Clinical trial NCT05556616
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2023-01-12; Completion date: 2024-06-04
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main aims of this study are to test for any side effects from modakafusp alfa in combination therapy and to determine the recommended dose of combination therapy with modakafusp alfa. The dose of modakafusp alfa will be increased a little at a time until the highest dose that does not cause harmful side effects is found. Participants will be given modakafusp alfa through a vein.

Detailed description:
The drug being tested in this study is called modakafusp alfa (TAK-573). The study will evaluate the safety, tolerability and determine the recommended dose of modakafusp alfa in combination with lenalidomide in participants with multiple myeloma (MM), or in combination with pomalidomide, bortezomib, carfilzomib, or daratumumab in participants with relapsed/refractory multiple myeloma (RRMM).

The study consists of 3 Groups: Group 1: MM Maintenance Therapy, Group 2: RRMM Doublets, Group 3: RRMM Triplets.

The study will enroll approximately 18 participants in Group 1, 66 in Group 2, and 36 in Group 3. Participants will be assigned to one of the following treatment groups as given below:

* Group 1 (MM Maintenance) Arm 1: Modakafusp alfa + Lenalidomide
* Group 2 (RRMM Doublets) Arm 2: Modakafusp alfa + Pomalidomide
* Group 2 (RRMM Doublets) Arm 3: Modakafusp alfa + Bortezomib
* Group 2 (RRMM Doublets) Arm 4: Modakafusp alfa + Carfilzomib
* Group 3 RRMM Triplets) Arm A: Modakafusp alfa + Pomalidomide + Bortezomib
* Group 3 (RRMM Triplets) Arm D: Modakafusp alfa + Daratumumab + Pomalidomide

Group 2 Arm 4 is closed for enrollment.

The study will be conducted worldwide. The maximum treatment duration in this study for Group 1 is until disease progression or unacceptable toxicity, or up to 2 years for minimal/measurable residual disease (MRD) negative \[-\] participants, whichever occurs first. The maximum treatment duration in this study for Group 2 and Group 3 is until disease progression, unacceptable toxicity or until any other discontinuation criterion is met, whichever occurs first. Overall time to participate in the study is approximately up to 5 years.

Arms: arm 1: Participants received 80 milligrams (mg) modakafusp alfa, infusion intravenously (IV), once on Day 1, once every 4 weeks (Q4W), in combination with 10 mg lenalidomide capsules orally once daily continuously on Days 1 to 28, in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or to a maximum of 2 years for measurable/minimal residual disease-negative (MRD \[-\]) participants, whichever occurred first. arm 2: Participants received 80 mg modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with 2 mg pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion was met, whichever occurred first. arm 3: Participants received 80 mg modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with 4 mg pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion was met, whichever occurred first. arm 4: Participants received 80 mg modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with 20/70 milligrams per meter square (mg/m\^2) carfilzomib IV, on Day 1, 8 and 15 of a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion was met, whichever occurred first. arm 5: Participants were planned to receive modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with bortezomib injection subcutaneously on Days 8, 15, and 22 for the first 8 cycles and subsequently on Days 8 and 22 of a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. arm 6: Participants were planned to receive modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle along with bortezomib injection subcutaneously on Days 8, 15 and 22 for the first 8 cycles and subsequently on Days 8 and 22 of a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first. arm 7: Participants were planned to receive modakafusp alfa, infusion IV, once on Day 1, Q4W in combination with daratumumab injection subcutaneously on Days 1, 8, 15 and 22 of Cycles 1 and 2, further followed by on Days 1 and 15 of Cycles 3 to 6, thereafter on Day 1 on a 28-day (4-week) treatment cycle along with pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle until disease progression, unacceptable toxicity, or until any other discontinuation criterion is met, whichever occurs first.
Interventions: intervention 1: Modakafusp alfa intervention 2: Lenalidomide intervention 3: Bortezomib intervention 4: Carfilzomib intervention 5: Daratumumab intervention 6: Pomalidomide
Intervention descriptions: intervention 1: Modakafusp alfa intravenous infusion. intervention 2: Lenalidomide capsules orally. intervention 3: Bortezomib injection subcutaneously. intervention 4: Carfilzomib intravenous infusion. intervention 5: Daratumumab injection subcutaneously. intervention 6: Pomalidomide capsules orally.

Protocol documents:
Prot_000.pdf: 
NCT Number: NCT05556616
Title: A Phase 1b Open-label Study to Evaluate the Safety and Tolerability of 
Intravenous Modakafusp Alfa as Part of Combination Therapy in Adult Patients 
With Multiple Myeloma
Study Number: TAK-573-1502 
Document Version and Date: Amendment 5 US v1, 19 September 2024 
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
Study No. TAK-573-1502  
1 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
CONFIDENTIAL 
PROTOCOL 
A Phase 1b Open-label Study to Evaluate the Safety and Tolerability of Intravenous 
Modakafusp Alfa as Part of Combination Therapy in Adult Patients With 
Multiple Myeloma 
Sponsor: 
Takeda Development Center Americas, Inc 
500 Kendall Street 
Cambridge, MA 02142 USA 
Study Number: 
TAK-573-1502 
Abbreviated EudraCT Number: 
2022-001418-20 
ClinicalTrials.gov Identifier: 
NCT05556616 
Compound: 
Modakafusp alfa (TAK-573) 
Date: 
19 September 2024 
Amendment Number: 5 US v1 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
19 September 2024 
Amendment 5 US v1 
Substantial; Regional 
United States 
03 April 2024 
Amendment 4 v2 
Substantial 
Global 
28 February 2024 
Amendment 4 v1 
(not implemented) 
Substantial 
Global 
13 June 2023 
Amendment 3 
Substantial 
Global 
17 August 2022 
Amendment 2 
Substantial 
Global 
27 May 2022 
Amendment 1 
Substantial 
Global 
13 May 2022 
Initial protocol EU v1 
Nonsubstantial; Regional 
European Union 
01 April 2022 
Initial protocol 
Not applicable 
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. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
2 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided to each site, which includes the names and 
contact information for the medical monitor and responsible medical officer. 
Serious adverse event (SAE) and pregnancy reporting information is presented in this protocol in 
Sections 10.2 and 10.4, respectively, and in the Investigator Site File (ISF). Information on 
reporting product complaints is in the pharmacy manual. 
Takeda Development Center–sponsored investigators per individual country requirements will 
be provided with emergency medical contact information cards to be carried by each subject. 
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 will 
be provided to the site. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
3 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
1.2 
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation (ICH) E6 (R2) Good Clinical Practice (GCP): 
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 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
4 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure (IB), 
prescribing information, 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. 
• ICH, E6 GCP: Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting SAEs 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 F 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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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
5 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
1.3 
Protocol Amendment 5 US v1 Summary of Changes 
Protocol Amendment 5 US v1 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 5 US 
v1. The primary reason for this amendment was to include the United States (US) Food and Drug 
Administration (FDA) recommendation of excluding patients with a high risk of bleeding events, 
including those on anticoagulation 
 
 
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 5 US v1 
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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised per FDA 
recommendation 
2.  
7.2 Exclusion Criteria 
Added exclusion criterion #18: “Patient 
has a high risk of hemorrhage such as 
uncontrolled chronic bleeding disorder 
or is currently being treated with 
therapeutic anticoagulation. 
Antithrombotic prophylaxis for 
lenalidomide and pomalidomide is 
authorized.” 
Revised per FDA 
recommendation 
FDA: Food and Drug Administration; TEAE: treatment-emergent adverse event. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
6 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 5 US v1 Summary of Changes ...................................................5 
2.0 
STUDY SUMMARY.........................................................................................................16 
3.0 
STUDY REERENCE INFORMATION ...........................................................................21 
3.1 
Study-Related Responsibilities ....................................................................................21 
3.2 
Principal/Coordinating Investigator .............................................................................21 
3.3 
List of Abbreviations ...................................................................................................22 
3.4 
Corporate Identification ...............................................................................................26 
4.0 
INTRODUCTION .............................................................................................................27 
4.1 
Multiple Myeloma .......................................................................................................27 
4.2 
Modakafusp Alfa (TAK-573) ......................................................................................27 
4.2.1 
Mechanism of Action ..........................................................................................27 
4.2.2 
Targets .................................................................................................................28 
4.2.3 
Nonclinical and Toxicology Studies ...................................................................29 
4.2.3.1 
Nonclinical Studies .....................................................................................30 
4.2.3.2 
Toxicology Studies .....................................................................................31 
4.2.4 
Clinical Experience .............................................................................................31 
4.2.4.1 
TAK-573-1501 ............................................................................................31 
4.2.4.2 
TAK-573-1001 ............................................................................................33 
4.2.4.3 
TAK-573-2001 ............................................................................................34 
4.2.4.4 
TAK-573-1502 Arm 4.................................................................................34 
4.3 
Combination Agents ....................................................................................................35 
4.3.1 
Lenalidomide .......................................................................................................35 
4.3.2 
Pomalidomide ......................................................................................................35 
4.3.3 
Bortezomib ..........................................................................................................35 
4.3.4 
Daratumumab and Hyaluronidase-fihj ................................................................36 
4.4 
Rationale for the Proposed Study ................................................................................36 
4.4.1 
Modakafusp Alfa .................................................................................................36 
4.4.1.1 
Rationale for Modakafusp Alfa Dose .........................................................37 
4.4.2 
Combination Agents ............................................................................................37 
4.4.2.1 
Lenalidomide...............................................................................................37 
4.4.2.2 
Pomalidomide .............................................................................................40 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
7 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
4.4.2.3 
Bortezomib ..................................................................................................42 
4.4.2.4 
Daratumumab ..............................................................................................45 
4.5 
Risks and Benefits........................................................................................................46 
4.5.1 
Benefit-Risk Profile of Modakafusp Alfa ...........................................................46 
4.5.1.1 
Nonclinical Safety Summary ......................................................................47 
4.5.1.2 
Clinical Safety Summary ............................................................................47 
4.5.2 
Benefit-Risk Profile of the Combination Agents ................................................48 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................49 
5.1 
Objectives ....................................................................................................................49 
5.1.1 
Primary Objectives ..............................................................................................49 
5.1.2 
Secondary Objectives ..........................................................................................50 
5.1.3 
 ..................................................................50 
5.2 
Estimands .....................................................................................................................50 
5.3 
Endpoints .....................................................................................................................50 
5.3.1 
Primary Endpoints ...............................................................................................50 
5.3.2 
Secondary Endpoints ...........................................................................................51 
5.3.3 
 .........................................................................................51 
6.0 
STUDY DESIGN...............................................................................................................52 
6.1 
Overview of Study Design ...........................................................................................52 
6.2 
Overview of Combination Therapy Groups and Dose Regimens ...............................54 
6.2.1 
Group 1: MM Maintenance .................................................................................54 
6.2.1.1 
Arm 1 Modakafusp alfa and Lenalidomide in MM After ASCT ...............54 
6.2.2 
Group 2: RRMM Doublets ..................................................................................55 
6.2.2.1 
Arm 2 MP in RRMM ..................................................................................55 
6.2.2.2 
Arm 3 MV in RRMM .................................................................................56 
6.2.2.3 
Arm 4 MK in RRMM (Closed to Enrollment) ...........................................57 
6.2.3 
Group 3: RRMM Triplets ....................................................................................57 
6.2.3.1 
Arm A MPV in RRMM ..............................................................................57 
6.2.3.2 
Arm D MDP in RRMM ..............................................................................58 
6.3 
Dose Escalation/De-escalation.....................................................................................59 
6.3.1 
Group 1: MM Maintenance .................................................................................60 
6.3.2 
Group 2: RRMM Doublets ..................................................................................61 
6.3.3 
Group 3: RRMM Triplets ....................................................................................61 
6.3.4 
 .......................................................................63 
6.4 
Number of Patients ......................................................................................................63 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
8 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
6.5 
Duration of the Study ...................................................................................................64 
6.5.1 
Duration of an Individual Patient’s Study Participation ......................................64 
6.5.2 
Total Study Duration ...........................................................................................64 
6.5.3 
Posttrial Access ...................................................................................................64 
6.5.3.1 
Duration of PTA ..........................................................................................65 
6.5.3.2 
Combination Agents ...................................................................................65 
6.5.4 
Definition of End of Study/Study Completion and Planned Reporting ..............65 
7.0 
STUDY POPULATION ....................................................................................................66 
7.1 
Inclusion Criteria .........................................................................................................66 
7.2 
Exclusion Criteria ........................................................................................................70 
8.0 
STUDY DRUG ..................................................................................................................72 
8.1 
Study Drug Administration ..........................................................................................72 
8.1.1 
Modakafusp Alfa .................................................................................................72 
8.1.1.1 
Premedications ............................................................................................72 
8.1.1.2 
Postinfusion Medication .............................................................................73 
8.1.1.3 
Prophylaxis Against Risk of Infection ........................................................73 
8.1.2 
Combination Agents ............................................................................................73 
8.1.2.1 
Lenalidomide Administration, Premedications and Prophylaxis ................73 
8.1.2.2 
Pomalidomide Administration, Premedications and Prophylaxis ...............74 
8.1.2.3 
Bortezomib Administration, Premedications and Prophylaxis ...................75 
8.1.2.4 
Daratumumab Administration, Premedications and Prophylaxis ...............76 
8.2 
Permitted Concomitant Medications and Procedures ..................................................77 
8.3 
Prohibited Medications and Procedures .......................................................................78 
8.4 
List of European Union Auxiliary Medicinal Products Used in the Trial Other 
Than the Investigational Products ................................................................................78 
8.5 
DLTs ............................................................................................................................79 
8.5.1 
Definition of DLT-Evaluable Patients .................................................................80 
8.5.2 
Intrapatient Dose Escalation ................................................................................80 
8.6 
Dose Modification Guidelines .....................................................................................81 
8.6.1 
Modakafusp Alfa and Combination Agent(s) .....................................................81 
8.6.1.1 
Criteria for Cycle 1 Day 1 ...........................................................................81 
8.6.1.2 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
(Cycle 2 Day 1 and Beyond) .......................................................................81 
8.6.1.3 
Modakafusp Alfa .........................................................................................81 
8.6.1.4 
Criteria for Dose Interruption .....................................................................82 
8.6.1.5 
Criteria for Dose Reduction ........................................................................84 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
9 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
8.6.1.6 
Criteria for Discontinuation ........................................................................84 
8.6.2 
Combination Agents ............................................................................................85 
8.7 
Management of Specific Adverse Reactions ...............................................................85 
8.7.1 
Modakafusp alfa ..................................................................................................85 
8.7.1.1 
Handling of IRRs Related to Modakafusp Alfa ..........................................85 
8.7.1.2 
Handling of Low Platelet Counts ................................................................87 
8.7.1.3 
Prophylaxis Against Risk of Infection ........................................................87 
8.7.2 
Combination Agents ............................................................................................87 
8.8 
Precautions and Restrictions ........................................................................................87 
8.8.1 
Contraception and Pregnancy Avoidance Procedures .........................................87 
8.8.2 
Pregnancy ............................................................................................................89 
8.9 
Blinding........................................................................................................................89 
8.10 
Description of Investigational Agents .........................................................................89 
8.10.1 
Packaging and Labeling ......................................................................................89 
8.11 
Clinical Study Storage, Handling, and Accountability ................................................90 
8.11.1 
Modakafusp Alfa .................................................................................................90 
8.11.2 
Combination Agents ............................................................................................90 
9.0 
STUDY CONDUCT ..........................................................................................................91 
9.1 
Study Personnel and Organizations .............................................................................91 
9.2 
Arrangements for Recruitment of Patients ..................................................................91 
9.3 
Administrative Procedures ...........................................................................................91 
9.4 
Informed Consent.........................................................................................................91 
9.5 
Screening......................................................................................................................92 
9.6 
Treatment Group Assignment ......................................................................................92 
9.7 
Study Procedures .........................................................................................................92 
9.7.1 
Patient Demographics ..........................................................................................92 
9.7.2 
Medical History ...................................................................................................92 
9.7.3 
Physical Examination ..........................................................................................92 
9.7.4 
Height and Weight ...............................................................................................93 
9.7.5 
Vital Signs ...........................................................................................................93 
9.7.6 
Pregnancy Testing ...............................................................................................93 
9.7.7 
Concomitant Medications and Procedures ..........................................................94 
9.7.8 
AE Monitoring .....................................................................................................94 
9.7.9 
ECOG Performance Status ..................................................................................94 
9.7.10 
Enrollment ...........................................................................................................94 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
10 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
9.7.11 
12-Lead ECG .......................................................................................................94 
9.7.12 
Pulmonary Function Testing ...............................................................................94 
9.7.13 
Patient Cards ........................................................................................................95 
9.7.13.1 PO Combination Agents Diary Card...........................................................95 
9.7.13.2 Subject Identification Card .........................................................................95 
9.7.14 
Clinical Laboratory Procedures and Assessments ...............................................95 
9.7.14.1 Clinical Laboratory Tests ............................................................................95 
9.8 
Study Compliance ........................................................................................................97 
9.9 
Disease Assessment .....................................................................................................97 
9.9.1 
Extramedullary Disease Imaging ........................................................................98 
9.9.2 
Bone Imaging ......................................................................................................98 
9.9.3 
Quantification of Igs ............................................................................................99 
9.9.4 
Quantification of M-Protein in Serum and Urine ................................................99 
9.9.5 
Serum FLC Assay ................................................................................................99 
9.9.6 
Immunofixation of Serum and Urine ..................................................................99 
9.9.7 
BMA ..................................................................................................................100 
9.9.7.1 
Local Laboratory Evaluations ...................................................................100 
9.9.7.2 
Central Laboratory Evaluations ................................................................100 
9.10 
Biomarker, PK, Pharmacodynamic, and Pharmacogenomics, Samples ....................101 
9.10.1 
Primary Specimen Collection for PK, Pharmacodynamic, and Biomarker 
Assessments .......................................................................................................101 
9.10.2 
PK Measurements ..............................................................................................102 
9.10.3 
 ..................................................................................102 
9.10.3.1 
 .........................................................................102 
9.10.3.2 
 .............................................................102 
9.10.4 
 ...................................................................103 
9.10.4.1 
 ..............................................................................103 
9.10.5 
Immunogenicity Sample Collection ..................................................................103 
9.11 
Criteria for Discontinuation or Withdrawal of a Subject ...........................................104 
9.12 
Procedures for Discontinuation or Withdrawal of a Subject .....................................105 
9.13 
Subject Replacement ..................................................................................................105 
9.14 
Completion of Study Treatment (for Individual Patients) .........................................105 
9.15 
Posttreatment Follow-up Assessments ......................................................................105 
10.0 
ADVERSE EVENTS .......................................................................................................105 
10.1 
Definitions and Elements of AEs ...............................................................................105 
10.1.1 
Pretreatment Event Definition ...........................................................................106 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
11 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
10.1.2 
AE Definition ....................................................................................................106 
10.1.3 
AESIs .................................................................................................................106 
10.1.4 
SAEs ..................................................................................................................106 
10.2 
Procedures for Reporting and Recording AEs and SAEs ..........................................107 
10.2.1 
Reporting AESIs ................................................................................................108 
10.3 
Monitoring AEs and Periods of Observation .............................................................108 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........109 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ...................................................................................................................109 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .........109 
11.0 
STUDY-SPECIFIC COMMITTEE .................................................................................109 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................110 
12.1 
eCRFs .........................................................................................................................110 
12.2 
Record Retention .......................................................................................................110 
13.0 
STATISTICAL METHODS ............................................................................................111 
13.1 
Statistical and Analytical Plans ..................................................................................111 
13.1.1 
Analysis Sets .....................................................................................................111 
13.1.1.1 Safety Analysis Set ...................................................................................111 
13.1.1.2 PK Analysis Set ........................................................................................111 
13.1.1.3 DLT-Evaluable Analysis Set ....................................................................111 
13.1.1.4 Response-Evaluable Analysis Set .............................................................111 
13.1.1.5 Immunogenicity-Evaluable Analysis Set ..................................................111 
13.1.1.6 MRD Analysis Set ....................................................................................112 
13.1.2 
Analysis of Demography and Other Baseline Characteristics ..........................112 
13.1.3 
Efficacy Analysis ...............................................................................................112 
13.1.3.1 Group 1: MM Maintenance .......................................................................112 
13.1.3.2 Group 2 and Group 3: RRMM Doublets and Triplets ..............................113 
13.1.4 
PK Analysis .......................................................................................................114 
13.1.5 
Immunogenicity Analyses .................................................................................114 
13.1.6 
Safety Analysis ..................................................................................................114 
13.1.6.1 TEAEs .......................................................................................................114 
13.1.6.2 Clinical Laboratory Evaluation .................................................................115 
13.1.6.3 Vital Signs .................................................................................................115 
13.1.6.4 Other Safety Parameters ............................................................................115 
13.2 
Interim Analysis and Criteria for Early Termination .................................................115 
13.3 
Determination of Sample Size ...................................................................................115 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
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Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................................116 
14.1 
Study-Site Monitoring Visits .....................................................................................116 
14.2 
Protocol Deviations ....................................................................................................116 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................116 
15.0 
ETHICAL ASPECTS OF THE STUDY .........................................................................117 
15.1 
IRB and/or IEC Approval ..........................................................................................117 
15.2 
Subject Information, Informed (e)Consent, and Subject Authorization ....................118 
15.3 
Subject Confidentiality ..............................................................................................119 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................119 
15.4.1 
Publication and Disclosure ................................................................................119 
15.4.2 
Clinical Trial Registration .................................................................................120 
15.4.3 
Clinical Trial Results Disclosure .......................................................................120 
15.5 
Insurance and Compensation for Injury .....................................................................120 
16.0 
REFERENCES ................................................................................................................121 
17.0 
APPENDICES .................................................................................................................124 
17.1 
Appendix A Schedules of Events ..............................................................................124 
17.2 
Appendix B Bone Marrow Collection and Assessment Schedules ...........................155 
17.3 
Appendix C PK Sampling ..........................................................................................158 
17.4 
Appendix D Responsibilities of the Investigator .......................................................159 
17.5 
Appendix E Elements of Informed Consent ..............................................................161 
17.6 
Appendix F Investigator Consent to the Use of Personal Information ......................164 
17.7 
Appendix G IMWG Definition of MM and Response Criteria .................................165 
17.8 
Appendix H ECOG Scale for Performance Status ....................................................168 
17.9 
Appendix I BOIN Design for Dose Escalation/De-escalation ...................................169 
17.10 Appendix J Protocol History ......................................................................................174 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
Reported Distribution of Human CD38 .....................................................29 
Table 6.a 
Arm 1: Modakafusp Alfa and Lenalidomide Dosing Schedule .................55 
Table 6.b 
Arm 2: Modakafusp Alfa and Pomalidomide Dosing Schedule ................56 
Table 6.c 
Modakafusp Alfa and Bortezomib Dosing Schedule.................................57 
Table 6.d 
Modakafusp Alfa, Bortezomib and Pomalidomide Dosing Schedule .......58 
Table 6.e 
Arm D: Modakafusp Alfa, Daratumumab and Pomalidomide Dosing 
Schedule .....................................................................................................59 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
13 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Table 6.f 
BOIN Design Decision Rule for Group 1: MM Maintenance and 
Group 2: RRMM Doublets ........................................................................61 
Table 6.g 
BOIN Design Decision Table for Group 3: RRMM Triplets ....................62 
Table 7.a 
Laboratory Values Required for Enrollment .............................................68 
Table 8.a 
Dose Modification Recommendations for Modakafusp Alfa 
Nonhematological Toxicities .....................................................................83 
Table 8.b 
Dose Modification Recommendations for Modakafusp Alfa 
Hematological Toxicities ...........................................................................83 
Table 8.c 
Dose Modification Recommendations for Modakafusp Alfa 
Bleeding TEAEs ........................................................................................84 
Table 8.d 
Dose Reduction Levels for Modakafusp Alfa ...........................................84 
Table 8.e 
Recommendations for Managing Grade 1 and Grade 2 IRRs ...................86 
Table 8.f 
Recommendations for Managing Grade ≥3 IRRs ......................................86 
Table 8.g 
Highly Effective and Effective Methods of Contraception .......................89 
Table 9.a 
Primary Specimen Collections .................................................................101 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Therapeutic Synergy of Modakafusp Alfa Combined With 
Lenalidomide (Revlimid) in NCI-H929 Mouse Xenograft Model ............39 
Figure 4.b 
Therapeutic Synergy of Modakafusp Alfa Combined With 
Lenalidomide (Revlimid) in OPM2 Mouse Xenograft Model ..................40 
Figure 4.c 
Activity of Modakafusp Alfa Combined With the IMiD 
Pomalidomide (Pomalyst) in NCI-H929 MM Xenograft Tumor 
Model .........................................................................................................42 
Figure 4.d 
Activity of Modakafusp Alfa Combined With the Proteasome 
Inhibitor Bortezomib (Velcade) in NCI-H929 MM Xenograft Tumor 
Model .........................................................................................................44 
Figure 4.e 
Therapeutic Synergy of Modakafusp Alfa Combined With the 
Proteasome Inhibitor Bortezomib (Velcade) in OPM2 Mouse 
Xenograft Model ........................................................................................44 
Figure 4.f 
Activity of Modakafusp Alfa Combined With the Anti-CD38 
Antibody Daratumumab in NCI-H929 MM Xenograft Tumor Model ......46 
Figure 6.a 
Schematic of Study Design ........................................................................53 
Figure 6.b 
Flowchart for Study Conduct Using the BOIN Design .............................60 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
14 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
LIST OF APPENDICES 
17.1 
Appendix A Schedules of Events ............................................................124 
17.2 
Appendix B Bone Marrow Collection and Assessment Schedules .........155 
17.3 
Appendix C PK Sampling ........................................................................158 
17.4 
Appendix D Responsibilities of the Investigator .....................................159 
17.5 
Appendix E Elements of Informed Consent ............................................161 
17.6 
Appendix F Investigator Consent to the Use of Personal Information ....164 
17.7 
Appendix G IMWG Definition of MM and Response Criteria ...............165 
17.8 
Appendix H ECOG Scale for Performance Status ..................................168 
17.9 
Appendix I BOIN Design for Dose Escalation/De-escalation .................169 
17.10 
Appendix J Protocol History ....................................................................174 
 
