporting SAEs were 
updated. 
Administrative update.  
35.  
10.5 Procedures for 
Reporting Product 
Complaints or Medication 
Errors (Including Overdose) 
Procedures for reporting product 
complaints and medication errors were 
clarified. 
Clarification.  
36.  
12.1 eCRFs 
Investigators are not to review PRO data. 
Administrative update.  
37.  
13.1.5 Biomarker and 
Pharmacodynamic Analysis 
Biomarker and pharmacodynamic analysis 
was revised. 
Clinical update.  
38.  
13.1.7 Immunogenicity 
Analyses 
Immunogenicity analysis was revised. 
Statistical update.  
39.  
Appendix C PK Sampling 
Schedules  
The Schedule D Cycles 3 and Beyond PK 
table, which had been inadvertently 
omitted, was included.  
Correction.  
40.  
Appendix F IMWG 
Definition of MM (Kumar et 
al. 2016)  
International Myeloma Working Group 
(IMWG) criteria were updated to 2016 
version.  
Clinical update.  
 

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CONFIDENTIAL 
Protocol Amendment 8 Summary of Changes  
This section describes the changes to the global protocol incorporating Amendment 8.  
Protocol Amendment 8 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
1.  
STUDY SUMMARY 
6.2 Number of Patients 
The number of planned study sites was 
increased to 100.  
Update. 
2.  
STUDY SUMMARY 
5.3.1 Part 3 Primary Objective 
7.1 Inclusion Criteria 
Revised eligibility criteria regarding disease 
characteristics required for Part 3.  
Clarification. 
3.  
7.1 Inclusion Criteria 
8.7 Precautions and Restrictions 
Postmenopausal status requirement for 
female patients aligned in all sections as 2 
years.  
Clarification. 
4.  
STUDY SUMMARY 
6.1 Overview of Study Design 
6.4 Randomization in Phase 2 Part 3 
Extension 
Stratification criteria revised to (IgA vs 
other).  
Update. 
5.  
STUDY SUMMARY 
5.3.3 Part 3 Exploratory Objectives 
Deleted 2 Part 3 exploratory objectives.  
Update. 
6.  
STUDY SUMMARY 
5.4.1.2 Part 1 Secondary Endpoints 
Clarified the definition of duration of 
response (DOR). 
Clarification. 
7.  
STUDY SUMMARY 
6.1 Overview of Study Design 
13.2.2 Part 3 Extension 
Appendix H Operating 
Characteristics of the Futility 
Stopping Rules  
Appendix I 
Statistical Guidance on 
Unacceptable Toxicity and Treatment 
Related Death  
Added a second interim analysis for Part 3.  
Update. 
8.  
4.6.2 Rationale for Part 3 
The rationale for Part 3 was updated based 
on current clinical data.  
Update. 
9.  
4.6.2.1 Rationale for Fixed Dosing 
The rationale for fixed dosing was updated 
based on current clinical data. 
Update.  
10.  
7.1 Inclusion Criteria 
Contraceptive guidelines (inclusion criterion 
#8) were clarified. 
Clarification. 
11.  
7.2 Exclusion Criteria 
Hepatitis exclusion criterion (#15) was 
clarified. 
Clarification. 
12.  
8.4.4 Part 3 
Dose modification guidelines for Part 3 were 
revised. 
Update. 

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Protocol Amendment 8 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
13.  
9.3.14 PRO Assessments 
Administration of patient-reported outcomes 
(PRO) instruments was clarified. 
Clarification. 
14.  
9.4.1 Discontinuation of Treatment 
with Study Drug and Patient 
Replacement 
Complete response (CR) was removed as a 
reason for discontinuation (already covered 
under “other). 
Clarification. 
15.  
13.2.2.2 Part 3 Continuous Safety 
Monitoring Plan and Stopping Rules 
Sentence added clarifying that regulatory 
agencies and investigators will be informed 
if the study is stopped or paused for 
unacceptable toxicity or death.  
Clarification. 
16.  
14.1 Study-Site Monitoring Visits 
Study monitoring guidelines were updated to 
allow for COVID-19 circumstances. 
Update. 
17.  
Appendix A 
The schedules of events for Part 3 were 
updated. 
Update.  
 