LIST OF APPENDIX TABLES 
Appendix A Table 1 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and 
Lenalidomide PO: Screening, Cycle 1, and Cycle 2 ................................124 
Appendix A Table 2 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and 
Lenalidomide PO: Cycle 3 and Beyond...................................................127 
Appendix A Table 3 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and 
Pomalidomide PO: Screening, Cycle 1, and Cycle 2...............................129 
Appendix A Table 4 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and 
Pomalidomide PO: Cycle 3 and Beyond .................................................132 
Appendix A Table 5 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and 
Bortezomib SC: Screening, Cycle 1, and Cycle 2 ...................................134 
Appendix A Table 6 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and 
Bortezomib SC: Cycle 3 and Beyond ......................................................137 
Appendix A Table 7 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV + 
Pomalidomide PO + Bortezomib SC: Screening, Cycle 1, and Cycle 
2................................................................................................................139 
Appendix A Table 8 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV+ 
Pomalidomide PO + Bortezomib SC: Cycle 3 and Beyond ....................142 
Appendix A Table 9 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV + 
Daratumumab SC + Pomalidomide PO: Screening, Cycle 1, and 
Cycle 2 .....................................................................................................144 
Appendix A Table 10 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV+ 
Daratumumab SC + Pomalidomide PO: Cycle 3 and Beyond ................147 
Appendix A Table 11 All Groups: EOT and Follow-up .............................................................149 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
15 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix B Table 1 Bone Marrow Collection and Assessment Schedule for Group 1: 
MM Maintenance Modakafusp Alfa and Lenalidomide ..........................155 
Appendix B Table 2 Bone Marrow Collection and Assessment Schedule for Group 2: 
RRMM Doublet Combinations ................................................................156 
Appendix B Table 3 Bone Marrow Collection and Assessment Schedule for Group 3: 
RRMM Triplet Combinations ..................................................................157 
Appendix I Table 1 
Simulation Settings for Arm 1: Modakafusp Alfa With 
Lenalidomide ...........................................................................................169 
Appendix I Table 2 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 1 as the Starting Dose .................................................170 
Appendix I Table 3 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 2 as the Starting Dose .................................................171 
Appendix I Table 4 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 3 as the Starting Dose .................................................172 
Appendix I Table 5 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 4 as the Starting Dose .................................................173 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
16 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc 
Compound: 
Modakafusp alfa (TAK-573) 
Title of Protocol: A Phase 1b Open-label Study to 
Evaluate the Safety and Tolerability of Intravenous 
Modakafusp Alfa as Part of Combination Therapy in 
Adult Patients With Multiple Myeloma 
EudraCT No: 2022-001418-20 
ClinicalTrials.gov Identifier: NCT05556616 
Study Number: TAK-573-1502 
Phase: 1b 
Study Design: 
This is a global multicenter, open-label, phase 1b study designed to evaluate the safety and tolerability of 
modakafusp alfa in combination therapy and to determine the recommended phase 2 dose (RP2D) of the 
combination therapy with modakafusp alfa in adult patients with multiple myeloma (MM). 
The study will be conducted in 3 groups: 
Group 1: MM in maintenance therapy. 
Group 2: Relapsed/refractory multiple myeloma (RRMM) doublets. 
Group 3: RRMM triplets. 
These groups will consist of 1 or more of the following combination therapy arms: 
Group 1: The MM maintenance combination will consist of a dose escalation/de-escalation of modakafusp alfa 
and lenalidomide guided by Bayesian Optimal Interval (BOIN) design. This group is designed to determine the 
recommended dose of modakafusp alfa in combination with lenalidomide as maintenance therapy in MM after 
autologous stem cell transplantation (ASCT). 
• 
Arm 1: Modakafusp alfa intravenous (IV) infusion in combination with lenalidomide orally (PO). 
Group 2: The RRMM doublet combinations, as listed below, will consist of a dose escalation/de-escalation of 
multiple doublet combination arms guided by BOIN design. The doublet combinations are designed to determine 
the recommended dose of modakafusp alfa with combination agents including, but not limited to, bortezomib 
and pomalidomide. Data will inform decisions regarding the respective triplet combination escalation/de-
escalation starting doses. 
• 
Arm 2 modakafusp alfa + pomalidomide: Modakafusp alfa IV infusion in combination with pomalidomide 
PO.  
• 
Arm 3 modakafusp alfa + bortezomib: Modakafusp alfa IV infusion in combination with bortezomib 
subcutaneous (SC). 
• 
Arm 4 modakafusp alfa + carfilzomib: Modakafusp alfa IV infusion in combination with carfilzomib IV 
(closed to enrollment). 
Group 3: The RRMM triplet combinations, as listed below, will consist of a dose escalation/de-escalation phase 
of multiple triplet combination arms guided by the doublet combination data, modakafusp alfa/daratumumab 
data from TAK-573-2001, and BOIN design. The triplet combinations are designed to determine the RP2D of 
modakafusp alfa with the 2 associated combination agents, thereby defining the triplet therapy dose. 
• 
Arm A modakafusp alfa + pomalidomide + bortezomib: Modakafusp alfa IV infusion in combination with 
bortezomib SC and pomalidomide PO.  
• 
Arm D modakafusp alfa + daratumumab + pomalidomide: Modakafusp alfa IV infusion in combination with 
pomalidomide PO and daratumumab SC. 
Duration of Study 
The treatment cycle duration is 28 days. Patients in Group 1 (MM maintenance) who are minimal/measurable 
residual disease (MRD)-negative (MRD[-]) may continue to receive modakafusp alfa in combination with 
lenalidomide until disease progression, unacceptable toxicity, or a maximum of 2 years for MRD[-] patients, 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
17 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
whichever occurs first. Patients who remain MRD-positive with demonstrated clinical benefit after 2 years of 
maintenance therapy may continue treatment beyond 2 years with agreement of the sponsor/designee. Patients in 
Groups 2 and 3 (RRMM doublets and RRMM triplets) may receive modakafusp alfa in combination with 
associated agents until disease progression, unacceptable toxicity, or until any other discontinuation criterion is 
met (Section 9.11), whichever occurs first. 
The follow-up phase of the study begins once a patient discontinues study treatment and completes the end-of-
treatment visit; study follow-up continues until the study ends or the patient completes overall survival (OS) 
follow-up. 
Primary Objectives 
Group 1: MM Maintenance  
• 
To determine the safety and tolerability of modakafusp alfa and lenalidomide combination therapy as 
maintenance in adult patients with MM after ASCT. 
• 
To determine the RP2D of the combination therapy with modakafusp alfa. 
Group 2 and Group 3: RRMM Doublets and Triplets 
• 
To determine the safety and tolerability of modakafusp alfa as part of either a 2- or 3-drug combination 
therapy in adult patients with RRMM. 
• 
To determine the RP2D of the combination therapy with modakafusp alfa (recommended doses of the 
doublet or triplet combinations). 
Secondary Objectives 
Group 1: MM Maintenance  
• 
To evaluate the preliminary efficacy of modakafusp alfa and lenalidomide combination therapy as 
maintenance in adult patients with MM after ASCT. 
• 
To evaluate rate and duration of MRD[-]. 
• 
To collect pharmacokinetic (PK) data to support population PK and exposure-response analysis of 
modakafusp alfa when given in combination therapy. 
• 
To characterize the immunogenicity profile of modakafusp alfa when given in combination therapy. 
Group 2 and Group 3: RRMM Doublets and Triplets 
• 
To evaluate the preliminary efficacy of modakafusp alfa as part of either a 2 or a 3-drug combination 
therapy in adult patients with RRMM. 
• 
To evaluate rate and duration of MRD[-]. 
• 
To collect PK data of modakafusp to support population PK and exposure-response analysis of modakafusp 
alfa when given in combination therapy. 
• 
To characterize the immunogenicity profile of modakafusp alfa when given in combination therapy. 
Patient Population: Patients aged 18 years or older with MM (Group 1) or RRMM (Groups 2 and 3). 
Number of Subjects: 
Approximately 120 patients will be enrolled. 
MM Maintenance: Approximately 18 patients (1 arm). 
RRMM Doublets: Approximately 66 patients. RRMM 
Triplets: Approximately 36 patients.  
Number of Sites:  
Approximately 50 sites globally.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
18 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Dose Level(s): 
Modakafusp alfa: 60, 80 (starting dose), 120, and 240 mg 
Lenalidomide: 10 mg, 15 mg 
Pomalidomide: 2 mg, 3 mg, 4 mg 
Bortezomib: 1.3 mg/m2 
Daratumumab: 1800 mg 
Route of Administration: 
Modakafusp alfa: IV infusion 
Lenalidomide: PO 
Pomalidomide: PO 
Bortezomib: SC 
Daratumumab: SC 
Duration of Treatment: For Group 1 (MM 
maintenance), patients may continue modakafusp alfa in 
combination with lenalidomide until disease progression, 
unacceptable toxicity, or a maximum of 2 years for 
MRD[-] patients, whichever occurs first. Patients who 
remain MRD positive with demonstrated clinical benefit 
after 2 years of maintenance therapy may continue 
treatment beyond 2 years with agreement of the 
sponsor/designee. 
For Group 2 and Group 3 (RRMM doublets and RRMM 
triplets), modakafusp alfa in combination with associated 
agents will be administered until disease progression or 
unacceptable toxicity, or until any other discontinuation 
criterion is met, whichever occurs first.  
Period of Evaluation: 5 years  
Main Criteria for Inclusion: 
All patients in Group 1 (MM maintenance: modakafusp alfa/lenalidomide) only must have: 
a) MM based on standard International Myeloma Working Group (IMWG) diagnostic criteria 
(Appendix G).  
b) Undergone ASCT for the treatment of MM within 12 months of the start of induction therapy and 
completed ASCT within 180 days before enrollment (regardless of the lines of treatment). 
Consolidation cycles are allowed. Tandem transplant is allowed.  
c) Not started lenalidomide maintenance before enrollment. Time to initiation of maintenance therapy: 
Patients may start maintenance therapy as early as 60 days after transplantation and up to 180 days after 
transplantation or consolidation. 
d) MRD positive after ASCT (MRD assessed at threshold of 10-5 by local standard-of-care methods or 
central assessment, if a prior local MRD assessment had not been performed). 
e) No prior progression after initial therapy (at any time before starting maintenance). Patients whose 
induction therapy was changed due to suboptimal response or toxicity will be eligible if they do not 
meet criteria for progression. In addition, no more than 2 regimens will be allowed before ASCT, 
excluding dexamethasone alone. 
f) 
No prior allogeneic hematopoietic stem cell transplant or solid organ transplant. 
g) Recovered to Grade ≤1 ASCT-related toxicities from the reversible effects of ASCT (except for 
alopecia and amenorrhea). MM based on standard IMWG diagnostic criteria. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
19 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
All patients in Group 2 and Group 3 (RRMM doublets and RRMM triplets) must have: 
a) Measurable disease, defined as at least 1 of the following:  
• 
Serum M-protein ≥0.5 g/dL (≥5 g/L) on serum protein electrophoresis. 
• 
Urine M-protein ≥200 mg/24 hours on urine protein electrophoresis. 
• 
Serum FLC assay result with an involved FLC level ≥10 mg/dL (≥100 mg/L), provided the serum 
FLC ratio is abnormal (per IMWG criteria).  
b) A confirmed diagnosis of MM according to IMWG criteria (Appendix G) with documented disease 
progression in need of additional therapy as determined by the investigator. 
c) For Group 2 RRMM doublet arms only: Patients who have received at least 3 prior lines of 
antimyeloma therapy, including at least 1 proteosome inhibitor (PI), 1 immunomodulatory drug (IMiD), 
and 1 anti-CD38 monoclonal antibody (mAb) drug, or who are triple refractory to a PI, and IMiD, and 
an anti-CD38 mAb drug regardless of the number of prior line(s) of therapy.  
d) For Group 3 RRMM triplet arms only: Patients who have received 1 to 3 prior lines of antimyeloma 
therapy, including at least 1 PI and 1 IMiD, and who are not refractory* to the combination partners. 
e) For anti-CD38 arms, forced expiratory volume in 1 second ≥50% predicted by pulmonary function 
testing. 
NOTES: 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a combination 
of several drugs, or a planned sequential therapy of various regimens. (For example, 3-6 cycles of initial 
therapy with bortezomib-dexamethasone followed by a stem cell transplantation, consolidation, and 
maintenance is considered 1 line.) 
* Refractory myeloma is defined as disease that is nonresponsive while the patient is receiving primary 
or salvage therapy or progresses within 60 days of last therapy. Nonresponsive disease is defined as 
either failure to achieve at least minimal response or development of PD while on therapy (Rajkumar et 
al. 2011).  
Main Criteria for Exclusion: 
1. The patient is currently participating in another MM interventional study. 
2. The patient received previous treatment with modakafusp alfa. 
3. The patient has a diagnosis of primary amyloidosis, Waldenström disease, monoclonal gammopathy of 
undetermined significance or smoldering MM per IMWG criteria or standard diagnostic criteria, plasma cell 
leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and 
skin changes), lymphoplasmacytic lymphoma. 
4. The patient has had another 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 and that in the opinion of the local investigator, with concurrence with the principal 
investigator, is considered cured with minimal risk of recurrence within 3 years. 
5. The patient has evidence of central nervous system involvement and/or meningeal involvement due to MM 
exhibited during screening. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
20 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Endpoints: 
The primary endpoints of the study for Groups 1, 2, and 3 (MM maintenance, RRMM doublets, and RRMM 
triplets) are occurrence of dose-limiting toxicities (DLTs) in Cycle 1 and frequency and severity of treatment-
emergent adverse events (TEAEs). 
Secondary endpoints are as follows: 
Group 1 MM Maintenance: Progression-free survival (PFS); overall response rate (ORR) (per investigator 
assessment); duration of response (DOR); rate of MRD[-] at a threshold of 10-5 at 6 months, 1 year, and 2 years 
after treatment; duration of MRD[-] at a threshold of 10-5 in patients achieving MRD[-]; and antidrug antibody 
(ADA) incidence and characteristics (eg, titer and specificity) and neutralizing antibody (NAb). 
Group 2 and Group 3 RRMM Doublets and Triplets: OS, ORR, PFS, time to progression (TTP), time to next 
treatment (TTNT), DOR, disease control rate (DCR), event-free survival (EFS), time to response (TTR), rate of 
MRD[-] complete response (CR) at a threshold of 10-5 with CR assessed by the investigator, rate of MRD[-] at a 
threshold of 10-5 , duration of MRD[-] at a threshold of 10-5 in patients achieving MRD[-], and ADA incidence 
and characteristics (eg, titer and specificity) and NAb. 
Statistical Considerations: 
Safety will be evaluated by the frequency of adverse event (AEs), severity, types of AEs, and changes from 
baseline in patients’ vital signs, weights, and clinical laboratory results using the safety analysis set.  
Group 1: MM Maintenance: PFS will be analyzed using the safety analysis set and summarized using the 
Kaplan-Meier (KM) method. ORR will be analyzed using the response-evaluable analysis set, and rate of 
MRD[-] will be analyzed on the basis of the MRD analysis set. Both endpoints will be summarized with 2-sided 
95% exact binomial CIs. Duration of MRD[-] will be analyzed in patients achieving MRD[-] using the KM 
method.  
Group 2 and Group 3 RRMM Doublets and Triplets: ORR and DCR will be analyzed using the response-
evaluable analysis set and summarized with 2-sided 95% exact binomial CIs. DOR and TTR will be analyzed for 
responders only. DOR will be summarized using KM method, and descriptive summary will be provided for 
TTR as a continuous variable. OS, PFS, EFS, TTP, and TTNT will be analyzed using the safety analysis set and 
summarized using KM method. Rate of MRD[-] CR will be analyzed for both the MRD-evaluable analysis set 
and the safety analysis set and summarized with 2-sided 95% exact binomial CIs. Rate of MRD[-] will be 
analyzed for the safety analysis set and summarized with 2-sided 95% exact binomial CIs. Duration of MRD[-] 
will be analyzed in patients achieving MRD[-] using KM method. 
Sample Size Justification: The BOIN design will be implemented. The target toxicity rate for MTD is set to be 
ϕ = 0.25 for MM maintenance and RRMM doublets and ϕ = 0.33 for RRMM triplets. Patients will be enrolled 
and treated in cohort sizes of approximately 3. It is estimated that a total of approximately 120 DLT-evaluable 
patients will be enrolled : approximately 18 for MM maintenance (Arm 1), approximately 66 for RRMM doublet 
combinations, and approximately 36 for RRMM triplet combinations. Please see Appendix I for further details. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
21 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
3.0 
STUDY REERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those performed by the 
study vendors. The identified vendors will perform specific study-related activities in full or in 
partnership with the sponsor. 
3.2 
Principal/Coordinating 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. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
22 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
3.3 
List of Abbreviations 
List of Abbreviations 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBs 
antibodies to hepatitis B surface antigen 
ASCT 
autologous stem cell transplantation 
AST 
aspartate aminotransferase 
auto-HSCT 
autologous hematopoietic stem cell transplantation 
BIW 
twice weekly 
BMA 
bone marrow aspirate, bone marrow aspiration 
BOIN 
Bayesian Optimal Interval 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CRS 
cytokine release syndrome  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVd 
bortezomib in combination with daratumumab and dexamethasone 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram electrocardiographic 
ECOG 
Eastern Cooperative Oncology Group 
eConsent 
electronic consent 
EDC 
electronic data capture 
eCRF 
electronic case report form  
EFS 
event-free survival  
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FLC 
free light chain 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
23 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
List of Abbreviations 
G-CSF 
granulocyte-colony stimulating factor 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
IB 
investigator’s brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IFN 
interferon 
IFN-α 
interferon alpha 
IFN-α2b 
interferon alpha 2b 
IFNAR 
interferon alpha receptor 
IFN-γ 
interferon gamma 
IL 
interleukin 
IMiD 
immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IP 
intraperitoneal(ly) 
IRB 
institutional review board 
IRR 
infusion-related reaction 
ISF 
Investigator Site File 
IV 
intravenous(ly) 
IVIG 
intravenous immunoglobulins 
KD 
binding affinity  
KM 
Kaplan-Meier 
mAb 
monoclonal antibody 
MDP 
modakafusp alfa + daratumumab + pomalidomide 
MedDRA 
Medical Dictionary for Regulatory Activities 
MK 
modakafusp alfa + carfilzomib 
MKP 
modakafusp alfa + carfilzomib + pomalidomide 
MM 
multiple myeloma  
MP 
modakafusp alfa + pomalidomide 
MPV 
modakafusp alfa + pomalidomide + bortezomib 
MRD 
measurable/minimal residual disease  
MRD[-] 
measurable/minimal residual disease-negative, measurable/minimal residual disease negativity 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MV 
modakafusp alfa + bortezomib 
NAb 
neutralizing antibody  
NCI 
National Cancer Institute 
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List of Abbreviations 
NDMM 
newly diagnosed multiple myeloma 
NK 
natural killer 
ORR 
overall response rate  
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PET-CT 
positron emission tomography–computed tomography 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PK 
pharmacokinetic(s) 
PO 
oral(ly) 
PR 
partial response 
PTA 
posttrial access 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QD 
once daily 
RBC 
red blood cell 
REMS 
Risk Evaluation and Mitigation Strategy 
RP2D 
recommended phase 2 dose 
RRMM 
relapsed/refractory multiple myeloma 
SAE 
serious adverse event 
SAR 
serious adverse reaction 
SC 
subcutaneous(ly) 
sCR 
stringent CR 
SOC 
standard-of-care 
SOE 
schedule of events 
SPEP 
serum protein electrophoresis 
SUSAR 
suspected unexpected serious adverse reaction 
SVd 
bortezomib/selinexor/dexamethasone 
 
 
TEAE 
treatment-emergent adverse event 
TMA 
thrombotic microangiography 
TNF-α 
tumor necrosis factor alpha 
TTNT 
time to next treatment 
TTP 
time to progression 
TTR 
time to response 
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List of Abbreviations 
UK 
United Kingdom 
UPEP 
urine protein electrophoresis 
US 
United States 
Vd 
bortezomib in combination with dexamethasone 
VGPR 
very good partial response 
VMP 
bortezomib in combination with melphalan/prednisone 
 
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3.4 
Corporate Identification 
Takeda 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
TDC Americas 
Takeda Development Center Americas, Inc 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Centre Europe Ltd 
TDC Japan 
Takeda Development Center Japan 
 
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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 that accounts for 10% of hematologic 
malignancies. According to statistics from the Global Cancer Observatory, there were an 
estimated 160,000 cases of MM globally in 2018. From 1990 to 2006, the global incidence of 
MM increased by 126% (Cowan et al. 2018). The incidence of MM is higher in male, black 
American, African American, and elderly populations. The median age at diagnosis is 69 years 
with only 3.1% of patients less than 45 years at diagnosis. It occurs slightly more frequently in 
males (8.8% in males versus 5.7% in females). MM incidence rate and mortality rate are twice as 
common in the black American and African American population compared with the white 
population (age-adjusted incidence rate and mortality rate of 13.8% and 6%, respectively, in the 
black American and African American population compared with 6.5% and 3%, respectively, 
among the white population (seer.cancer.gov/csr/1975_2018/, SEER Cancer Statistics Review, 
1975-2018. National Cancer Institute, Bethesda, MD, Accessed March 15, 2022). This racial 
disparity is related to the higher prevalence of monoclonal gammopathy of undetermined 
significance in black American and African American populations (Rajkumar and Kumar 2016). 
The 5-year survival rate of patients with MM is approximately 45% (Aletaha et al. 2008). MM 
persists as a mostly incurable disease because of its highly complex and diverse cytogenetic and 
molecular abnormalities (Chapman et al. 2011). The outcome for patients with MM patients has 
improved in the last decade with the discovery, development, and approval of proteasome 
inhibitors (PIs) (eg, bortezomib) and immunomodulatory drugs (IMiDs) (eg, lenalidomide), but 
patients whose disease becomes refractory or who are ineligible to receive bortezomib and 
IMiDs have an unfavorable prognosis (Kumar et al. 2012). Substantial progress in treatment has 
been made with recent approvals of biologic agents with newer mechanisms of action, such as 
anti-CD38 monoclonal antibody (mAb) drugs including daratumumab and isatuximab (Darzalex 
Faspro (daratumumab and hyaluronidase-fihj) injection for subcutaneous use 2021; 
Sarclisa (Isatuximab) 2020), belantamab mafodotin (BCMA [B-cell maturation antigen]–
targeting antibody drug conjugate) (Abecma (idecabtagene vicleucel) suspension for intravenous 
infusion 2021), and idecabtagene vicleucil (chimeric antigen receptor T-cell therapy) (Abecma 
(idecabtagene vicleucel) suspension for intravenous infusion 2021). Despite these recent 
advances, there is still a need for the development of novel targeted therapies that act in safe and 
effective ways against MM cells and are able to overcome certain limitations of current 
therapies. 
4.2 
Modakafusp Alfa (TAK-573) 
4.2.1 Mechanism of Action 
Modakafusp alfa is a first-in-class innate immunity enhancer that functions through the induction 
of targeted type I interferon (IFN) signaling in immune cells and MM cells. It is a recombinant 
humanized immunoglobulin (Ig)G4 anti-CD38 mAb fused to attenuated interferon alpha 2 beta 
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(IFN-α2b) that is produced by recombinant DNA technology in a mammalian cell expression 
system and is purified by a process that includes specific viral inactivation and removal steps. 
The CD38 antibody portion of modakafusp alfa directs the attenuated interferon alpha (IFN-α) 
portion to CD38+ cells, thus achieving a high local concentration on IFN-α2b at the surface of 
these target cells. On CD38 cells, the attenuation results in approximately 130,000-fold reduced 
potency compared with IFN-α2b. 
Modakafusp alfa binds with high affinity to human and cynomolgus CD38, with a binding 
affinity (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 
[IC50] = 19.9 pM), whereas potency on CD38 nonexpressing (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). IFN-
α2b (Intron A), by comparison, has similar potency to modakafusp alfa on CD38+ cells 
(IC50 = 12.3 pM), but on CD38– cells, it is approximately 130,000-fold more potent than 
modakafusp alfa (half-maximal effective concentration [EC50] ~0.37 pM). 
Through the induction of targeted IFN signaling, modakafusp alfa activates innate and adaptive 
immune cells and elicits direct antiproliferative and apoptotic signals in MM cells, which have 
the potential to help patients with MM. 
4.2.2 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. 2001). Being highly expressed on the myeloma cell 
surface and not highly expressed on normal cells makes CD38 an appropriate target for 
antibodies conjugated with cytokines, radioisotopes (Green et al. 2014), or toxins 
(Bolognesi et al. 2005; Goldmacher et al. 1994). One cytokine of particular interest is IFN-α, 
which was used in MM as a maintenance treatment option following primary treatment and 
autologous or allogeneic stem cell transplantation. IFN-α shows direct inhibitory effects on some 
tumors, including myeloma, and it is a potent stimulator of both the innate and adaptive immune 
systems. However, systemic toxicity of IFN-α precludes the use of the cytokine at therapeutically 
effective doses for most patients. By reducing the KD of IFN-α for its receptor, interferon alpha 
receptor (IFNAR), modakafusp alfa is expected to reduce binding of IFN-α to IFNAR on 
nontargeted, CD38– cells. 
In contrast, binding of modakafusp alfa with high affinity via its CD38-targeting moieties is 
expected to increase the local concentration of attenuated IFN-α on CD38+ target cells, thereby 
inducing desired on-target IFNAR binding and subsequent IFN pathway activation. Additionally, 
IFN-α pathway activation induces upregulation of CD38 expression 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 and thus 
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overcome 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 overexpressed 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). It is an approximately 45 kDa transmembrane 
glycoprotein expressed by immature hematopoietic cells, which is downregulated 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 that 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 (Deaglio et al. 2008) reviewed the main tissues 
and cells where CD38 is present and these findings are summarized in Table 4.a. CD38 is also 
found in a soluble form in normal and pathological fluids (Funaro et al. 1996). 
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, and natural killer cells, 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). 
4.2.3 Nonclinical and Toxicology Studies 
Brief summaries of nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies are 
provided in the following sections. More detailed information is provided in the IB. 
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4.2.3.1 Nonclinical Studies 
4.2.3.1.1 Pharmacology Related to the Proposed Mechanism of Action 
Modakafusp alfa effectively induces apoptosis in high-expressing CD38+ human myeloma cells 
as demonstrated in a caspase activation assay (EC50 = 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 [TNF-α], interleukin (IL)-6, IL-8, 
interferon gamma [IFN-γ], and IL-2) from human PBMCs in vitro, less than or comparable to 
that reported with palivizumab (IgG1 against the respiratory syncytial virus). 
In several human myeloma xenograft models, modakafusp alfa induced complete regressions at 
tolerable doses. A single modakafusp alfa dose of 10 mg/kg in the National Cancer Institute 
(NCI) H929 human myeloma xenograft model resulted in complete regression in all treated 
animals. In comparative xenograft studies, modakafusp alfa showed greater efficacy relative to 
established myeloma therapies, including bortezomib, lenalidomide, and daratumumab. 
Furthermore, under conditions of suboptimal activity of modakafusp alfa, strong synergy has 
been observed with other standard MM treatment agents such as bortezomib and lenalidomide. 
4.2.3.1.2 Safety Pharmacology 
No stand-alone safety pharmacology studies have been conducted with modakafusp alfa. 
However, in a Good Laboratory Practice (GLP) repeat-dose toxicity study in cynomolgus 
monkeys (Report DS-2015-055), central nervous system (CNS), cardiovascular, and respiration 
endpoints were included, in line with the ICH Guidance S6 (R1) for biotechnology products. No 
modakafusp alfa–related cardiovascular or CNS findings were identified at doses up to 30 mg/kg 
(the highest dose level tested). Increases in respiratory rate observed in the pivotal GLPcompliant 
repeat-dose study on Day 22 were attributed to effects secondary to the antidrug antibody (ADA) 
response. 
4.2.3.1.3 PK and Product Metabolism in Animals 
The PK of modakafusp alfa were characterized in CB17 SCID (severe combined 
immunodeficiency) mice bearing H929 human MM tumor and in cynomolgus monkeys. In mice, 
modakafusp alfa exhibited dose-proportional exposure following intraperitoneal (IP) injection at 
3 and 10 mg/kg dose levels. The t1/2 (terminal disposition phase half-life) of modakafusp alfa 
was 82 to 100 hours (Report TPA-38-021). In monkeys, modakafusp alfa exhibited a greater than 
dose proportional exposure following 1-hour intravenous (IV) infusions over a 3 to 30 mg/kg 
dose range (Reports DS-2014-055, DS-2014-097, and DS-2015-055). The mean systemic 
clearance was 7.54, 3.05, 2.38, and 1.24 mL/h/kg at 3, 10, 20, and 30 mg/kg, respectively. The 
mean volume of distribution during the terminal disposition phase after IV administration ranged 
between 57 and 70 mL/kg in all dose groups, suggesting that modakafusp alfa is confined to a 
large extent to the circulatory system. The estimated mean t1/2 (half-life) value ranged from 9.97 
to 33.8 hours over the 3 to 30 mg/kg dose range. There were no noteworthy sex-related 
differences in toxicokinetic parameter values. 
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4.2.3.2 Toxicology Studies 
A series of toxicology studies were conducted in the cynomolgus monkey with a 1-hour IV 
infusion of modakafusp alfa, including a single-dose exploratory study; an exploratory 
repeat-dose, range-finding study with weekly and twice-weekly (BIW) dosing; a GLP-compliant, 
once weekly, 29-day repeat-dose study with a 14-day recovery period and safety pharmacology 
endpoints; and a second 4-week, GLP-compliant, repeat-dose study with once-weekly dosing. 
Monkeys are the only relevant nonclinical species identified based on the binding of modakafusp 
alfa to CD38 from various species.  
No remarkable toxicity was noted following a single 1-hour IV infusion of modakafusp alfa at 
dose levels up to 20 mg/kg. Neopterin levels (a biomarker of IFN biological activity) were 
increased at 24 hours postdose and were still above baseline at up to 240 hours postdose. Slight 
decreases in leukocytes driven primarily by decreases in lymphocytes, and transient slight 
increases in liver parameters (alanine aminotransferase [ALT] and aspartate aminotransferase 
[AST]) were also observed. 
In repeat-dose studies longer than 14 days, in addition to similar findings as described above, 
ADA-mediated loss of exposure and hypersensitivity reactions were observed that resulted in 
early mortalities at ≥10 mg/kg. However, these reactions are considered poorly predictive of a 
human health risk. 
Tolerability was also assessed in a pharmacology combination study of modakafusp alfa with 
lenalidomide (Report H929-e284), pomalidomide (Report H929-e285), and daratumumab 
(Report H929-e324) in female CB17 SCID mice bearing H929 xenografts. No modakafusp alfa- 
or combination related mortality, clinical signs, or body weight effects were noted. 
4.2.4 Clinical Experience 
Clinical studies are ongoing with modakafusp alfa as a single agent in adult patients with 
relapsed or refractory multiple myeloma (RRMM) (Study TAK-573-1501) and with modakafusp 
alfa as a single agent and in combination with pembrolizumab in adult patients with advanced or 
metastatic solid tumors (TAK-573-1001). TAK-573-2001 is a newly opened study evaluating the 
safety, tolerability, PK, pharmacodynamics, and efficacy of modakafusp alfa in combination 
with daratumumab in patients with RRMM.  
4.2.4.1 TAK-573-1501 
The first-in-human study TAK-573-1501, “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,” enrolled the first 
patient on 09 October 2017. As of the data cutoff date of 22 October 2021, 90 subjects have been 
enrolled into the study. 
This study is being conducted in 3 parts: Part 1 is dose escalation, Part 2 is dose expansion, and 
Part 3 is designed as an extension study to assess safety and efficacy. The phase 1 single agent 
portion of the study follows a 3 + 3 dose escalation design to determine a maximum tolerated 
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dose (MTD) based on the observation of dose-limiting toxicities (DLTs) or an optimal biologic 
dose. 
Part 1 of Study TAK-573-1501 involved extensive dose escalation with 10 modakafusp alfa dose 
levels ranging from 0.001 mg/kg to 6.0 mg/kg on 4 different dosing schedules and included a 
total of 54 patients. The optimal schedule for modakafusp alfa in MM patients was assessed as 
once every 4 weeks (Q4W) based on the recovery time of hematological toxicities. The MTD at 
this schedule was established as 3 mg/kg as 6 mg/kg exceeded the MTD with 2 DLTs (NCI 
Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0 Grade 3 infusion-
related reaction [IRR] and prolonged Grade 4 thrombocytopenia and neutropenia, resulting in a 
greater than 2-week delay in start of Cycle 2). No DLTs were seen at 3 mg/kg. Preliminary 
efficacy activity was also seen in dose escalation, with 1 partial response (PR) and 2 minimal 
responses in 5 patients at 1.5 mg/kg on the Q4W schedule and 1 PR and 1 complete response 
(CR) (patient ongoing at Cycle 21) in 7 patients at 3 mg/kg on the Q4W schedule.  
The primary objective of Part 2 of Study TAK-573-1501 (dose expansion) is to provide a 
preliminary evaluation of the clinical activity of 1 or more schedules of single-agent modakafusp 
alfa. Additional cohorts in combination with dexamethasone are to be carried out with one or 
more selected schedules. 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. 
As of the data cutoff of 17 November 2022, 100 patients have been enrolled into Parts 1 and 2 of 
Study TAK-573-1501, and 22 patients have been enrolled into Part 3 as of 14 December 2022. 
The optimal schedule for modakafusp alfa was determined to be Q4W based on the recovery 
time of hematological toxicities, and the MTD is 3 mg/kg, which was exceeded at 6 mg/kg with 
2 DLTs (1 event of thrombocytopenia and neutropenia and 1 event of Grade 3 IRR).  
In the 1.5 mg/kg treatment group (N = 30), 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%, with only 2 events (2.2%) 
Grade ≥3. Toxicities have been managed with dose delays and supportive care and have rarely 
resulted in study drug discontinuation or dose reduction. 
Based on overall study data, 11 of 85 immunogenicity-evaluable patients (13%) tested ADA 
positive and 4 of the 85 immunogenicity-evaluable patients (5%) tested NAb positive at the 
beginning of the study before modakafusp alfa treatment (ie, at baseline). After initiation of 
modakafusp alfa treatment (ie, after treatment), 49 of 85 immunogenicity-evaluable patients 
(58%) were ADA positive and 36 of 85 immunogenicity-evaluable patients (42%) were NAb 
positive at least 1 posttreatment visit, with 48% of the immunogenicity-evaluable patients having 
treatment-induced ADA and 6% having treatment-boosted ADA. The incidence of patients who 
tested ADA positive post-treatment was similar across the dose groups. The maximum 
posttreatment titers for ADA-positive patients ranged from 75 to 1,480,000. 
In terms of potential impact of immunogenicity outcomes, modakafusp alfa Cmax tended to be 
lower in ADA-positive patients than ADA-negative patients. The degree of reduction tended to 
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increase as the study duration increased and the magnitude of immunogenicity increased. The 
reduction in Cmax may be partly due to the potential interference of high-tittered ADA in the 
modakafusp alfa unbound PK assay. The impact of immunogenicity on modakafusp alfa PK 
remains to be further characterized. 
The potential impact of the ADA and NAb on PK, safety, efficacy, and clinical endpoints will be 
further evaluated in this and future studies. 
Integrated dose- and exposure-response relationships based on preliminary pharmacodynamic 
(eg, serum M-protein and free light chain [FLC]), efficacy, and safety data indicate that 1.5 and 