Protocol Amendment 7 Summary of Changes (Not Implemented) 
This section describes the changes in reference to the protocol incorporating Amendment 7 (not 
implemented). The primary reasons for this amendment are to update the drug name from TAK-
573 to modakafusp alfa throughout, add a Part 3 dose extension component, and add patient-
reported outcome (PRO) assessments.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
Protocol Amendment 7 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and 
Rationale 
Location 
Description  
Rationale 
1.  
Throughout protocol 
TAK-573 was changed to 
modakafusp alfa.  
Update.  
2.  
Title 
“Relapsed” was added. 
Update. 
3.  
2.0 STUDY SUMMARY 
Efficacy was added to the 
study design. 
Update. 
4.  
2.0 STUDY SUMMARY 
6.0 Study Design 
Schedule A (Part 1) was 
noted to be no longer 
under evaluation. 
Update. 

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CONFIDENTIAL 
Protocol Amendment 7 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and 
Rationale 
Location 
Description  
Rationale 
5.  
2.0 STUDY SUMMARY 
4.6.2 Rationale for Part 3 
5.3 Part 3 Dose Extension Objectives 
5.4.3 Part 3 Extension Endpoints 
6.0 Study Design 
6.4 Randomization in Phase 2 Part 3 Extension 
7.0 Study Population 
8.0 Study Drug 
9.3 Study Procedures 
9.4 Completion of Study Treatment (for Individual 
Patients) 
11.0 STUDY-SPECIFIC COMMITTEES 
13.0 STATISTICAL METHODS 
Appendix A 
Appendix B 
Appendix C 
Part 3 extension and 
corresponding eligibility 
requirements, 
assessments, objectives, 
and endpoints were added 
to the study.  
Update.  
6.  
2.0 STUDY SUMMARY 
5.1.3 Part 1 Exploratory Objectives 
5.4.1.3 Part 1 Exploratory Endpoints 
6.0 Study Design 
Part 1 Escalation 
exploratory objectives 
and endpoints were 
clarified. 
Update. 
7.  
2.0 STUDY SUMMARY 
5.4.2.2 Part 2 Secondary Endpoints 
5.2.2 Part 2 Secondary Objectives 
6.0 Study Design 
Part 2 Expansion 
secondary objectives and 
endpoints were clarified. 
Update. 
8.  
2.0 STUDY SUMMARY 
5.2.3 Part 2 Exploratory Objectives  
5.4.2.3 Part 2 Exploratory Endpoints 
6.0 Study Design 
Part 2 Expansion 
exploratory objectives 
and endpoints were 
clarified. 
Update. 
9.  
2.0 STUDY SUMMARY 
6.0 Study Design 
13.0 STATISTICAL METHODS 
Sample size and 
statistical considerations 
were revised to include 
Part 3.  
Update. 
10.  
2.0 STUDY SUMMARY 
13.0 STATISTICAL METHODS 
The number of study sites 
and projected patient 
enrollment were 
increased.  
Update. 