3 mg/kg Q4W dosing are within the optimal biological dose range. The 1.5 mg/kg Q4W dose 
group (N = 30) demonstrated an objective response rate of 43.3% and a clinical benefit rate 
(CBR) of 53.3%. Although median duration of response (DOR) has not been reached, 7 patients 
have had a response >6 months and are being followed up to assess durability and deepening of 
response. Given the small sample size at the 3 mg/kg dose, the possibility of improved clinical 
benefit at a dose of 3 mg/kg compared with 1.5 mg/kg cannot be ruled out; therefore, a 2-dose 
randomization is planned (Part 3) to identify the optimal dose of single-agent modakafusp. Part 3 
(extension phase) of Study TAK-573-1501 is designed as a noncomparative 2-arm study (118 
patients planned in each arm) that randomizes patients to modakafusp alfa 120 or 240 mg (the 
fixed-dose equivalents of 1.5 and 3.0 mg/kg, respectively) to assess response rates, DOR, and 
safety to identify the modakafusp alfa dose with the optimal benefit-risk profile. As of the data 
cutoff of 14 December 2022, 22 patients have been enrolled in Part 3. The primary endpoint is 
the confirmed objective response rate assessed by an independent review committee according to 
the International Myeloma Working Group (IMWG) Uniform Response Criteria 
(Kumar et al. 2016). In addition, the efficacy of modakafusp alfa will be assessed by measuring 
EFS, progression-free survival (PFS), time to response (TTR), DOR, time to progression (TTP), 
and overall survival (OS). 
4.2.4.2 TAK-573-1001 
TAK-573-1001, “An Open-Label, Dose-Escalation Phase 1b/2 Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor activity of Modakafusp Alfa 
(TAK-573) as a Single Agent and in Combination with Pembrolizumab in Adult Patients with 
Advanced or Metastatic Solid Tumors,” is an ongoing study in patients with histologically 
confirmed advanced or metastatic solid tumors. As of the data cutoff of 23 November 2021, 
21 patients have been enrolled into modakafusp alfa single-agent treatment cohorts ranging from 
0.1 to 1.5 mg/kg once every 3 weeks (Q3W). 
As of Protocol Amendment 6 (28 July 2022), the study consists of 2 phases. The phase 1b 
dose-escalation portion of the study enrolled patients with advanced/metastatic solid tumors to 
determine the single-agent recommended phase 2 dose (RP2D) and schedule of modakafusp alfa 
for further testing. Enrollment into the phase 2 expansion portion of the study was initiated once 
the RP2D of modakafusp alfa was determined in phase 1b of the study. The phase 2 part is 
assessing modakafusp alfa in combination with pembrolizumab, beginning with a safety-lead in 
period to evaluate safety and tolerability of the combination during the Cycle 1 DLT evaluation 
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period. Following completion of the safety lead-in phase and review of safety data, the 
combination cohorts are enrolling patients with unresectable/metastatic melanoma in 
3 subgroups: patients with primary resistance to no more than 2 prior lines of treatments 
containing anti–programmed cell death protein 1 (PD-1) in the metastatic setting, patients with 
acquired resistance to no more than 2 prior lines of anti-PD1–containing treatments in the 
metastatic setting, and patients naïve to prior line of anti-PD1–containing treatments in the 
metastatic setting. 
As of the data cutoff of 23 October 2022, a total of 28 patients have been enrolled in the study: 
21 in the phase 1b dose escalation, 3 in the phase 2 safety lead-in, and 4 in the phase 2 expansion 
portion. The phase 1b dose-escalation portion treated patients with single-agent modakafusp alfa 
doses ranging from 0.1 to 1.5 mg/kg Q3W. A total of 2 DLTs were identified across all dose 
levels, both occurring at the 1.5 mg/kg dose: Grade 4 thrombocytopenia and Grade 3 confusion 
(n = 1 each). The MTD was determined to be 1.5 mg/kg Q3W based on protocol-defined MTD 
declaration rules following a Bayesian Logistic Regression Model. The RP2D was determined to 
be 1.0 mg/kg Q3W, and the PAD range was determined to be 0.1 to 1.5 mg/kg Q3W.  
Based on the available data as of August 2022, 1 of 19 (12%) and 19 of 19 (100%) of the 
immunogenicity-evaluable patients (ie, patients with ADA evaluated at baseline and at least 
1 posttreatment visit) with solid tumors had positive ADA assays at baseline and after treatment, 
respectively. No dose response on the ADA incidence and titer was observed. The first incidence 
of posttreatment ADA was reported as early as Cycle 2 Day 1 (earliest posttreatment sampling), 
and both transient and persistent ADA were observed. The ADA titer ranged from 75 to 
1,480,000. 
The potential impact of the ADA and NAb on PK, pharmacodynamics, safety, efficacy will be 
further evaluated in this and future studies.  
4.2.4.3 TAK-573-2001 
TAK-573-2001, “A Phase 1/2a Open-label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of Modakafusp Alfa in Combination with 
Daratumumab SC in Patients With Relapsed or Refractory Multiple Myeloma” is a newly 
opened study in patients with RRMM. The first part of the study is designed to assess the safety 
and tolerability of modakafusp alfa and daratumumab administered subcutaneously (SC). The 
data from TAK-573-2001 will guide the TAK-573-1502 dose escalation/de-escalation phase of 
multiple triplet combination arms. 
4.2.4.4 TAK-573-1502 Arm 4  
As of 27 April 2023, 3 patients had been enrolled in the Arm 4 (modakafusp alfa 80 mg on 
Day 1 and carfilzomib 20/70 mg/m2). This cohort was stopped and closed due to SAEs in the 
first 3 patients treated. These events consisted of 2 cases of thrombotic microangiopathy (TMA) 
resulting in hemolytic uremic syndrome and 1 case of acute myocardial infarction. TMA is a 
known risk with carfilzomib; however, with 2 of 3 initial patients experiencing TMA, a potential 
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synergistic interaction between carfilzomib and modakafusp alfa resulting in an increased 
incidence of TMA cannot be excluded. These cases are described in the IB. 
4.3 
Combination Agents 
4.3.1 Lenalidomide 
Lenalidomide is an analog of thalidomide with immunomodulatory, antiangiogenic, and 
antineoplastic properties. Cellular activities of lenalidomide are mediated through its target, 
cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. Lenalidomide 
inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM 
(Revlimid (lenalidomide) 2021). 
Lenalidomide has been indicated for the treatment of adult patients with MM in combination 
with dexamethasone since 2006. It was also approved as maintenance following autologous 
hematopoietic stem cell transplantation (auto-HSCT). 
4.3.2 Pomalidomide 
Pomalidomide is a thalidomide analog with immunomodulatory, antiangiogenic, and 
antineoplastic properties. Cellular activities of pomalidomide are mediated through its target 
cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. Pomalidomide 
inhibited the proliferation of lenalidomide-resistant MM cell lines. Pomalidomide enhanced 
T-cell– and NK cell–mediated immunity and inhibited production of proinflammatory cytokines 
by monocytes (Pomalyst (pomalidomide) Capsules 2020). 
Pomalidomide was approved in combination with dexamethasone for patients with MM who 
have received at least 2 prior therapies, including lenalidomide and a PI, and had demonstrated 
disease progression on or within 60 days of completion of the last therapy. 
In patients with RRMM, pomalidomide is indicated in combination with 
daratumumab/dexamethasone in patients who have received at least 1 prior line of therapy 
including lenalidomide and a PI (Darzalex Faspro (daratumumab and hyaluronidase-fihj) 
injection for subcutaneous use 2021). Pomalidomide is also used as part of different regimens in 
combination with bortezomib/dexamethasone, carfilzomib/dexamethasone, 
daratumumab/dexamethasone, or ixazomib/dexamethasone in RRMM patients 
(Moreau et al. 2021). 
4.3.3 Bortezomib 
Bortezomib is a boronic acid PI which is cytotoxic to a variety of cancer cell types in vitro. 
Bortezomib delays tumor growth in vivo in nonclinical tumor models, including MM. 
Bortezomib is indicated for treatment of adult patients with MM (Velcade (bortezomib) for 
Injection 2019). In previously untreated MM patients, bortezomib is approved in combination 
with melphalan/prednisone (VMP) (Velcade (bortezomib) for Injection 2019). Bortezomib is 
indicated for the treatment of adult patients with MM in combination with 
daratumumab/melphalan/prednisone (ie, DVMP) in patients with newly diagnosed multiple 
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myeloma (NDMM) who are ineligible for autologous stem cell transplantation (ASCT) and in 
combination with daratumumab/thalidomide/dexamethasone (DVTd) in NDMM patients who 
are eligible for ASCT (Darzalex Faspro (daratumumab and hyaluronidase-fihj) injection for 
subcutaneous use 2021). In patients with RRMM, bortezomib is indicated in combination with 
daratumumab and dexamethasone (DVd) (Darzalex Faspro (daratumumab and 
hyaluronidase-fihj) injection for subcutaneous use 2021), or with selinexor/dexamethasone 
(SVd) (Xpovio (selinexor) tablets for oral use 2021). Bortezomib is also used in patients with 
RRMM as part of several different regimens in combination with pomalidomide/dexamethasone 
(PVd), thalidomide/dexamethasone, cyclophosphamide/dexamethasone (VCd), 
melphalan/prednisone (VMP), or with dexamethasone (Vd) (Moreau et al. 2021). 
4.3.4 Daratumumab and Hyaluronidase-fihj 
Daratumumab is an IgG1ĸ human mAb that binds to CD38 antigens and inhibits the growth of 
CD38expressing tumor cells by inducing apoptosis directly through Fc (fragment crystallizable) 
mediated cross-linking as well as by immune-mediated tumor cell lysis through 
complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and 
antibody-dependent cellular phagocytosis. 
Daratumumab and hyaluronidase-fihj is a combination of daratumumab, a CD38-directed 
cytolytic antibody, and hyaluronidase, which is an englycosidase that is approved as a 
monotherapy and in combination with standard antimyeloma therapies for patients with MM 
(Darzalex (daratumumab) injection for intravenous use 2021). 
4.4 
Rationale for the Proposed Study 
4.4.1 Modakafusp Alfa 
The use of combination strategies is a mainstay of myeloma treatment. Partnering with agents 
such as PIs and IMiDs for additive or synergistic effects by combining different mechanisms of 
action allows the targeting of multiple pathways in 1 regimen. 
Despite recent advances in the MM field, including the approval of immune-based therapies 
beyond mAbs such as antibody-drug conjugates and chimeric antigen receptor T-cell therapies 
(eg, idecabtagene vicleucel and ciltacabtagene autoleucel) (Abecma (idecabtagene vicleucel) 
suspension for intravenous infusion 2021), long-term disease control is not assured and cure 
remains elusive. As the vast majority of patients will require ongoing therapies, there is still a 
need for novel therapies and regimens, especially those that introduce a unique mechanism of 
action. 
Modakafusp alfa displayed robust antitumor activity in combination with standard-of-care (SOC) 
agents in mouse models of MM. Cotreatment with a suboptimal dose of modakafusp alfa 
improved the antitumor activity of IMiDs (lenalidomide, pomalidomide), PIs (bortezomib, 
ixazomib), melphalan, and cyclophosphamide (Reports H929-e284 and TPA-38-053). 
Clinical studies are ongoing with modakafusp alfa as a single agent in adult patients with RRMM 
(TAK-573-1501) and with modakafusp alfa in combination with pembrolizumab in adult patients 
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with advanced or metastatic solid tumors (TAK-573-1001) (Section 4.2.4). Single-agent activity 
was confirmed in patients with RRMM. The main Grade 3/4 toxicities observed were 
hematologic (Vogl et al. 2021).  
The rationale for associating modakafusp alfa with the proposed combination agents in patients 
with MM in maintenance therapy and in patients with RRMM is based on the single-agent 
activity observed in the TAK-573-1501 study and preclinical combinatorial activity observed 
with lenalidomide, pomalidomide, bortezomib, and carfilzomib. Based on the known toxicity 
profiles of each of these agents, overlapping toxicities are predicted, but they are anticipated to 
be manageable. Therefore, the objective of this phase 1b study is to determine the safety and 
tolerability of modakafusp alfa as part of combination therapy in adult patients with MM. 
4.4.1.1 Rationale for Modakafusp Alfa Dose 
Modakafusp alfa has been characterized in nonclinical studies (see the IB for current 
information). Two clinical studies, TAK-573-1501 in MM and TAK 573-1001 in solid tumors, 
are ongoing (Section 4.2.4), and Study TAK-573-2001 has begun enrollment.  
The proposed starting dose for modakafusp alfa in all arms of Study TAK-573-1502 is 80 mg 
Q4W, which is N-1 or N-2 of the potential modakafusp alfa single-agent doses of 120 or 240 mg 
Q4W, respectively, which are currently being assessed in Part 3 of Study TAK573-1501 for 
selection of an optimal single-agent dose. 
With the modakafusp alfa 80 mg Q4W dose regimen, the median single-dose AUC is expected to 
be approximately 3 and 6-fold below the potential single agent dose of 120 or 240 mg Q4W, 
respectively.  
Based on the single-agent safety profile of modakafusp alfa from Study TAK-573-1501, the 
major potential overlapping toxicities anticipated in this study are thrombocytopenia and 
neutropenia, with the possible clinical manifestations of bleeding and infection. As such, these 
clinical events were analyzed in patients treated with modakafusp alfa (Study TAK-573-1501) at 
body weight-based Q3W and Q4W dosing schedules equivalent to flat doses of 70 to 90 mg.  
Thrombocytopenia may increase the risk of bleeding. Therefore, in patients treated with 
modakafusp alfa and concurrent anticoagulation, platelet counts should be carefully monitored 
and antithrombotic/anticoagulant therapy managed accordingly in an effort to balance the risk of 
bleeding versus the risk of a venous thromboembolic event or stroke. 
Intensive safety monitoring, including rigorous chemistry and hematologic assessments, is 
included in the initial cycles of the current study. This will enable close monitoring of TEAEs for 
prompt medical interventions, if needed.  
4.4.2 Combination Agents 
4.4.2.1 Lenalidomide 
Thalidomide is a known human teratogen that causes life-threatening birth defects or 
embryo-fetal death and is available only under a restricted program. Treatment of patients with 
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MM with PD-1 or programmed cell death ligand 1 (PD-L1) blocking antibody in combination 
with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical 
studies. Lenalidomide (Revlimid), a thalidomide analog, is indicated for the treatment of adult 
patients with MM in combination with dexamethasone. It was also approved as maintenance 
therapy following auto-HSCT. The recommended starting dose in maintenance therapy 
following auto-HSCT is 10 mg once daily (QD) continuously on Days 1 to 28 of repeated 28-day 
cycles. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg QD if 
tolerated (Revlimid (lenalidomide) 2021). 
Four randomized phase 3 studies have evaluated lenalidomide in maintenance therapy following 
auto-HSCT. In 2 trials (CALGB 100104, 460 patients and IFM 2005-02, 614 patients), the 
maintenance dose was 10 mg QD and could be increased to 15 mg QD after 3 months. The dose 
was increased to 15 mg in 135 patients (58 %) in the CALGB trial and 185 patients (60%) in the 
IFM trial (Revlimid (lenalidomide) 2021). The CALGB trial reported median TTP and OS of 57 
and 114 months, respectively, in the lenalidomide arm versus 29 and 84 months, respectively, 
compared with placebo (Holstein et al. 2017). Similar results were shown in the IFM study 
(median PFS 41 months in the lenalidomide group versus 23 months in the placebo group). Two 
other trials (RV-MM-209, 402 patients and Myeloma XI, 1247 patients) evaluated another 
dosing schedules at 10 mg, 21 out of 28 days, with no increase of the dose. The RV-MM-209 
study reported median PFS and 3-year OS of 42 months and 88%, respectively, in the 
maintenance arm versus 22 months and 79% in the placebo arm. The Myeloma XI study 
revealed median PFS and 3-year OS of 57 months and 88% in the lenalidomide group versus 
30 months and 80% in the control group. 
Most common adverse reactions (more than 20% in the lenalidomide arm) across both CALGB 
and IFM studies included neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory 
tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, 
asthenia, muscle spasm and pyrexia (Revlimid (lenalidomide) 2021). 
Lenalidomide maintenance therapy after ASCT is the current SOC in many regions. Several 
randomized phase 3 studies and meta-analysis reported significant PFS and OS benefits for 
lenalidomide compared with observation/placebo. However, patients will experience relapse and 
require new therapy. There is a need to develop new strategies to improve upon lenalidomide 
maintenance. 
As outlined in Figure 4.a and Figure 4.b, lenalidomide combined with modakafusp alfa 
demonstrated a significant reduction of the median tumor volume in both the NCI-H929 and 
OPM2 xenograft models. 
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Figure 4.a 
Therapeutic Synergy of Modakafusp Alfa Combined With Lenalidomide 
(Revlimid) in NCI-H929 Mouse Xenograft Model 
 