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CONFIDENTIAL 
Protocol Amendment 7 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and 
Rationale 
Location 
Description  
Rationale 
11.  
3.3 Committees in Part 3 Dose Extension 
An independent review 
committee and 
independent data 
monitoring committee 
were added for Part 3. 
Update. 
12.  
3.3.2 Independent Data Monitoring Committee 
Interim futility analysis 
was added. 
Update. 
13.  
4.4.2 Toxicology Studies 
Toxicology data was 
removed and a statement 
regarding genotoxicity 
was added.  
Update. 
14.  
4.5.1 Nonclinical Safety Summary 
Nonclinical data and 
details were removed and 
the reader referred to the 
investigator’s brochure 
(IB).  
Update. 
15.  
4.5.2 Clinical Safety 
Clinical data and details 
were removed and the 
reader referred to the IB.  
Update. 
16.  
8.4 Dose Modification Guidelines 
Dose modification 
guidelines were clarified. 
Update. 
17.  
8.13 Storage, Handling, and Accountability 
Drug storage and usage 
instructions were 
updated. 
Update. 
18.  
2.0 STUDY SUMMARY 
7.0 Study Population 
Wash-out periods were 
defined.  
Update. 
19.  
2.0 STUDY SUMMARY 
9.3.14 PRO Assessments 
13.1.6 PRO Analyses 
Appendix A 
PRO assessments were 
added for Part 3. 
Update. 
20.  
2.0 STUDY SUMMARY 
4.6.2 Rationale for Part 3 
Flat dosing will be used 
for Part 3. 
Update. 
21.  
4.5.2 Clinical Safety 
Safety information was 
updated. 
Update 
22.  
2.0 STUDY SUMMARY 
4.5.2 Clinical Safety 
8.0 Study Drug 
10.0 ADVERSE EVENTS 
Updated CTCAE to 
Version 5.0. 
Update. 
23.  
7.1 Inclusion Criteria 
ECOG criteria was 
modified to ≤2. 
Update. 

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CONFIDENTIAL 
Protocol Amendment 7 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Section(s) Affected by Change 
Description of Each Change and 
Rationale 
Location 
Description  
Rationale 
24.  
8.6.1 Premedication 
Guidance for 
premedications in second 
paragraph was changed to 
“should.” 
Update. 
25.  
8.7.1.1 Handling of IRRs 
Premedication guidelines 
were revised. 
Update. 
26.  
9.3.10.1 Extramedullary Disease Imaging 
Heading title was revised 
and text added describing 
Part 3 assessments.  
Update. 
27.  
9.3.10.2 Bone Imaging  
Heading title was revised 
and text added describing 
Part 3 assessments.  
Update. 
28.  
9.3.10.4 Quantification of M-Protein in Serum and 
Urine 
Urine collection for the 
different parts of the 
study was clarified. 
Update. 
29.  
9.3.10.8.1 Bone Marrow Central Laboratory 
Evaluations 
Sample collection and 
analysis requirements 
were clarified 
Update. 
30.  
Table 9.c Primary Specimen Collection 
Specimen collection table 
was updated to include 
Part 3 assessments. 
Update. 
Protocol Amendment 6 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 6. The 
primary reasons for this amendment are to maintain patient safety, confidentiality, and study 
integrity in the context of healthcare challenges presented by the coronavirus disease 2019 
(COVID-19) public health emergency. This amendment allows investigators and study personnel 
to conduct visits remotely and electronic informed consent if these comply with national and 
local laws and regulations, use local laboratory and imaging results if patients are unable to 
travel to the investigative site, and remotely access patient records for data monitoring as 
necessary during the COVID-19 public health emergency.  
Additionally, safety data, premedication requirements for doses of 6 mg/kg or greater and 
recommendations for all dose levels were updated, secondary endpoints and the sample size were 
revised, the criteria for early termination were expanded, clinical chemistry parameters were 
revised, and blood samples were added for pharmacokinetic (PK) and pharmacodynamic 
assessments.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 

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CONFIDENTIAL 
Protocol Amendment 6 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 1.2 Approval  
Updated study personnel  
To reflect change in Takeda 
representatives.  
Section 4.5.1.3 Potential Effects Based on 
Nonclinical and Clinical Studies 
Added new safety data 
To include additional safety 
data now available.  
Section 4.6.2 Changes to TAK-573 Infusion 
Over the Course of the Study 
Section 8.6.1 Premedication 
Section 8.6.2 Postinfusion Medication 
Clarified use of premedication 
requirements and 
recommendations prior to the 
dosing of TAK-573 
To update guidance to 
include additional clinical 
experience.  
Section 2.0 STUDY SUMMARY 
Section 5.2.2 Phase 1 Secondary Endpoints 
Section 5.2.3 Phase 2 Primary Endpoints 
Section 6.1 Overview of Study Design 
Section 13.1.3 Efficacy Analysis 
Added clinical benefit rate and 
disease control rate as a 
secondary endpoint for phase 1 
and as a primary endpoint for 
phase 2 
To adjust endpoints to be 
more relevant in this early-
phase study.  
Section 2.0 STUDY SUMMARY 
Section 5.2.2 Phase 1 Secondary Endpoints 
Section 5.2.3 Phase 2 Primary Endpoints 
Section 6.3.1 Duration of an Individual 
Patient’s Study Participation 
Section 6.3.4 Total Study Duration 
Section 9.8 Posttreatment Follow-up 
Assessments (PFS) 
Appendix A  
Removed overall survival as a 
secondary endpoint 
To reflect determination that 
the endpoint of overall 
survival is not informative 
without a comparator group.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Overview of Study Design 
Section 8.1 Study Drug Administration 
Section 8.8.1 Handling of IRRs 
Appendix A 
Added further dosing instructions 
To update guidance to reflect 
additional clinical 
experience. 
Section 2.0 STUDY SUMMARY 
Section 6.2 Number of Patients 
Changed number of sites and 
expected study duration  
To reflect current 
expectations for number of 
sites and predicted duration 
of study. 
Section 6.3.2 End of Study/Study 
Completion Definition and Planned 
Reporting 
Revised end-of-study criteria  
To clarify conditions for 
study completion. 
Section 8.8.1 Handling of IRRs 
Section 10.2.1 Monitoring and Reporting 
IRRs 
Appendix A 
Defined infusion-related reaction 
(IRR) and treatment of IRRs 
To include additional safety 
data now available. 

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CONFIDENTIAL 
Protocol Amendment 6 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 9.3 Study Procedures 
Section 9.3.1 Informed Consent 
Section 9.3.4 Physical Examination 
Section 9.3.13 Clinical Laboratory 
Evaluations 
Section 9.3.14 Disease Assessment 
Clarified exceptions for site visits 
and procedural adjustments 
during unforeseen situations, like 
the COVID-19 public health 
emergency  
To maintain patient safety, 
confidentiality, and study 
integrity in the context of 
health care challenges 
presented by the COVID-19 
public health emergency. 
Section 9.3.8 Vital Signs 
Appendix A 
Added oxygen saturation as a 
vital sign 
To clarify this information, 
which is routinely clinically 
assessed, should be collected 
and documented.  
Section 9.3.13.1 Clinical Chemistry, 
Hematology, and Urinalysis 
Removed coagulation, activated 
partial thromboplastin time, and 
prothrombin time from 
hematology panel 
To eliminate tests determined 
not to be necessary given 
further experience with 
TAK-573.  
Section 9.3.17 Immunogenicity Sample 
Collection 
Added text to “strongly suggest” 
sample collection 
To clarify recommendations 
for sample collection. 
Section 9.4 Completion of Study Treatment 
(for individual patients) 
Appendix A 
Revised content regarding 
completion of study treatment 
To clarify criteria for 
completion of study 
treatment. 
Section 10.1.3 AESIs 
Section 10.2.1 Monitoring and Reporting 
IRRs 
Added definition of adverse 
events of special interest (AESI) 
To clarify the definition and 
reporting of adverse events 
that should be classified as 
special interest, highlighting 
that IRRs would be 
designated as AESIs in 
studies of this compound. 
Section 13.1.1 Analysis Sets 
Added response-evaluable 
analysis set 
To align statistical content 
with change in study 
endpoints. 
Section 13.2 Criteria for Early Termination 
Added criteria for early 
termination 
To clarify conditions for 
early termination and clarify 
that no interim analysis is 
planned. 
Section 13.3 Determination of Sample Size 
Changed planned sample size for 
phase 2 
To align sample size with 
change in study endpoints. 