Source: H929-e284 report. 
i.p.: intraperitoneal; len: lenalidomide; qd: once daily; q4wk: once every 4 weeks; TEV-48573: modakafusp alfa 
(TAK-573). 
Mice bearing subcutaneous NCI-H929 tumors (170-350 mm3) were randomized and treated with vehicle, 
lenalidomide, modakafusp alfa, or a combination of lenalidomide + modakafusp alfa. 
Graph shows median tumor volume per group. 
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Figure 4.b 
Therapeutic Synergy of Modakafusp Alfa Combined With Lenalidomide 
(Revlimid) in OPM2 Mouse Xenograft Model 
 
Days Post-Treatment Start 
Source: H929-e284 report. 
mpk: mg/kg; QD21: every day for 21 days; TAK-573: modakafusp alfa. 
Mice bearing subcutaneous OPM2 tumors (average starting volume ~150 mm3) were randomized and treated with 
vehicle, lenalidomide, modakafusp alfa, or a combination of lenalidomide + modakafusp alfa. 
Graph shows median tumor volume per group. 
4.4.2.2 Pomalidomide 
Pomalidomide was approved in combination with dexamethasone for patients with MM who 
have received at least 2 prior therapies, including lenalidomide and a PI, and had demonstrated 
disease progression on or within 60 days of completion of the last therapy. Pomalidomide is 
supplied in 1, 2, 3, and 4 mg capsules. The recommended dosage is 4 mg per day taken orally 
(PO) on Days 1 through 21 of repeated 28-day cycles until disease progression; reduced doses 
are recommended for patients with hepatic impairment.  
In a trial of 221 patients with relapsed MM who were refractory to their last myeloma therapy 
and had received lenalidomide and bortezomib, patients were randomized to pomalidomide alone 
or pomalidomide with low-dose dexamethasone. The overall response rate (ORR) by an 
independent review committee using EBMT (European Blood and Marrow Transplantation) 
criteria was 7.4% in the pomalidomide alone and 29.2% in the combination arm. A second trial 
comparing these treatment regimens in 455 patients with RRMM reported median PFS and ORR 
of 3.6 months and 23.5%, respectively, in the combination arm versus 1.8 months and 3.9%, 
respectively, with pomalidomide alone (Pomalyst (pomalidomide) Capsules 2020).  
Thalidomide is a known human teratogen that causes severe life-threatening birth defects. 
Pomalidomide is a thalidomide analog and is available only under a restricted program. 
Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a 
 
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thalidomide analog plus dexamethasone is not recommended. Coadministration of strong 
cytochrome P450 (CYP)1A2 inhibitors (eg, ciprofloxacin and fluvoxamine) should be avoided. 
Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, 
constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia 
(Pomalyst (pomalidomide) Capsules 2020). 
Pomalidomide in combination with bortezomib and dexamethasone was evaluated and compared 
with bortezomib plus dexamethasone in patients with RRMM (OPTIMISMM trial). 
Pomalidomide was also combined with carfilzomib and dexamethasone (EMN011/HO114 trial). 
(Moreau et al. 2021). In the EQUULEUS trial, pomalidomide in combination with daratumumab 
and dexamethasone was evaluated in patients with MM who had received a prior PI and an IMiD 
(see Section 4.4.2.4). 
Lower dosing regimens of pomalidomide were evaluated. Lacy et al have shown that 
pomalidomide 2 mg daily with weekly dexamethasone demonstrated impressive activity in 
RRMM: 63% of the patients had a confirmed response (Lacy et al. 2009). Later, Lacy et al also 
reported 2 sequential phase 2 trials comparing pomalidomide 2 versus 4 mg daily (on Days 1-28 
of a 28-day cycle) with weekly low-dose dexamethasone in patients with MM refractory to both 
lenalidomide and bortezomib. Results showed no advantage for 4 mg over the 2 mg daily dosing 
of pomalidomide (Lacy et al. 2011). 
Modakafusp alfa in combination with pomalidomide was evaluated in the NCI-H929 xenograft 
tumor model. Mice bearing NCI-H929 SC tumors (average starting tumor volume = 150 mm3) 
were randomized and treated with vehicle (200 μL, IP, BIW × 3), pomalidomide (2.5 mg/kg, 
QD × 21), modakafusp alfa (2 mg/kg, BIW × 4, IP) or pomalidomide + modakafusp alfa. 
Individual tumor volumes were measured BIW. Figure 4.c shows median tumor volume per 
treatment arm BIW × 4 QD × 21. Pomalidomide combination with modakafusp alfa 
demonstrated a significant reduction of the median tumor volume in the NCI-H929 xenograft 
models (Figure 4.c). 
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Figure 4.c 
Activity of Modakafusp Alfa Combined With the IMiD Pomalidomide 
(Pomalyst) in NCI-H929 MM Xenograft Tumor Model 
 
Source: H929-e285 report. 
IMiD: immunomodulatory drug; MM: multiple myeloma; TAK-573: modakafusp alfa. 
Pomalidomide treatment ended at Day 21. 
4.4.2.3 Bortezomib 
Bortezomib (Velcade) is a PI indicated for treatment of adult patients with MM. The 
recommended dosage is 1.3 mg/m2 BID on Days 1, 4, 8, and 11, followed by a 10-day rest period 
from Days 12 to 21. After 8 cycles, patients can follow a maintenance schedule of once weekly 
for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) 
(Velcade (bortezomib) for Injection 2019). 
An integrated safety analysis of 1008 patients who received single-agent bortezomib at the above 
dosage demonstrated that >20% of patients had adverse events (AEs) of nausea (49%), diarrhea 
(46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies 
(38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%); 
11% of patients experienced at least 1 Grade ≥4 toxicity, and 22% of patients discontinued due 
to AEs (Velcade (bortezomib) for Injection 2019). 
Bortezomib in combination with pomalidomide plus dexamethasone was evaluated in patients 
with RRMM (see Section 4.4.2.2).  
DVd was evaluated in the CASTOR trial. ORR was 79.3% in the DVd group and 59.9% in the 
Vd group. In responders, the median TTR was 0.8 months (range: 0.7 to 4 months) in the DVd 
group and 1.5 months (range: 0.7 to 5 months) in the Vd group. Serious adverse reactions 
(SARs) occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. SARs 
with at least a 2% greater incidence in the DVd arm compared with the Vd arm were upper 
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respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs 
Vd 0% for each) (Darzalex Faspro (daratumumab and hyaluronidase-fihj) injection for 
subcutaneous use 2021). 
Bortezomib weekly schedule was evaluated in several trials. In the BOSTON trial, once weekly 
bortezomib in combination with Selinexor was compared with BIW bortezomib plus 
dexamethasone. In the SVd group, bortezomib was administered once per week SC on Days 1, 8, 
15, and 22 of a 5-week cycle. In the Vd group, bortezomib was administered SC in accordance 
with the approved regimen of 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 3-week cycle (Grosicki et 
al. 2020). In the RVD-lite regimen (Revlimid, Velcade, dexamethasone), bortezomib 1.3 mg/m2 
was administered weekly SC on Days 1, 8, 15 and 22 of a 35-day cycle (O’Donnell et al. 2018). 
In a retrospective study, Cook et al. evaluated the response rates and outcomes with different 
schedules of bortezomib in the induction therapy VRd (bortezomib/lenalidomide/ 
dexamethasone) administered in patients with NDMM. Bortezomib was administered BIW every 
21 days in 43%, once weekly every 21 days in 41%, and once weekly every 28 days in 16% of 
patients. With a median follow-up time of 37 months, no difference in PFS or OS among the 
groups was found (Cook et al. 2021). 
Combination therapy with bortezomib and IFN-α was explored in melanoma. In their preclinical 
study, Lesinski et al demonstrated that IFN-α in combination with bortezomib induced synergetic 
apoptosis in human melanoma cell lines, prolonged survival in a murine model of melanoma, 
and significantly reduced tumor growth in a xenograft model of human melanoma in athymic 
mice compared with either agent alone (Lesinski et al. 2008). 
This combination therapy was evaluated in a phase 1 study (16 patients) and was well tolerated 
overall; toxicities were similar to those with bortezomib and/or IFN-α treatment alone. Common 
Grade 3 toxicities included fatigue, vomiting, and diarrhea. Grade 4 toxicities were fatigue and 
lymphopenia (Markowitz et al. 2014). 
As shown in Figure 4.d and Figure 4.e, bortezomib combined with modakafusp alfa 
demonstrated a significant reduction of the median tumor volume in both the NCI-H929 and 
OPM2 xenograft models. 
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Figure 4.d 
Activity of Modakafusp Alfa Combined With the Proteasome Inhibitor 
Bortezomib (Velcade) in NCI-H929 MM Xenograft Tumor Model 
 
Source: TPA-38-053 report. 
BIW: twice weekly; IP: intraperitoneal(ly); MM: multiple myeloma; QD: once daily. TAK-573: modakafusp alfa. 
Mice bearing subcutaneous NCI-H929 tumors (average starting tumor volume = 250 mm3) were randomized and 
treated with vehicle (200 μL, IP, BIW × 3), bortezomib (1 mg/kg, BIW × 4), modakafusp alfa (2.5 mg/kg, BIW × 3, 
IP) or bortezomib + modakafusp alfa. 
Individual tumor volumes were measured BIW. Graph shows median tumor volume per treatment arm. 
Figure 4.e 
Therapeutic Synergy of Modakafusp Alfa Combined With the Proteasome 
Inhibitor Bortezomib (Velcade) in OPM2 Mouse Xenograft Model 
 
Source: TPA-38-053 report 
TAK-573: modakafusp alfa.  
Mice bearing subcutaneous OPM2 tumors (average starting volume ~150 mm3) were randomized and treated with 
vehicle, bortezomib (Velcade), modakafusp alfa, or a combination of bortezomib (Velcade) + modakafusp alfa.  
Graph shows median tumor volume per group.  
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4.4.2.4 Daratumumab 
Daratumumab is an IgG1ĸ human mAb that binds to CD38 antigens and inhibits the growth of 
CD38-expressing tumor cells. 
Daratumumab monotherapy was evaluated in patients with RRMM who had received at least 
3 prior lines of therapy, including a PI and an immunomodulatory agent, or who were double-
refractory to a PI and an immunomodulatory agent (SIRIUS trial, 106 patients) with RRMM in 
3 open-label, clinical trials. The ORR was 29.2% with stringent CR (sCR) of 2.8%. The median 
DOR was 7.4 months (range: 1.2 to 13.1+ months). Study GEN501 was an open-label dose 
escalation trial evaluating daratumumab monotherapy in patients with RRMM who had received 
at least 2 different cytoreductive therapies (42 patients). ORR was 36% (95% CI: 21.6, 52.0%) 
with 1 CR and 3 very good partial responses (VGPRs). 
The safety of daratumumab was evaluated in 156 adult patients with RRMM in 3 open-label, 
clinical trials. The most frequent SARs were pneumonia (6%), general physical health 
deterioration (3%), and pyrexia (3%). Adverse reactions resulted in treatment delay for 24 (15%) 
patients, most frequently for infections.  
EQUULEUS was an open-label, multicohort trial that evaluated the combination of 
daratumumab with once-weekly carfilzomib (20/70 mg/m2) and dexamethasone in patients with 
RRMM who had received at least 1 to 3 prior lines of therapy. The ORR was 81% with sCR of 
21% and CR of 14%. The median DOR was 28 months (95% CI: 20.5, not estimable). SARs 
were reported in 48% of patients. The most frequent SARs reported were pneumonia (4.7%), 
upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general 
physical health deterioration (3.5%), and hypercalcemia (3.5%). IRRs on the day of 
administration of any daratumumab dose or on the next day occurred in 44% of patients. 
Daratumumab in combination with pomalidomide and dexamethasone was also evaluated in the 
EQUULEUS trial, in which 103 patients with MM who had received a prior PI and an 
immunomodulatory agent received 16 mg/kg daratumumab in combination with pomalidomide 
and low-dose dexamethasone until disease progression. The ORR was 59.2% with sCR of 7.8% 
and CR of 5.8%. The median DOR was 13.6 months (range: 0.9+ to 14.6+ months). The overall 
incidence of SARs was 49%. SARs reported in ≥5% patients included pneumonia (7%). Adverse 
reactions resulted in discontinuations for 13% of patients (Darzalex Faspro (daratumumab and 
hyaluronidase-fihj) injection for subcutaneous use 2021). Daratumumab was also evaluated in 
combination with bortezomib and dexamethasone (see Section 4.3.3). 
Daratumumab in combination with modakafusp alfa was evaluated in the NCI-H929 xenograft 
model. As shown in Figure 4.f, daratumumab combined with modakafusp alfa demonstrated a 
significant reduction of the median tumor volume in the NCI-H929 xenograft models. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
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Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Figure 4.f 
Activity of Modakafusp Alfa Combined With the Anti-CD38 Antibody 
Daratumumab in NCI-H929 MM Xenograft Tumor Model 
 
Source: H929-e284 report. 
BIW: twice weekly; IP: intraperitoneal(ly).  
Mice bearing subcutaneous NCI-H929 tumors (average starting tumor volume = 250 mm3) were randomized and 
treated with vehicle (200 μL, IP, BIW × 3), daratumumab (5 mg/kg, BIW × 4), CD38-attenukine (modakafusp alfa 
0.3 mg/kg, BIW × 4, IP) or daratumumab + modakafusp alfa.  
Individual tumor volumes were measured BIW. Graph shows median tumor volume per treatment arm. 
4.5 
Risks and Benefits 
4.5.1 Benefit-Risk Profile of Modakafusp Alfa 
Modakafusp alfa has been administered to a limited number of patients with MM and solid 
tumors in ongoing studies. 
In Study TAK-573-1501, initial efficacy with modakafusp alfa was observed on Schedule A at a 
dose of 0.1 mg/kg, with 1 patient having a PR at Cycle 2 and remaining in PR until Cycle 14. 
Two additional responses were observed in patients treated at 0.4 mg/kg. Of the 12 patients 
receiving modakafusp alfa 0.75 mg/kg (3 patients per Schedule A, 3 patients per Q3W, and 
6 patients Q4W), 1 patient treated on the Q3W schedule had a minimal response for 2 cycles. 
Thus, of the 52 patients treated at doses less than 1.5 mg/kg (41 patients in escalation cohorts at 
4 schedules and 11 patients in expansion cohorts at a dose of 0.4 mg/kg Q3W), responses were 
observed in only 2 patients. 
As of the data cutoff of 17 November 2022, a total of 30 patients were enrolled in the expansion 
and escalation parts at the dose of 1.5 mg/kg Q4W. The objective response rate in these patients 
was 43.3%, and the CBR was 53.3%. In 22 triple-refractory and penta-exposed patients, the 
objective response rate was 40.9%. 
0
2 0
4 0
6 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
D a y s
M e d ia n  T u m o r V o lu m e (m m 3)
V e h ic le
C D 3 8 -A tte n u k in e   (0 .3 m g /k g )
D a r a tu m u m a b  (5 m g /k g )
C o m b in a tio n
tre a tm e n t 2 8 d a y s
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Study No. TAK-573-1502  
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CONFIDENTIAL 
4.5.1.1 Nonclinical Safety Summary 
Based on nonclinical studies in cynomolgus macaques, the adverse drug reactions that may be 
associated with modakafusp alfa administration are decreases in blood cell counts and elevations 
in liver enzymes. Other findings from repeat-dose general toxicity studies were thought to result 
from ADA-mediated hypersensitivity reactions, which are considered poorly predictive of 
responses in humans. Additional information regarding benefits and risks to patients can be 
found in the IB. 
There were no direct modakafusp alfa-induced changes in CNS, respiratory, and cardiovascular 
parameters evaluated on general toxicity studies in cynomolgus monkeys. 
In MM mouse pharmacology models, no effects on mortality, body weight, or clinical signs were 
noted following the administration of modakafusp alfa with combination agents including 
lenalidomide (H929-e284), pomalidomide (H929-e285) or daratumumab (H929-e324). 
Combination toxicity studies have not been performed. 
4.5.1.2 Clinical Safety Summary 
Please see the current IB for details of modakafusp alfa clinical safety. 
Hematologic Toxicities 
The predominant toxicities of modakafusp have been hematologic, and these effects have been 
managed with supportive care and dose delays. 
In Study TAK-573-1501, the most common TEAEs were hematologic, including 
thrombocytopenia (including platelet count decreased), followed by neutropenia (including 
neutrophil count decreased), leukopenia, anaemia, and lymphocyte count decreased. 
IRRs 
Patients receiving modakafusp alfa have experienced IRRs. No patients have experienced 
anaphylactic shock. Reactions such as pyrexia, chills, nausea, vomiting, ﬂushing, dyspnea, 
cough, headache, dizziness, rash, pruritus, hypoxia, hypertension, tachycardia, blurred vision, 
abdominal pain, and back pain were observed. In modakafusp alfa studies, IRRs are designated 
as adverse events of special interest (AESIs). 
It is important to monitor for signs and symptoms of hypersensitivity reactions and treat the 
patient accordingly. Resuscitation medications and equipment should be available before, during, 
and after the infusion. Premedications and treatment should be provided as described in 
Section 8.1.1.1. 
Neuropsychiatric AEs 
Neuropsychiatric AEs have been reported in modakafusp alfa clinical trials.  
Liver Function  
Patients receiving modakafusp alfa have experienced elevation in liver enzymes. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
48 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Cytokine Release Syndrome 
Modakafusp alfa elicited a low level of cytokine release (TNF-α, IL-6, IL-8, IFN-γ, and IL-2) 
from human PBMCs in vitro, less than or comparable to that observed with palivizumab, and is 
therefore unlikely to induce cytokine release syndrome (CRS) in the clinic. However, CRS is a 
potential outcome of treatment with therapeutic protein products and patients should be 
monitored for this potential event. 
Interference With Serologic Testing 
Modakafusp alfa has been shown to interfere with serological testing due to binding to CD38 on 
red blood cells (RBCs), which results in positive direct and indirect antiglobulin tests. The 
duration of modakafusp alfa–mediated positive direct and indirect antiglobulin tests has 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. 
For more detailed information on the 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 schedules of events 
(SOEs). Dose modification should be applied per the guidelines in Section 8.6. 
4.5.2 Benefit-Risk Profile of the Combination Agents 
Benefits of the combination agents are described in Section 4.3. 
Adverse Effects of Lenalidomide 
The most common adverse reactions occurring in at least 20% of patients treated with 
lenalidomide in MM trials were diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, 
peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, 
pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, 
rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor. 
Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis and 
pulmonary embolism as well as risk of myocardial infarction and stroke in patients with MM 
who were treated with lenalidomide and dexamethasone therapy. Refer to the lenalidomide 
prescribing information for more details (Revlimid (lenalidomide) 2021). 
Adverse Effects of Pomalidomide 
In patients with MM treated with pomalidomide, the most common adverse reactions (≥30%) 
included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, upper 
respiratory tract infection, back pain, and pyrexia. Neutropenia was the most frequently reported 
Grade 3/4 AE. Refer to the pomalidomide prescribing information for more details (Pomalyst 
(pomalidomide) Capsules 2020). 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
49 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Adverse Effects of Bortezomib 
Most commonly reported adverse reactions (≥20%) in clinical studies of bortezomib in patients 
with MM include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, 
fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia and 
anorexia. Refer to the bortezomib prescribing information for more details (Velcade 
(bortezomib) for Injection 2019). 
Adverse Effects of Daratumumab and Hyaluronidase-fihj 
The most frequently reported adverse reactions (incidence ≥20%) were upper respiratory 
infection, neutropenia, IRRs, thrombocytopenia, anemia, leukopenia, and lymphocytopenia. 
Refer to daratumumab and hyaluronidase-fihj prescribing information for more details (Darzalex 
Faspro (daratumumab and hyaluronidase-fihj) injection for subcutaneous use 2021). 
Systemic administration-related reactions occurred in 9% of patients (Grade 2: 3.2%, Grade 
3: 1%). Eight percent of patients experienced systemic administration-related reactions with the 
first injection, 0.3% with the second injection. The median time to onset was 3.2 hours 
(range: 4 minutes to 3.5 days). 
Daratumumab binds to CD38 on RBCs and results in a positive indirect antiglobulin test 
(indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for 
up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks 
detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s 
blood group and Rh are not impacted (Darzalex Faspro (daratumumab and hyaluronidase-fihj) 
injection for subcutaneous use 2021). 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objectives 
The primary objectives of the study are: 
Group 1: MM Maintenance 
• To determine the safety and tolerability of modakafusp alfa and lenalidomide combination 
therapy as maintenance in adult patients with MM after ASCT. 
• To determine the RP2D of the combination therapy with modakafusp alfa. 
Group 2 and Group 3: RRMM Doublets and Triplets 
• To determine the safety and tolerability of modakafusp alfa as part of either a 2- or 3-drug 
combination therapy in adult patients with RRMM. 
• To determine the RP2D of the combination therapy with modakafusp alfa (recommended 
doses of the doublet or triplet combinations). 
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Study No. TAK-573-1502  
50 of 200 
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CONFIDENTIAL 
5.1.2 Secondary Objectives 
The secondary objectives of the study are: 
Group 1: MM Maintenance 
• To evaluate the preliminary efficacy of modakafusp alfa and lenalidomide combination 
therapy as maintenance in adult patients with MM after ASCT. 
• To evaluate the rate and duration of minimal/measurable residual disease (MRD) negativity 
(MRD[-]). 
• To collect PK data to support population PK and exposure-response analysis of modakafusp 
alfa when given in combination therapy. 
• To characterize the immunogenicity profile of modakafusp alfa when given in combination 
therapy. 
Group 2 and Group 3: RRMM Doublets and Triplets 
• To evaluate the preliminary efficacy of modakafusp alfa as part of either a 2- or 3-drug 
combination therapy in adult patients with RRMM. 
• To evaluate the rate and duration of MRD[-]. 
• To collect PK data for modakafusp alfa to support population PK and exposure-response 
analysis of modakafusp alfa when given in combination therapy. 
• To characterize the immunogenicity profile of modakafusp alfa when given in combination 
therapy. 
5.1.3 
 