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Protocol Amendment 6 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Appendix A Table 6 Schedule C (Q3W) 
Schedule of Events: Screening, Baseline, 
Cycle 1, and Cycle 2 
Appendix A Table 9 Schedule D (Q4W) 
Schedule of Events: Screening, Baseline, 
Cycle 1, and Cycle 2 
Appendix A Table 10 Schedule D (Q4W) 
Schedule of Events, Continued: Cycle 3 to 
Cycle 13 and Beyond 
Addition of time points for blood 
sample for flow cytometry (CD38 
occupancy in PBMCs), blood 
sample for flow cytometry 
(immunoprofiling), serum sample 
for PK, circulating biomarkers, 
and blood sample for RNA 
To generate data evaluating a 
longer duration of CD38 
receptor occupancy and how 
it relates to subsequent 
pharmacodynamic 
biomarkers as we continue to 
dose escalate.  
To characterize PK for a 
longer duration on Cycles 1 
and 2 as dose escalates to 
greater than 6 mg/kg, and to 
collect Day 2 PK for limited 
visits beyond Cycle 2 to 
further characterize potential 
impact of ADA on PK. 
Appendix A Table 11 Schedules A, B, C 
and D: End of Treatment and Follow-up 
Removal of collection of 
subsequent therapy 
Data on subsequent therapy 
is not needed since OS is no 
longer an endpoint.  
Appendix C Table 8 Schedule D (Q4W) PK 
Sampling: Cycle 1 and Cycle 2 
Addition of time point “end of 
infusion (+/- 5 min)” on Day 1 
Removal of time point “1 hour 
after end of infusion (+/- 15 min)” 
on Day 1 
Addition of time point on “504 
hours after end of infusion (+/-1 
hour)” on Day 22, strongly 
recommended for > 6 mg/kg only. 
 
To characterize PK for a 
longer duration as dose 
escalates to greater than 6 
mg/kg. 
Appendix C Table 9 Schedule D (Q4W) PK 
Sampling: Cycle 3 and Beyond  
Addition of time point for Day 2 
of Cycle 3, 7, and 11 only  
Collect Day 2 PK for limited 
visits beyond Cycle 2 to 
further characterize potential 
impact of ADA on PK.  
 
Protocol Amendment 5 Summary and Rationale  
This document describes the changes in reference to the protocol incorporating Amendment 
No. 05. The primary reasons for this amendment are to reduce infusion time for TAK-573 
(Section 4.6.2), to remove the requirement for pre- and postinfusion medication, to add 
combination cohort(s) with dexamethasone during phase 2 expansion phase, and to update the 
expected number of cohorts and patients for phase 2. Minor grammatical, editorial, and 
formatting changes are included for clarification purposes only. For specific descriptions of text 
changes, rationales for the changes, and where the changes are located, see Appendix H.  

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Changes in Amendment 5 
1. Global changes:  
i. 
Changed phase 2a to phase 2 throughout protocol. 
ii. 
For consistency of terminology, replaced “monotherapy” with “single agent” 
throughout protocol. 
iii. 
Added “relapsed” to description of study population (eg, patients with 
relapsed/refractory MM) throughout protocol.  
2. Updated Introduction for consistency with recently updated Investigator’s Brochure 
(Edition 2). 
3. Added Clinical Safety section. 
4. Updated and reorganized Potential Effects Based on Nonclinical and Clinical Studies section 
to include clinical data. 
5. Updated study rationale section, which includes reduction in study drug infusion time and 
removal of requirement for pre- and postinfusion medications. 
6. Updated phase 2 primary and secondary objectives to reflect addition of dexamethasone 
combination cohort. 
7. Included description of dexamethasone combination arm in study design section and study 
design figure. 
8. Added definition of “DLT-like.”  
9. Updated expected number of patients. 
10. Added guidance regarding discontinuation of dexamethasone for combination arm. 
11. Revised end of study description. 
12. Increased frequency of PFS follow-up to 4 weeks for patients who discontinue for reasons 
other than progressive disease. 
13. Added Posttrial Access section.  
14. Updated inclusion criterion for females of childbearing potential and male patients. 
15. Revised exclusion criterion regarding severe allergic or anaphylactic reactions. 
16. Revised Study Drug Administration section to change infusion time, remove unnecessary 
detail, remove pre- and postinfusion medications, and add Administration of Dexamethasone 
section. 
17. Clarified Dose Escalation Rules. 
18. Clarified Dose Modification Guidelines and added Dexamethasone Dose Modification 
section. 

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19. Updated Excluded Concomitant Medications and Procedures to address treatment of 
thrombocytopenia and tumor flare. 
20. Moved Premedication section from Study Drug Administration section to Permitted 
Concomitant Medications and Procedures section. 
21. Moved Postinfusion Medication subsection from Study Drug Administration section to 
Permitted Concomitant Medications and Procedures section and added guidance regarding 
Grade ≥2 IRRs. 
22. Clarified guidance in Other Permitted Concomitant Medications and Procedures section. 
23. Provided additional guidance regarding Handling of IRRs (Table 8.b and Table 8.c). 
24. Provided additional guidance regarding Handling of Low Platelet Counts. 
25. Added guidance regarding procurement and sourcing of dexamethasone.  
26. Added antiplatelet antibody testing to table for Clinical Chemistry and Hematology Tests 
(Table 9.a). 
27. Added Bone Marrow Morphology subsection to Bone Marrow Aspiration. 
28. Corrected sentence regarding serum PK samples. 
29. Added blood sample for T-lymphocyte, B-lymphocyte, and natural killer cells (TBMK). 
30. Provided additional reason for withdrawal of patient from study. 
31. Provided additional guidance for posttreatment imaging of patients with extramedullary 
disease. 
32. Revised list of analysis sets and efficacy analyses in statistical plans section. 
33. Updated Determination of Sample Size for phase 2. 
34. Revised Schedule of Events (Appendix A) as follows: 
• Revised visit days for Schedules C and D: C1D4 changed to C1D3; C2D4 changed to 
C2D3. 
• Removed the following visits:  
− Schedule B: C1D4, C1D18, C2D4 
− Schedule C: C3D15 
− Schedule D: C3D15. 
• Added parentheses to crosses (indicating that tests are only to be performed under 
certain circumstances as indicated in footnotes) throughout SOE for 24-hour urine 
protein. 
• Revised SOE to make collection of the following tests consistent and, where 
previously missing at C1D1, added footnote k and parentheses to crosses (indicating 

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that tests are only to be performed under certain circumstances as indicated in 
footnote) for the following tests: 
− Serum M-protein 
− 24-hour urine M-protein (also, throughout SOE, added parentheses to all 
crosses) 
− Serum FLC assay 
− Immunofixation – serum and urine 
− Quantification of Ig. 
• Added blood sample for TBNK assay (local analysis if available) (also see Change 
29). 
• Removed triplicate 12-lead ECGs from Schedule B visits on C1D8 and C2D8. 
• Clarified screening visit for Skeletal Survey rows, added visit time points, and, where 
missing, added parentheses to time points. 
• Added PET-CT to CT or MRI rows and, where missing, added parentheses to time 
points. 
• Added PET-CT to CT or MRI rows. 
• Added anti-platelet antibody testing rows. 
• Added time points to Immunofixation–serum and urine rows. 
• Added investigator assessment of disease response/status rows. 
• Added time points to quantification of Ig rows. 
• Added time points to serum FLC assay rows. 
• Clarified screening visit for Immunofixation-serum and urine rows. 
• End of Treatment and Follow-up: changed PFS follow-up visit from 12 to 4 weeks. 
35. Revised Schedule of Events footnotes to: 
• Clarify note regarding crosses in parentheses (X). 
• Clarify footnote c regarding collection of ECG(s). 
• Clarify footnote f regarding patients who have a complete skeletal survey at screening 
and regarding posttreatment follow-up of patients with extramedullary disease. 
• Revise footnotes k, m, and x. 
• Add footnotes aa, bb, cc and dd. 