 
 
5.2 
Estimands 
Not applicable. 
5.3 
Endpoints 
5.3.1 Primary Endpoints 
The primary endpoints of the study for Groups 1, 2, and 3 (MM maintenance, RRMM doublets, 
and RRMM triplets) are: 
• Occurrence of DLTs in Cycle 1. 
• Frequency and severity of TEAEs. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
51 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
5.3.2 Secondary Endpoints 
Secondary endpoints are: 
Group 1: MM Maintenance 
• PFS. 
• ORR (per investigator assessment). 
• DOR. 
• Rate of MRD[-] at a threshold of 10-5 in patients at 6 months, 1 year, and 2 years after the 
start of treatment.  
• Duration of MRD[-] at a threshold of 10-5 in patients achieving MRD[-]. 
• ADA incidence and characteristics (eg, titer and specificity) and neutralizing antibody 
(NAb). 
Group 2 and Group 3: RRMM Doublets and Triplets 
• OS. 
• ORR. 
• PFS. 
• TTP. 
• Time to next treatment (TTNT). 
• DOR. 
• Disease control rate (DCR). 
• EFS.  
• TTR. 
• Rate of MRD[-] CR at a threshold of 10-5 with CR assessed by the investigator. 
• Rate of MRD[-] at a threshold of 10-5. 
• Duration of MRD[-] at a threshold of 10-5 in patients achieving MRD[-]. 
• ADA incidence and characteristics (eg, titer and specificity) and NAb. 
5.3.3 
 
 
 
 
 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a global multicenter, open-label, phase 1b study designed to evaluate the safety and 
tolerability of modakafusp alfa in combination therapy and determine the RP2D of the 
combination therapy with modakafusp alfa in adult patients with MM. The study will be 
conducted using 3 groups based on MM status; the combinations to be evaluated within each 
group are as follows. 
Group 1: MM Maintenance 
Arm 1: Modakafusp alfa + lenalidomide after ASCT as maintenance therapy in MM  
Group 2: RRMM Doublets 
Arm 2: Modakafusp alfa + pomalidomide (MP) in RRMM 
Arm 3: Modakafusp alfa + bortezomib (MV) in RRMM 
Arm 4: Modakafusp alfa + carfilzomib (MK) in RRMM (closed to enrollment) 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
53 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Group 3: RRMM Triplets 
Arm A: Modakafusp alfa + pomalidomide + bortezomib (MPV) in RRMM 
Arm D: Modakafusp alfa + daratumumab + pomalidomide (MDP) in RRMM 
The overall study schema is shown in Figure 6.a. 
Figure 6.a 
Schematic of Study Design 
 
ASCT: autologous stem cell transplantation; MDP: modakafusp alfa, daratumumab, and pomalidomide; 
MK: modakafusp alfa and carfilzomib (Kyprolis); MM: multiple myeloma; MP: modakafusp alfa and 
pomalidomide; MPV: modakafusp alfa, pomalidomide, and bortezomib (Velcade); MV: modakafusp alfa and 
bortezomib (Velcade); RP2D: recommended phase 2 dose; RRMM: relapsed/refractory multiple myeloma. 
➔ After the doublet RP2D is determined in Group 2 RRMM doublet combinations, dose escalation of modakafusp 
alfa in Group 3 RRMM triplet combinations will begin. 
 
Patient participation will include a screening phase, a treatment phase, and a follow-up phase. 
The screening phase will be up to approximately 21 days before Cycle 1 Day 1. 
Patients will be evaluated approximately 30 days after the last dose of treatment 
(end-of-treatment [EOT] visit) or before the start of subsequent systemic anticancer therapy to 
permit the detection of any delayed TEAEs.  
Patients who discontinue study treatment for reasons other than progressive disease (PD) will 
complete the EOT visit and continue PFS follow-up Q4W from the EOT visit until the 
occurrence of PD, death, the start of subsequent systemic antineoplastic therapy, study 
termination (Section 6.5.4), whichever occurs first. OS follow-up continues every 12 weeks until 
death, study termination, or patient withdrawal. 
Group 2: Doublets 
RRMM 
Arm 1: Modakafusp alfa + lenalidomide after ASCT as maintenance therapy in MM 
Group 1: MM Maintenance 
Arm 2: Modakafusp alfa + 
pomalidomide in RRMM (MP in 
RRMM) 
Arm 3: Modakafusp alfa + bortezomib 
in RRMM (MV in RRMM) 
Arm 4: Modakafusp alfa + carfilzomib 
(MK) in RRMM (closed to enrollment) 
Group 3: Triplets 
Arm A: Modakafusp alfa + 
pomalidomide + bortezomib in 
RRMM (MPV in RRMM) 
Arm D: Modakafusp alfa + 
daratumumab + pomalidomide in 
RRMM (MDP in RRMM) 
Doublets 
RP2D and 
safety 
determined 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
54 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
The Bayesian Optimal Interval (BOIN) design (Liu and Yuan 2015) will be implemented for 
dose escalation/de-escalation. The target toxicity rate for MTD is set to be ϕ = 0.25 for MM 
maintenance and RRMM doublets and ϕ = 0.33 for RRMM triplets, unless otherwise specified. 
A total of approximately 120 DLT-evaluable patients will be enrolled: approximately 18 for MM 
maintenance (Arm 1), approximately 66 for RRMM doublet combinations, and approximately 36 
for RRMM triplet combinations.  
The operating characteristics of the BOIN design evaluated with 1000 simulations assuming 
various distributions of toxicity across dose levels are presented in Appendix I. 
6.2 
Overview of Combination Therapy Groups and Dose Regimens 
6.2.1 Group 1: MM Maintenance 
6.2.1.1 Arm 1 Modakafusp alfa and Lenalidomide in MM After ASCT 
Modakafusp alfa IV infusions in combination with lenalidomide PO will be administered on a 
28-day (4-week) cycle (Table 6.a). Modakafusp alfa will be given on Day 1. 
The following dose levels and schedules in treatment Arm 1 will be evaluated during phase 1b 
guided by BOIN design:  
• Dose level -1 will consist of modakafusp alfa 60 mg IV on Day 1 and lenalidomide 10 mg 
PO QD continuously (Days 1 to 28). 
• Dose level 0 (starting dose) will consist of modakafusp alfa 80 mg IV on Day 1 and 
lenalidomide 10 mg PO QD continuously (Days 1 to 28). 
• Dose level 1 will consist of modakafusp alfa 120 mg IV on Day 1 and lenalidomide 10 mg 
PO QD continuously (Days 1 to 28). 
• Dose level 2 will consist of modakafusp alfa 240 mg IV on Day 1 and lenalidomide 10 mg 
PO QD continuously (Days 1 to 28). 
After 3 cycles of maintenance therapy, the dose of lenalidomide, per label, can be increased to 
15 mg QD if tolerated.  
Other dosing schedules may be explored on the basis of emerging data. 
Patients in the MM maintenance group may continue to receive modakafusp alfa in combination 
with lenalidomide until disease progression, unacceptable toxicity, or to a maximum of 2 years 
for MRD[-] patients, whichever occurs first. Patients who remain MRD-positive with 
demonstrated clinical benefit after 2 years of maintenance therapy may continue treatment 
beyond 2 years with agreement of the sponsor/designee. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
55 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Table 6.a 
Arm 1: Modakafusp Alfa and Lenalidomide Dosing Schedule 
 
Cycle 1 and Later 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp Alfa IV (mg) 
60, 80, 120 or 240 mg 
- 
- 
- 
Lenalidomide PO (mg) 
10 mg QD continuously (Days 1 to 28) * 
IV: intravenous(ly); PO: oral(ly); QD: once daily. 
* After 3 cycles of maintenance therapy, the dose of lenalidomide, per label, can be increased to 15 mg QD if 
tolerated. 
6.2.2 Group 2: RRMM Doublets 
Because of the predicted overlapping toxicities, the study will initially determine the safety and 
tolerability of modakafusp alfa as part of doublet combination therapy. 
The doublet combinations (Arms 2 to 4) will consist of a dose escalation/de-escalation of 
multiple doublet combination arms guided by BOIN design. This part of the study is designed to 
determine the recommended dose of modakafusp alfa and the recommended dose of the 
combination agent, including, but not limited to, bortezomib and pomalidomide, for the 
respective triplet combination escalation/de-escalation starting dose within the range of approved 
dosage in the label. 
The doublet schedules to be evaluated during this study include, but are not limited to, those 
described in Sections 6.2.2.1 through 6.2.2.3. 
6.2.2.1 Arm 2 MP in RRMM 
Modakafusp alfa IV infusions in combination with pomalidomide PO will be administered on a -
28-day (4-week) cycle (Table 6.b). Modakafusp alfa will be given Q4W. 
• Dose level -1 will consist of modakafusp alfa 60 mg IV on Day 1 and pomalidomide 4 mg 
PO on Days 1 to 21.* 
• Dose level 0 (starting dose) will consist of modakafusp alfa 80 mg IV on Day 1 and 
pomalidomide 4 mg PO on Days 1 to 21.* 
• Dose level 1 will consist of modakafusp alfa 120 mg IV on Day 1 and pomalidomide 4 mg 
PO on Days 1 to 21.* 
• Dose level 2 will consist of modakafusp alfa 240 mg IV on Day 1 and pomalidomide 4 mg 
PO on Days 1 to 21.* 
Other dosing regimens (eg, pomalidomide 2 or 3 mg) and schedules may be explored the basis of 
emerging data. 
* Pomalidomide 2 mg (Day 1 through Day 21 of each 28-day cycle) and pomalidomide 3 mg 
(Day 1 through Day 21 of each 28-day cycle) may be explored in a new cohort on the basis of 
emerging data. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
56 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Table 6.b 
Arm 2: Modakafusp Alfa and Pomalidomide Dosing Schedule 
 
Cycle 1 and Later 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp alfa IV (mg) 
60, 80, 120 or 240 mg 
- 
- 
- 
Pomalidomide PO (mg) 
4 mg, Day 1 through Day 21 of each 28-day cycle. a 
IV: intravenous(ly); PO: oral(ly). 
a Pomalidomide 2 mg (Day 1 through Day 21 of each 28-day cycle) and pomalidomide 3 mg (Day 1 through Day 
21 of each 28-day cycle) may be explored in a new cohort on the basis of emerging data. 
6.2.2.2 Arm 3 MV in RRMM 
Modakafusp alfa IV infusion in combination with SC bortezomib will be administered in a 
28-day (4-week) cycle (Table 6.c). Modakafusp alfa will be given Q4W. 
• Dose level -1 will consist of modakafusp alfa 60 mg IV on Day 1 and bortezomib 1.3 mg/m2 
SC on Days 8, 15, and 22. 
• Dose level 0 (starting dose) will consist of modakafusp alfa 80 mg IV on Day 1 and 
bortezomib 1.3 mg/m2 SC on Days 8, 15, and 22. 
• Dose level 1 will consist of modakafusp alfa 120 mg IV on Day 1 and bortezomib 1.3 mg/m2 
SC on Days 8, 15, and 22. 
• Dose level 2 will consist of modakafusp alfa 240 mg IV on Day 1 and bortezomib 1.3 mg/m2 
SC on Days 8, 15, and 22. 
Bortezomib will be administered 1.3 mg/m2 SC on Days 8, 15, and 22 for the first 8 cycles and 
subsequently on Days 8 and 22 (Table 6.c). Other dosing regimens and schedules may be 
explored on the basis of emerging data. 
At dose level 0, the first 3 patients of the first cohort must meet the following inclusion criterion: 
creatinine clearance ≥60 mL/min. If no renal safety events are observed during Cycle 1 in the 
first 3 patients (dose level 0), subsequent patients may be enrolled with a creatinine clearance 
≥30 mL/min at screening. Enrollment for the first 3 patients will be staged; the next patient will 
be enrolled after the previous patient has finished Cycle 2 Day 8. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
57 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Table 6.c 
Modakafusp Alfa and Bortezomib Dosing Schedule 
 
Cycle 1 Through Cycle 8 
 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Bortezomib SC (mg/m2) 
- 
1.3 
1.3 
1.3 
 
Cycle 9 and Later 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Bortezomib SC (mg/m2) 
- 
1.3 
- 
1.3 
IV: intravenous(ly); SC: subcutaneous(ly). 
6.2.2.3 Arm 4 MK in RRMM (Closed to Enrollment) 
This arm was closed after 3 patients were enrolled at dose level 0. Dose level 0 (starting dose) 
consisted of modakafusp alfa 80 mg IV on Day 1 and carfilzomib IV on Days 1, 8, and 15 (at an 
initial dose of 20 mg/m2 on Cycle 1 Day 1 then at 70 mg/m2 starting Cycle 1 Day 8). See 
Section 4.2.4.4. for further details. 
6.2.3 Group 3: RRMM Triplets 
Once the safety and tolerability of modakafusp alfa as part of doublet combination therapy is 
evaluated, the study is designed to determine the safety and tolerability of modakafusp alfa as 
part of triplet combination therapy (Arms A and D) based on the emerging data from the Group 2 
doublet arms. Triplet combinations will consist of a dose escalation/de-escalation phase of triplet 
combination arms guided by the doublet combination data, modakafusp alfa/daratumumab data 
from TAK-573-2001, and the BOIN design. This part of the study is designed to determine the 
recommended triplet therapy modakafusp alfa dose and recommended dose of the 2 associated 
combination agents. 
Treatment cycle duration is 28 days. Modakafusp alfa in combination with associated agents will 
be administered until disease progression or unacceptable toxicity, whichever comes first. Other 
dosing schedules may be explored on the basis of emerging data. 
The triplet schedules to be evaluated during phase 1b include, but are not limited to, those 
described in Sections 6.2.3.1 through 6.2.3.2.  
6.2.3.1 Arm A MPV in RRMM 
Modakafusp alfa IV infusions in combination with bortezomib SC and pomalidomide PO will be 
administered on a 28-day (4-week) cycle (Table 6.d). Modakafusp alfa will be given Q4W. 
• Dose level -1 will consist of modakafusp alfa IV 60 mg IV on Day 1 with bortezomib 
1.3 mg/m2 SC on Days 8, 15, and 22 and pomalidomide 4 mg PO on Days 1 to 21. 
• Dose level 0 will consist of modakafusp alfa IV 80 mg IV on Day 1 with bortezomib 
1.3 mg/m2 SC on Days 8, 15, and 22 and pomalidomide 4 mg PO on Days 1 to 21. 
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• Dose level 1 will consist of modakafusp alfa IV 120 mg IV on Day 1 with bortezomib 
1.3 mg/m2 SC on Days 8, 15, and 22 and pomalidomide 4 mg PO on Days 1 to 21. 
• Dose level 2 will consist of modakafusp alfa IV 240 mg IV on Day 1 with bortezomib 
1.3 mg/m2 SC on Days 8, 15, and 22 and pomalidomide 4 mg PO on Days 1 to 21. 
Bortezomib will be administered on 1.3 mg/m2 SC on Days 8, 15, and 22 for the first 8 cycles 
and subsequently on Days 8 and 22. 
The starting dose will be the lowest dose of modakafusp alfa doublet RP2D (60, 80, 120, or 
240 mg). Other dosing schedules may be explored on the basis of emerging data. 
Other dosing regimens (eg, pomalidomide 2 or 3 mg) and schedules may be explored on the 
basis of emerging data. 
Table 6.d 
Modakafusp Alfa, Bortezomib and Pomalidomide Dosing Schedule 
 
Cycle 1 Through Cycle 8 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Bortezomib SC (mg/m2) 
- 
1.3 
1.3 
1.3 
Pomalidomide PO (mg) 
4 mg, Day 1 through Day 21 of each 28-day cycle. a 
 
Cycle 9 and Later 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Bortezomib SC (mg/m2) 
- 
1.3 
- 
1.3 
Pomalidomide PO (mg) 
4 mg, Day 1 through Day 21 of each 28-day cycle. a 
IV: intravenous(ly); PO: oral(ly); SC: subcutaneous(ly). 
a Pomalidomide 2 mg (Day 1 through Day 21 of each 28-day cycle) and pomalidomide 3 mg (Day 1 through Day 
21 of each 28-day cycle) may be explored in a new cohort on the basis of emerging data. 
6.2.3.2 Arm D MDP in RRMM 
Modakafusp alfa IV infusions in combination with pomalidomide PO and daratumumab SC will 
be administered on a 28-day (4-week) cycle (Table 6.e). Modakafusp alfa will be given Q4W. 
• Dose level -1 will consist of modakafusp alfa IV 60 mg IV on Day 1 with daratumumab 
1800 mg SC and pomalidomide 4 mg PO on Days 1 to 21. 
• Dose level 0 will consist of modakafusp alfa IV 80 mg IV on Day 1 with daratumumab 
1800 mg SC and pomalidomide 4 mg PO on Days 1 to 21. 
• Dose level 1 will consist of modakafusp alfa IV 120 mg IV on Day 1 with daratumumab 
1800 mg SC and pomalidomide 4 mg PO on Days 1 to 21. 
• Dose level 2 will consist of modakafusp alfa IV 240 mg IV on Day 1 with daratumumab 
1800 mg SC and pomalidomide 4 mg PO on Days 1 to 21. 
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Daratumumab 1800 mg SC is administered on Days 1, 8, 15, and 22 of Cycles 1 and 2, then on 
Days 1 and 15 of Cycles 3 to 6, then on Day 1 thereafter. No dose reduction is permitted for 
daratumumab. The starting dose of modakafusp alfa will be the lowest dose of modakafusp alfa 
doublet RP2D (60, 80, 120, or 240 mg).  
Other dosing regimens (eg, pomalidomide 2 or 3 mg) and schedules may be explored on the 
basis of emerging data. 
Table 6.e 
Arm D: Modakafusp Alfa, Daratumumab and Pomalidomide Dosing 
Schedule 
 
Cycle 1 & Cycle 2 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp Alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Daratumumab SC (mg) 
1800 
1800 
1800 
1800 
Pomalidomide (PO) 
4 mg, Day 1 through Day 21 of each 28-day cycle.* 
 
Cycle 3 to Cycle 6 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp Alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Daratumumab SC (mg) 
1800 
- 
1800 
- 
Pomalidomide (PO) 
4 mg, Day 1 through Day 21 of each 28-day cycle.* 
 
Cycle 7 and Later 
Day 1 
Day 8 
Day 15 
Day 22 
Modakafusp Alfa IV (mg) 
60, 80, 120, or 240 mg 
- 
- 
- 
Daratumumab SC (mg) 
1800 
- 
- 
- 
Pomalidomide (PO) 
4 mg, Day 1 through Day 21 of each 28-day cycle.* 
IV: intravenous(ly); PO: oral(ly); SC: subcutaneous(ly). 
* Pomalidomide 2 mg (Day 1 through Day 21 of each 28-day cycle) and pomalidomide 3 mg (Day 1 through 
Day 21 of each 28-day cycle) may be explored in a new cohort on the basis of emerging data. 
6.3 
Dose Escalation/De-escalation 
The BOIN design (Liu and Yuan 2015) will be implemented to guide the dose escalation/de-
escalation (Figure 6.b). The target toxicity rate for MTD is set to be 𝜙= 0.25 for MM 
maintenance as well as RRMM doublets and 𝜙= 0.33 for RRMM triplets, unless otherwise 
specified. Further details and simulations are found in Appendix I. 
Patients will be enrolled and treated in cohort sizes of approximately 3. The starting dose will 
need to treat at least 3 DLT-evaluable patients. It is estimated that a total of approximately 120 
DLT-evaluable patients will be enrolled: approximately 18 for MM maintenance (Arm 1), 
approximately 66 for RRMM doublet combinations, and approximately 36 for RRMM triplet 
combinations.  
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Figure 6.b 
Flowchart for Study Conduct Using the BOIN Design 
 
BOIN: Bayesian Optimal Interval; DLT: dose-limiting toxicity; MTD: maximum tolerated dose; λd: DLT rate 
de-escalation boundary; λe: DLT rate escalation boundary. 
6.3.1 Group 1: MM Maintenance 
The BOIN design will be used for dose escalation/de-escalation for MM maintenance. The target 
toxicity rate is set to be 𝜙= 0.25. Patients will be enrolled and treated in cohorts of 
approximately 3. The starting dose will need to treat at least 3 evaluable patients. For the purpose 
of overdose control, doses 𝑗 and higher levels will be eliminated from further examination if 
Pr(𝑝𝑗> 0.25 | data) >0.95 and at least 3 evaluable patients have been treated at dose level 𝑗, 
where 𝑝𝑗 is the true DLT rate of dose level 𝑗. When the lowest dose is eliminated, that arm will 
be stopped for safety. It is estimated that approximately 18 DLT-evaluable patients will be 
enrolled. 
The BOIN design will be implemented following the steps described below: 
1. Patients in the first cohort are treated at a starting dose with at least 3 evaluable patients. 
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2. A dose is assigned to the next cohort of patients according to the rule below: 
• If the observed DLT rate at the current dose is ≤𝜆𝑒= 0.197, escalate the dose to the 
next higher level. 
• If the observed DLT rate at the current dose is > 𝜆𝑑= 0.298, de-escalate the dose to the 
next lower dose level. 
• Otherwise, stay at the current dose. 
3. Repeat Step 2 until the maximum sample size of 18 is reached or stop the arm if the number 
of DLT-evaluable patients treated at the current dose level reaches 6 and the decision is made 
to stay at the current dose. Table 6.f presents the BOIN design decision rules for Group 1 
MM maintenance. 
Table 6.f 
BOIN Design Decision Rule for Group 1: MM Maintenance and Group 2: 
RRMM Doublets 
Number of evaluable patients treated 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if number of DLT ≤ 
0 
0 
0 
0 
0 
1 
1 
1 
1 
Deescalate if number of DLTs ≥ 
1 
1 
1 
2 
2 
2 
3 
3 
3 
Eliminate if number of DLTs ≥  
NA 
NA 
3 
3 
3 
4 
4 
4 
5 
BOIN: Bayesian Optimal Interval; DLT: dose-limiting toxicity; NA: not applicable, dose cannot be eliminated 
before 3 evaluable patients are treated; RRMM: relapsed/refractory multiple myeloma. 
Note: Number of DLTs is the number of patients with at least 1 DLT. If none of the actions (ie, escalate, 
de-escalate or eliminate) are triggered, stay at the current dose for treating the next cohort of patients.  
6.3.2 Group 2: RRMM Doublets 
The BOIN design will be implemented for dose escalation/de-escalation for RRMM doublets in 
the same way as in the MM maintenance group. The BOIN design decision rules are presented in 
Table 6.f. 
For Arm 2 (modakafusp + pomalidomide 4 mg), other dosing and/or schedules for 
pomalidomide (eg, 2 mg, 3 mg) may be explored on the basis of emerging data. If a different 
dose level of pomalidomide needs to be explored, the previous BOIN design will be considered 
to have stopped early, and a new BOIN design will be started for modakafusp alfa dose 
escalation/de-escalation with the new fixed pomalidomide dosing. 
Approximately 36 DLT-evaluable patients will be enrolled in the RRMM doublet combinations. 
Patients will be enrolled and treated in cohorts of approximately 3. At least 3 DLT-evaluable 
patients need to be treated at the starting dose prior to escalating to the next dose level, unless 
2 DLTs have been observed in the first 2 patients. 
6.3.3 Group 3: RRMM Triplets 
After the doublet RP2D is determined in RRMM doublets, dose escalation of modakafusp alfa in 
triplet combinations will begin. BOIN design will be employed to provide statistical guidance for 
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the dose escalation/de-escalation decisions. The target toxicity rate for the MTD is set to be 
𝜙= 0.33. For the purpose of overdose control, doses 𝑗 and higher levels will be eliminated from 
further examination if Pr(𝑝𝑗> 0.33 | data) >0.95 and at least 3 evaluable patients have been 
treated at dose level 𝑗, where 𝑝𝑗 is the true DLT rate of dose level 𝑗. When the lowest dose is 
eliminated, stop that arm for safety. It is estimated that approximately 36 DLT-evaluable patients 
will be enrolled.  
The escalation/de-escalation will be conducted in steps as follows: 
Patients in the first cohort are treated at the starting dose level with at least 3 evaluable patients. 
Assign a dose to the next cohort of patients according to the rule below: 
• If the observed DLT rate at the current dose is ≤𝜆𝑒= 0.260, escalate the dose to the next 
higher level. 
• If the observed DLT rate at the current dose is > 𝜆𝑑= 0.395, de-escalate the dose to the next 
lower dose level. 
• Otherwise, stay at the current dose. 
Repeat Step 2 until the maximum sample size of 18 is reached or stop that arm if the number of 
evaluable patients treated at the current dose reaches 9 and the decision is to stay at the current 
dose. Table 6.g presents the BOIN design decision rules for Group 3. 
Table 6.g 
BOIN Design Decision Table for Group 3: RRMM Triplets 
Number of evaluable patients treated 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Escalate if number of DLTs ≤ 
0 
0 
0 
1 
1 
1 
1 
2 
2 
2 
2 
3 
Deescalate if number of DLTs ≥ 
1 
1 
2 
2 
2 
3 
3 
4 
4 
4 
5 
5 
Eliminate if number of DLTs ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
6 
6 
7 
7 
BOIN: Bayesian Optimal Interval; DLT: dose-limiting toxicity; NA: not applicable, a dose cannot be eliminated 
before treating 3 evaluable patients; RRMM: relapsed/refractory multiple myeloma.  
Note: Number of DLTs is the number of patients with at least 1 DLT. If none of the actions (ie, escalate, de-
escalate or eliminate) are triggered, stay at the current dose for treating the next cohort of patients. 
 
Based on emerging data and/or and discussions between the sponsor and the investigators, the 
following measures are all permissible if such measures are needed for patient safety or for a 
better understanding of dose-related toxicity, exposure, or pharmacodynamics: 
• More conservative dose escalation. 
• Evaluation of intermediate doses. 
• Different dose schedule(s), alternative dose combinations, and/or dose schedule(s). 
• Expansion of an existing dose level. 
Before initiating dosing at the next dose level, when safety data are available for all patients in 
the current dose level, key safety data will be reviewed and evaluated by the study team 
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consisting of sponsor representatives and investigators who will review the safety of all treated 
patients and make decisions regarding dose escalation. All decisions will be documented in 
writing. Any decision to modify the dose escalation scheme in a direction that increases the 
already approved frequency of administration or dose escalation steps will be communicated to 
institutional review boards (IRBs), and the protocol will be amended accordingly. 
Details about the management of dose escalation decisions can be found in the cohort 
management plan. 
6.3.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4 
Number of Patients 
Approximately 120 patients will be enrolled into the following groups: 
• Group 1 (MM maintenance; Arm 1): Approximately 18 patients will be enrolled. 
• Group 2 (RRMM doublets): Approximately 66 patients will be enrolled.  
• Group 3 (RRMM triplets): Approximately 36 patients will be enrolled.  
Details on the definition of evaluable patients and sample size are given in Sections 13.1.1 and 
13.3, respectively.  
The study is planned to be conducted globally at approximately 50 investigational sites. 
Patients who are determined to be DLT nonevaluable will be replaced. The definition of DLT 
evaluable patients is provided in Section 8.5.1.  
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6.5 
Duration of the Study 
6.5.1 Duration of an Individual Patient’s Study Participation 
In the Group 1 MM maintenance, MRD[-] patients may receive modakafusp alfa in combination 
with lenalidomide for up to 2 years or until they experience disease progression or unacceptable 
toxicity, or until any other discontinuation criterion is met, whichever occurs first. MRD-positive 
patients at 2 years of maintenance may continue treatment with the agreement of the 
sponsor/designee. 
In the Group 2 RRMM doublets and Group 3 RRMM triplets, patients may receive modakafusp 
alfa in combination with associated agents until disease progression or unacceptable toxicity 
occurs or until any other discontinuation criterion is met (Section 9.11), whichever occurs first. 
Patients will be evaluated approximately 30 days (EOT visit) after the last dose of treatment or 
before the start of subsequent alternative anticancer therapy to permit the detection of any 
delayed TEAEs. 
For patients who discontinue modakafusp alfa in combination with associated agents before PD, 
disease evaluation should continue to be performed as specified in the SOEs (Appendix A). 
Patients who discontinue for PD will be followed for survival after documented PD for up to 
12 months after the last patient discontinues or completes treatment, or until loss of follow-up, 
consent withdrawal, death, study termination, or until ≥50% of patients in the cohort have died, 
whichever occurs first. 
Patients who discontinue for reasons other than PD will continue PFS follow-up Q4W from the 
EOT visit until the occurrence of PD, death, the start of subsequent systemic antineoplastic 
therapy, study termination (Section 6.5.4), or until 6 months after the discontinuation of study 
treatment, whichever occurs first. OS follow-up continues every 12 weeks until death, study 
termination, or patient withdrawal. 
6.5.2 Total Study Duration 
The study is expected to enroll patients for approximately 24 to 30 months and continue 
follow-up for a total duration of approximately 5 years. 
6.5.3 Posttrial Access 
At the conclusion or termination of the study (Section 6.5.4) or termination of a treatment arm in 
the study, ongoing patients who are continuing to experience clinically important benefit from 
modakafusp alfa in combination with assigned agent(s), have no locally available comparable or 
satisfactory alternative therapeutic option, and would be negatively affected without continued 
access to modakafusp alfa, in the opinion of the investigator and confirmed by the sponsor, may 
continue to receive modakafusp alfa through the posttrial access (PTA) program (where 
permitted by local regulations). 
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6.5.3.1 Duration of PTA 
Conditions under which the sponsor may terminate PTA to modakafusp alfa: 
• Patient has completed the protocol-defined course or duration of therapy as defined for the 
PTA program. 
• The benefit-risk profile is no longer favorable (eg, their disease has progressed, or treatment 
is no longer tolerable). 
• Modakafusp alfa becomes commercially available or another appropriate access mechanism 
becomes available. 
• An appropriate alternative therapy becomes available. 
• Marketing authorization has been rejected in the respective country. 
• Development of modakafusp alfa is suspended or ceased, or the sponsor cannot adequately 
supply modakafusp alfa.  
• After a predetermined period agreed on by the sponsor with input from investigators before 
the start of the study, documented in protocol and informed consent. 
6.5.3.2 Combination Agents 
Only modakafusp alfa, which should be used in combination only as part of a study-specified 
combination, will be provided by the PTA program, unless any country-specific laws and 
regulations require the sponsor to provide combination therapies as part of PTA. 
6.5.4 Definition of End of Study/Study Completion and Planned Reporting 
The final analysis for the clinical study report will be conducted after all patients enrolled in the 
study have completed all study assessments as outlined in the SOEs or have withdrawn from the 
study. 
Study participation by individual sites or the entire study may be prematurely terminated if, in 
the opinion of the investigator or the sponsor (Takeda), there is sufficient reasonable cause. 
Written notification documenting the reason for study termination will be provided 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 interim analysis.  
• Plans to modify, suspend, or discontinue development of the study drug.  
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Should the study be closed prematurely, the site will no longer be able to access the electronic 
data capture (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 independent ethics committees (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. 
7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all the following criteria to be enrolled in the study: 
1. Adult patient aged ≥18 years at the time of the informed consent. 
2. All patients in Group 1 (MM maintenance: modakafusp alfa/lenalidomide) only must have: 
a) MM based on standard IMWG diagnostic criteria (Appendix G).  
b) Undergone ASCT for the treatment of MM within 12 months of the start of induction 
therapy and completed ASCT within 180 days before enrollment (regardless of the lines 
of treatment). Consolidation cycles are allowed. Tandem transplant is allowed.  
c) Not started lenalidomide maintenance before enrollment. Time to initiation of 
maintenance therapy: Patients may start maintenance therapy as early as 60 days after 
transplantation and up to 180 days after transplantation or consolidation. 
d) MRD positive after ASCT (MRD assessed at a threshold of 10-5 by local SOC methods or 
central assessment, if a prior local MRD assessment had not been performed). 
e) No prior progression after initial therapy (at any time before starting maintenance). 
Patients whose induction therapy was changed due to suboptimal response or toxicity will 
be eligible if they do not meet criteria for progression. In addition, no more than 
2 regimens will be allowed before ASCT, excluding dexamethasone alone. 
f) No prior allogeneic hematopoietic stem cell transplant or solid organ transplant. 
g) Recovered to Grade ≤1 ASCT-related toxicities from the reversible effects of ASCT 
(except for alopecia and amenorrhea). 
3. All patients in Groups 2 and 3 (RRMM doublets and RRMM triplets) must have  
a) Measurable disease, defined as at least 1of the following:  
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• Serum M-protein ≥0.5 g/dL (≥5 g/L) on serum protein electrophoresis (SPEP).  
• Urine M-protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).  
• Serum FLC assay result with an involved FLC level ≥10 mg/dL (≥100 mg/L), 
provided the serum FLC ratio is abnormal (per IMWG criteria).  
b) A confirmed diagnosis of MM according to IMWG criteria (Appendix G) with 
documented disease progression in need of additional therapy as determined by the 
investigator. 
c) For Group 2 RRMM doublet arms only: Patients who have received at least 3 prior lines 
of antimyeloma therapy, including at least 1 PI, 1 IMiD, and 1 anti-CD38 mAb drug, or 
who are triple refractory to a PI, and IMiD, and an anti-CD38 mAb drug regardless of the 
number of prior line(s) of therapy.  
d) For Group 3 RRMM triplet arms only: Patients who have received 1 to 3 prior lines of 
antimyeloma therapy, including at least 1 PI and 1 IMiD, and who are not refractory* to 
the combination partners. 
e) For anti-CD38 arms, forced expiratory volume in 1 second (FEV1) ≥50% predicted by 
pulmonary function testing. 
NOTES: 
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of 
a combination of several drugs, or a planned sequential therapy of various regimens. (For 
example, 3-6 cycles of initial therapy with bortezomib-dexamethasone followed by a 
stem cell transplantation, consolidation, and maintenance is considered 1 line.)  
* Refractory myeloma is defined as disease that is nonresponsive while the patient is 
receiving primary or salvage therapy or progresses within 60 days of last therapy. 
Nonresponsive disease is defined as either failure to achieve at least a minimal response 
or the development of PD while on therapy (Rajkumar et al. 2011). 
4. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 
or 2 at screening (Appendix H). 
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5. The patient has adequate organ function at screening as determined by the laboratory values 
shown in Table 7.a: 
Table 7.a 
Laboratory Values Required for Enrollment 
ANC a 
≥1000/mm3 (≥1.0×109/L) 
Platelets a 
≥75,000/mm3 (≥75 × 109/L) 
Hemoglobin 
≥8.0 g/dL 
Estimated creatinine clearance 
≥30 mL/min (Cockcroft-Gault formula) b 
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: ANC: absolute neutrophil count; AST: aspartate aminotransferase; ULN: 
upper limit of normal. 
a  
Without ongoing growth factor for at least 3 days before Day 1 or transfusion support for at least 1 week 
before Day 1. 
b  Estimated creatinine clearance ≥60 mL/min (Cockcroft-Gault formula) for the first 3 patients in Arm 3. 
6. The patient has recovered from adverse reactions to prior myeloma treatment or procedures 
(eg, chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5.0 
Grade ≤1 or baseline treatment or have the toxicity established as sequela, except for sensory 
or motor neuropathy, which should have recovered to Grade ≤2 or baseline (Grade 1 for the 
bortezomib arm). 
7. Patients with uterus and ovary(ies) who: 
• Are postmenopausal (amenorrheic) 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 modakafusp alfa or through the period 
defined by label for combination agents, whichever is longer, 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 of the informed consent through 
7 days after the last dose of modakafusp alfa or through the period defined by label 
for combination agents, whichever is longer. (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.) 
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▪ Agree not to donate an egg or eggs (ova) during the study and for 7 days after the last 
dose of modakafusp alfa or through the period defined by label for combination 
agents, whichever is longer.  
• Must also adhere to guidelines to any treatment-specific pregnancy prevention program, 
if applicable, as appropriate in the country (eg, Risk Evaluation and Mitigation Strategy 
[REMS] or Pregnancy Prevention Program for lenalidomide or pomalidomide). 
8. Patients with testis(es), even if surgically sterilized (ie, status postvasectomy), who: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and through 7 days after the last dose of modakafusp alfa or through the period defined 
by label for combination agents, whichever is longer, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject, from the signing of the informed consent form (ICF) through 
7 days after the last dose of modakafusp alfa or through the period defined by label for 
combination agents, whichever is longer. (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 from the signing of the ICF through 7 days after the last dose 
of modakafusp alfa or through the period defined by label for combination agents, 
whichever is longer. 
• Must also adhere to guidelines to any treatment-specific pregnancy prevention program, 
if applicable, as appropriate in the country (eg, REMS or Pregnancy Prevention Program 
for lenalidomide or pomalidomide). 
9. The minimal interval between the last dose of any of the following treatments/procedures and 
the first dose of the study treatment must be at least those shown below:  
Chemotherapy, including PIs and IMiDs 
14 days 
Bispecific antibodies 
28 days 
Any investigational anticancer product 
28 days 
Corticosteroid therapy for myeloma. 
7 days 
Radiation therapy for localized bone lesions: Prophylactic 
localized (“spot”) radiation for areas of pain is allowed. 
7 days 
Major surgery: Patients should be fully recovered from 
any surgically-related complications. 
28 days 
Plasmapheresis 
28 days 
Inoculation with any live virus (eg, varicella) 
30 days 
IMiD: immunomodulatory drug; PI: proteosome inhibitor.  
 