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36. Revised Appendix B Bone Marrow Collection and Assessment Schedules. 
• Changed PFS follow-up from every 12 to every 4 weeks. 
• Added bone marrow morphology to row for disease assessment and added time 
points. 
• Added footnote e. 
37. Revised Appendix C Pharmacokinetic Sampling Schedules: Table 4 through Table 9 for 
Schedules B (Q2W), C (Q3W) and D (Q4W). 
• Revised column headings for visit days. 
• Revised descriptions of time points. 
• Removed/revised certain visits or visit days. 
• Revised footnotes pertaining to timeframe of eating and drinking in relation to ECGs 
and PK.  
Protocol Amendment 4 Summary and Rationale 
This document describes the changes in reference to the protocol incorporating Amendment 
No. 04. Minor grammatical, editorial, and formatting changes are included for clarification 
purposes only. For specific descriptions of text changes, rationales for the changes, and where 
the changes are located, see Appendix H.  
Changes in Amendment 4 
1. Added 3 schedules (Schedule B, C and D) to the original schedule (Schedule A) to be 
evaluated during the dose escalation phase. 
2. Modified hematologic TEAEs to be considered DLTs. 
3. Modified criteria for beginning or delaying a subsequent treatment cycle. 
4. Modified triplicate 12-lead ECGs as a separate procedure from safety 12-lead ECGs. 
5. Added coagulation tests and removed “serum” from categorization of chemistry tests. 
6. Modified bone marrow aspirate sample collection time points. 
7. Added subsequent anticancer therapy to AE and SAE reporting timelines. 
8. Modified details of patients who withdraw or miss doses for reasons other than a DLT. 
9. Added option for eligible patients for intrapatient dose escalation to continue in a different 
schedule. 
10. Miscellaneous changes. 

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Protocol Amendment 3 Summary and Rationale 
This document describes the changes in reference to the protocol incorporating Amendment 
No. 03.  
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. 
For specific descriptions of text changes, rationales for the changes, and where the changes are 
located, see Appendix H.  
Changes in Amendment 3 
1. Removed test dose.  
2. Reduced number of dose escalation levels to remove possible subtherapeutic doses.  
3. Removed baseline visit (Day -1) associated with test dose administration.  
4. Revised enrollment staggering to allow concurrent enrollment of second and third patients 
within a cohort.  
5. Removed measurement of soluble CD38 in serum.  
6. Clarified collection of bone marrow aspirates and added collection time points during 
screening and on-treatment.  
7. Clarified inclusion criterion for hepatitis.  
8. Clarified definition of excluded corticosteroid treatment.  
9. Clarified observation time for vital signs after TAK-573 infusion.  
10. Clarified that serum samples collected for pharmacokinetic (PK) analysis may also be used 
for exploration of pharmacodynamic markers.  
11. Clarified that blood samples will be collected in case of an infusion-related reaction. 
12. Added statement that treatment with TAK-573 may be continued after progressive disease 
under certain circumstances.  
13. Revised the number of sampling time points for serum biomarkers.  
14. Added predose sampling for baseline reference on C1D1 for serum biomarkers, serum 
immunogenicity, blood flow immunoprofiling and blood flow receptor occupancy.  
15. Added Cycle 1 Day 15 and Cycle 2 Day 15 serum M-protein for modeling purposes and 
immunoprofiling.  
16. Added electrocardiogram (ECG) assessments and clarified that triplicate ECG readings can 
be used for purposes of local safety ECG evaluation.  
17. Added the possibility of defining an optimal biologic dose (OBD) based on 
pharmacodynamic endpoints as an alternative to the maximum tolerated dose (MTD) based 
on dose-limiting toxicities DLTs as a possible dose for future studies.  
18. Revised PK sample collection schedule.  

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19. Modified Schedule of Events.  
20. Changed the ECOG performance status requirement from 0-2 to 0-1.  
 
Protocol Amendment 2 Summary and Rationale 
This document describes the changes in reference to the protocol incorporating Amendment 
No. 02. The primary reason for this amendment is to update the original protocol to comply with 
Takeda standards and standard operating procedures. 
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. 
For specific descriptions of text changes and where the changes are located, see Appendix H.  
Changes in Amendment 2 
1. Edited so that testing is not limited to antibody drug conjugates. 
2. Toxicology section updated with more recent data.  
3. Clarified central versus local ECG analysis.  
4. Added detail regarding study drug infusion.  
5. Corrected description of postinfusion medication.  
6. Clarified method and type of laboratory testing (central versus local laboratories).  
7. Changed definition of complement analysis.  
8. Clarified the collection and usage of clinical samples (blood and bone marrow) for 
pharmacodynamic analysis and sample utilization.  
9. Provided additional detail regarding biomarker measurement.  
10. Clarified description of serum samples for immunogenicity testing.  
11. Removed text regarding antidrug neutralizing antibodies.  
12. Deleted mention of Day 29 assessment from sample size section.  
13. Changed at time of “enrollment” and “randomization” to “first dose”.  
14. Study conduct sections were added for patient weight and ECOG performance status.  
15. End-of-treatment language was standardized.  
16. Clarified definition of disease assessment.  
17. Modified triplicate ECG measurement time points.  
18. Deleted Appendix F.  
19. Clarified timing when concomitant medications will be recorded.  
20. Clarified handling procedures for TAK-573.  
21. Removed enrollment section.  

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22. Reduced the number of time points for immunofixation of serum and urine.  
23. Modified Schedule of Events.  
24. Measurement of IgD and IgE no longer a requirement for all patients at baseline.  
 
Protocol Amendment 1 Summary and Rationale 
This document describes the changes in reference to the protocol incorporating Amendment 
No. 01. The primary reason for this amendment is to update the original protocol to comply with 
Takeda standards and standard operating procedures. 
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only. 
For specific descriptions of text changes and where the changes are located, see Appendix I.  
Changes in Amendment 1 
Global Changes 
1. Change the compound name from TEV-48573 to TAK-573.  
2. Change the protocol study number from TV48573-ONC-10128 to TAK-573-1501.  
Study Objectives and Endpoints 
3. Clarify the Phase 1 and 2A study objectives. 
4. Clarify the Phase 1 and 2A study endpoints. 
Study Design 
5. Update the Overall Study Schematic diagram. 
6. Revise the number of patients in the Phase 1 and 2a portions of the study. 
7. Clarify the duration of the study. 
Study Population 
8. Clarify the inclusion criteria. 
9. Clarify the exclusion criteria. 
Study Drug 
10. Clarify the definition of dose-limiting toxicity. 
11. Clarify the dose modifications. 
12. Clarify the handling of patients who experience infusion-related reactions. 

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Study Procedures 
13. Clarify the primary specimen collection for pharmacokinetics (PK) and biomarker 
assessments. 
14. Update the definition of PK, biomarker, and pharmacodynamics measurements.  
Schedule of Events 
15. Update the Schedule of Events to reflect changes in Protocol Amendment 1. 
 

Signature Page for TAK-573-1501 Protocol Amend 10 v2 2024-04-03
Title: Amend 10 v2 to A Phase 1/2 Open-label Study to Investigate the Safety and
Document Number: TDN-000239972 v2.0
Approval
Clinical
05-Apr-2024 11:45:01 GMT+0000
Approval
Research
05-Apr-2024 16:45:05 GMT+0000