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10. The patient has suitable venous access for safe drug administration and the study-required 
blood sampling. 
11. Voluntary written or electronic consent (eConsent) must be given before performance of any 
study‑related procedure that is 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. 
12. 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 criteria are not to be enrolled in the study: 
1. The patient is currently participating in another MM interventional study, including other 
clinical trials with investigational agents (including investigational vaccines or 
investigational medical device for disease under study) throughout the duration of this study. 
2. The patient received previous treatment with modakafusp alfa.  
3. The patient has a diagnosis of primary amyloidosis, Waldenström disease, monoclonal 
gammopathy of undetermined significance or smoldering MM per IMWG criteria or standard 
diagnostic criteria, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes), or lymphoplasmacytic lymphoma. 
4. The patient has been diagnosed with another 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 and that in the opinion of 
the local investigator, with concurrence with the sponsor, is considered cured with minimal 
risk of recurrence within 3 years. 
5. The patient has evidence of CNS involvement and/or meningeal involvement due to MM 
exhibited during screening. 
6. The patient has a known severe allergic or anaphylactic reactions to human recombinant 
proteins or excipients used in the modakafusp alfa formulation or to the study combination 
agents, the study medications, their analogs, or excipients in the various formulations of any 
agent per the prescribing information. 
7. The patient has a history of treatment discontinuation due to treatment-related toxicity to the 
combination agent per the investigator. For lenalidomide arm: The patient is intolerant to 
lenalidomide. 
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8. The patient is unable to take label-recommended/required prophylaxis needed for 
combination agents (eg, antithrombotic prophylaxis for lenalidomide and pomalidomide, 
antiviral prophylaxis for PI). 
9. The patient is unable or unwilling to swallow PO medication or to comply with the drug 
administration requirements, or gastrointestinal procedure that could interfere with the PO 
absorption or tolerance of PO combination agents.  
10. The patient has a known history of seropositivity for HIV. 
11. The patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface 
antigen [HBsAg]). Patients with 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 hepatitis B virus (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. 
12. The patient has a known history of seropositivity for hepatitis C (anti-hepatitis C virus 
antibody positive or anti-hepatitis C virus–RNA quantitation positive). Exception: Patients 
with a sustained virologic response with undetectable HCV RNA level at least 12 weeks after 
completion of antiviral therapy. 
13. For bortezomib arms: patient received a strong CYP3A4 inducer within 5 half-lives prior to 
randomization. 
14. The patient has a chronic condition requiring the use of systemic corticosteroids >10 mg/d of 
prednisone or equivalent in addition to any required corticosteroids for the treatment of MM. 
15. The patient has a QTcF (QT interval corrected with Fridericia correction method) >480 ms 
(Grade ≥2).  
16. Patient has a history of acute myocardial infarction within 5 months from enrollment or has 
electrocardiographic (ECG) abnormalities during screening that are deemed medically 
relevant by the investigator. 
17. Patient has congestive heart failure (New York Heart Association Grade ≥II), cardiac 
myopathy, active ischemia, or any other uncontrolled cardiac conditions such as angina 
pectoris, clinically significant arrhythmias requiring therapy (eg, anticoagulants), or clinically 
significant uncontrolled hypertension. 
18. Patient has a high risk of hemorrhage such as uncontrolled chronic bleeding disorder or is 
currently being treated with therapeutic anticoagulation. Antithrombotic prophylaxis for 
lenalidomide and pomalidomide is authorized. 
19. The patient has any concurrent or uncontrolled medical, comorbid, or psychiatric condition 
or disease that is likely to interfere with the study procedures or results, or that in the opinion 
of the investigator, would constitute a hazard for participating in this study. 
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20. The patient has a psychiatric illness/social circumstance that would limit compliance with 
study requirements and substantially increase the risk of TEAEs or compromised ability to 
provide written informed consent. 
21. Patient is lactating and breastfeeding or has a positive urine or serum pregnancy test during 
the screening period or a positive urine or serum pregnancy test before first dose of study 
drug. 
8.0 
STUDY DRUG 
8.1 
Study Drug Administration 
8.1.1 Modakafusp Alfa 
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 identified sub investigator(s). 
Modakafusp will be administered by infusion over 1 hour (±10 minutes). Any decrease in 
infusion duration must be discussed with and agreed upon by the sponsor. 
In the combination arms with SC combination agents (eg, bortezomib, daratumumab), the 
combination agent will be administered before modakafusp alfa on days on which both agents 
are given on the same visit day. At least 30 minutes should elapse between the completion of the 
injection of the first study drug and the initiation of the infusion of modakafusp alfa. 
In the combination arms with PO combination agents (eg, lenalidomide, pomalidomide), the PO 
combination agent should be administered at about the same time each day. When both 
modakafusp alfa and the PO combination agent are given on the same visit day, the PO 
combination agent should not be taken at the same time as modakafusp alfa (at least 30 minutes 
should elapse between the administration of the 2 drugs). 
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. 
8.1.1.1 Premedications 
It is mandatory 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 infusion of modakafusp alfa, patients must receive the following premedications 
unless contraindicated per investigator discretion: 
• Corticosteroid IV or PO (methylprednisolone 100 mg, dexamethasone 20 mg, or equivalent). 
If a patient does not experience a significant IRR, the dose of methylprednisolone may be 
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decreased to 60 mg (or dexamethasone to 12 mg) after Cycle 3. Intermediate- or long-lasting 
steroids of equivalent dose can be substituted.  
• Acetaminophen 650 to 1000 mg PO.  
• Antihistamine: Diphenhydramine 25 to 50 mg PO or equivalent. A second-generation 
antihistamine (eg, cetirizine) may be substituted if a first-generation antihistamine is not 
tolerated or available. 
Montelukast 10 mg PO and/or H2 blockers may be given to patients who are intolerant to 
antihistamines or for whom antihistamines are ineffective or not available. 
Premedications must be administered before daratumumab SC to comply with the daratumumab 
label. When daratumumab is given during the same visit as modakafusp alfa, administer the 
modakafusp alfa–specific premedications only prior to the daratumumab. Do not administer 
daratumumab-specific premedications on modakafusp alfa administration days (CxD1) when 
patients have received modakafusp alfa premedication. 
8.1.1.2 Postinfusion Medication 
Administer 20 to 25 mg of prednisone or 4 mg of dexamethasone PO or equivalent on the first 
and second days after all full-dose infusions (CxD2 and CxD3). Other concomitant medications 
can be administered per institutional protocols. 
During all infusions and for at least 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. See Section 8.7 for further information. 
On days when both daratumumab and hyaluronidase-fihj and modakafusp alfa are given on the 
same visit day, administer the modakafusp alfa–specific postmedication only. 
8.1.1.3 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 or as recommended with specific combinations agents as 
described below.  
8.1.2 Combination Agents 
8.1.2.1 Lenalidomide Administration, Premedications and Prophylaxis 
Lenalidomide 10 mg will be administered QD continuously (Days 1 to 28) per Section 6.2.1. 
After 3 cycles of maintenance therapy, the dose of lenalidomide, per label, can be increased to 
15 mg QD if tolerated. Lenalidomide should be taken at about the same time each day. When 
both modakafusp alfa and lenalidomide are given on the same visit day, lenalidomide should not 
be administered at the same time as modakafusp alfa. (At least 30 minutes should elapse between 
the administration of the 2 drugs.) 
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Usage should be in accordance with the precautions and instructions provided by the 
manufacturer. Additional drug description, preparation, storage, and handling instructions will be 
provided in the pharmacy manual. 
Antithrombotic prophylaxis is recommended. The choice of regimen should be based on 
assessment of the patient’s underlying risk factors. Monitoring of liver enzymes and thyroid 
function during therapy is recommended. 
Lenalidomide is similar to thalidomide and may cause severe life-threatening birth defects. 
Mandatory adherence to guidelines to any treatment-specific pregnancy prevention program, if 
applicable, as appropriate in the country (eg, REMS or Pregnancy Prevention Program for 
lenalidomide) is required. 
Participants with a uterus/ovary(ies) must avoid pregnancy for at least 4 weeks before beginning 
lenalidomide therapy, during therapy, during dose interruptions, and for at least 4 weeks after 
completing therapy. Participants must commit either to abstain continuously from heterosexual 
sexual intercourse or to use 2 methods of reliable birth control beginning 4 weeks before 
initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing 
for 4 weeks after discontinuation of lenalidomide therapy. 
Two negative pregnancy test results must be obtained before initiating therapy. The first test 
should be performed within 10 to 14 days and the second test within 24 hours before the 
beginning of lenalidomide therapy. Pregnancy tests should then be obtained weekly during the 
first month, and monthly thereafter for participants with regular menstrual cycles, or every 
2 weeks for participants with irregular menstrual cycles. 
Drug Interactions 
Digoxin: Lenalidomide may increase digoxin plasma levels. Periodically monitor digoxin plasma 
levels with concomitant lenalidomide therapy in accordance with clinical judgment and based on 
standard clinical practice in patients receiving this medication. 
Concomitant therapies that may increase the risk of thrombosis: Erythropoietic agents, or other 
agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be 
used with caution after making a benefit-risk assessment in patients receiving lenalidomide. 
Warfarin: Close monitoring of PT and INR is recommended in patients with MM receiving 
lenalidomide and taking concomitant warfarin (Revlimid (lenalidomide) 2021). 
8.1.2.2 Pomalidomide Administration, Premedications and Prophylaxis 
The pomalidomide dose will be 4 mg PO on Days 1 through 21 of each 28-day cycle per 
Sections 6.2.2 and Section 6.2.3. Pomalidomide should be taken at about the same time each day. 
When both modakafusp alfa and pomalidomide are given on the same visit day, pomalidomide 
should not be administered at the same time as modakafusp alfa. (At least 30 minutes should 
elapse between the administration of the 2 drugs.)  
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Usage should be in accordance with the precautions and instructions provided by the 
manufacturer. Additional drug description, preparation, storage, and handling instructions will be 
provided in the pharmacy manual. 
Antithrombotic prophylaxis is recommended. The choice of regimen should be based on 
assessment of the patient’s underlying risk factors. Monitoring of liver enzymes monthly is 
recommended. 
For patients with hepatic impairment, reduce the dosage of pomalidomide per label. 
Pomalidomide is similar to thalidomide and may cause severe life-threatening birth defects. 
Mandatory adherence to guidelines to any treatment-specific pregnancy prevention program, if 
applicable, as appropriate in the country (eg, REMS or Pregnancy Prevention Program for 
pomalidomide) is required. 
Participants with a uterus/ovary(ies) must avoid pregnancy for at least 4 weeks before beginning 
pomalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after 
completing therapy. Participants must commit either to abstain continuously from heterosexual 
sexual intercourse or to use 2 methods of reliable birth control beginning 4 weeks before 
initiating treatment with pomalidomide, during therapy, during dose interruptions, and 
continuing for 4 weeks following discontinuation of pomalidomide therapy. 
Two negative pregnancy test results must be obtained before initiating therapy. The first test 
should be performed within 10 to 14 days and the second test within 24 hours before prescribing 
pomalidomide therapy. Pregnancy tests should then be obtained weekly during the first month, 
and monthly thereafter for participants with regular menstrual cycles, or every 2 weeks for 
participants with irregular menstrual cycles.  
Drug Interactions 
Strong CYP1A2 Inhibitors: Avoid concomitant use of strong CYP1A2 inhibitors. If concomitant 
use of a strong CYP1A2 inhibitor is unavoidable, reduce pomalidomide dose per label (Pomalyst 
(pomalidomide) Capsules 2020).  
8.1.2.3 Bortezomib Administration, Premedications and Prophylaxis 
The bortezomib dose will be 1.3 mg/m2 SC on Days 8, 15 and 22 of each 28-day cycle for the 
first 8 cycles and subsequently on Days 8 and 22 per Section 6.2.2 and Section 6.2.3. Use should 
be in accordance with the precautions and instructions provided by the manufacturer. Additional 
drug description, preparation, storage, and handling instructions will be provided in the 
pharmacy manual. 
When administered SC, sites for each injection (thigh or abdomen) should be rotated. New 
injections should be given at least 1 inch from a recent site and never into areas that are tender, 
bruised, erythematous, or indurated. 
Antiviral prophylaxis for herpes zoster reactivation is recommended. 
For patients with hepatic impairment, adjust the starting dose of bortezomib per label. 
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Drug Interactions 
Strong CYP3A4 Inducers: Avoid concomitant use of strong CYP3A4 Inducers.  
Strong CYP3A4 Inhibitors: Closely monitor patients for signs of bortezomib toxicity with 
concomitant use of strong CYP3A4 inhibitors and consider a bortezomib dose reduction if 
bortezomib must be given in combination with strong CYP3A4 inhibitors per label 
(Velcade (bortezomib) for Injection 2019). 
For the reconstitution/preparation of bortezomib, please refer to the prescribing information. 
8.1.2.4 Daratumumab Administration, Premedications and Prophylaxis 
8.1.2.4.1 Administration 
The daratumumab dose will be 1800 mg SC on Days 1, 8, 15, and 22 of Cycles 1 and 2, then on 
Days 1 and 15 of Cycles 3 to 6, then on Day 1 thereafter per Section 6.2.3. No dose reduction is 
permitted for daratumumab. Usage should be in accordance with the precautions and instructions 
provided by the manufacturer. Additional drug description, preparation, storage, and handling 
instructions will be provided in the pharmacy manual. 
Daratumumab and hyaluronidase-fihj will be administered before modakafusp alfa on days when 
both agents are given on the same visit day. At least 30 minutes should elapse between the 
completion of the injection of the first study drug and the initiation of the infusion of the second 
study drug. 
Further information about SC daratumumab can be found in Section 4.3.4. 
8.1.2.4.2 Premedications 
Before each injection, patients will receive the following premedications approximately 1 to 
3 hours before the daratumumab and hyaluronidase-fihj on each dosing day (Darzalex Faspro 
(daratumumab and hyaluronidase-fihj) injection for subcutaneous use 2021). 
• Methylprednisolone 100 mg (or approximate equivalent such as dexamethasone 20 mg) PO 
or IV for the initial injection. Consider reducing the dose of methylprednisolone to 60 mg (or 
approximate equivalent such as dexamethasone 12 mg) PO or IV following the second dose 
of daratumumab and hyaluronidase-fihj before subsequent injections. 
• Antipyretics: PO acetaminophen (650 to 1000 mg). 
• Antihistamines: PO or IV diphenhydramine (25 to 50 mg, or equivalent). 
On days when both daratumumab and hyaluronidase-fihj and modakafusp alfa are given on the 
same visit day, administer the modakafusp alfa-specific premedications only. 
8.1.2.4.3 Postmedication 
Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting 
corticosteroid such as dexamethasone 4 mg) PO for 2 days starting the day after the 
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administration of daratumumab and hyaluronidase-fihj (Darzalex Faspro (daratumumab and 
hyaluronidase-fihj) injection for subcutaneous use 2021). 
On days when both daratumumab and hyaluronidase-fihj and modakafusp alfa are given on the 
same visit day, administer the modakafusp alfa–specific postmedication only. 
If the patient does not experience a major systemic administration-related reaction after the first 
3 doses of daratumumab and hyaluronidase-fihj, consider discontinuing the administration of 
corticosteroids (excluding any background regimen-specific corticosteroid or corticosteroids 
required as a premedication/postmedication for the combination drug such as modakafusp alfa). 
Note: For any patient with a history of chronic obstructive pulmonary disease, consider 
prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 
4 doses of daratumumab and hyaluronidase-fihj, consider discontinuing these additional 
postmedications if the patient does not experience a major systemic administration-related 
reaction (Darzalex Faspro (daratumumab and hyaluronidase-fihj) injection for subcutaneous use 
2021). 
8.1.2.4.4 Prophylaxis for Herpes Zoster Reactivation 
Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting 
daratumumab and hyaluronidase-fihj and continue for 3 months following EOT. 
8.2 
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 electronic 
case report forms (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 [G-CSF], granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. G-CSF is allowed to 
accelerate the recovery of neutropenia to enable the start of new cycle (Section 8.6.1.1). 
• Patients should be transfused with RBCs 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 or antiosteolytic mAbs 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. 
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• Systemic steroids for acute management of pain, suspected or confirmed immune-mediated 
thrombocytopenia or other disease or treatment-related complications are permitted. 
• Plasmapheresis. 
• Intravenous immunoglobulin (IVIG) usage is acceptable for prolonged Grade 4 transfusion-
dependent thrombocytopenia, hypogammaglobulinemia, 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. 
8.3 
Prohibited 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 or the study combination agents, 
including agents that are commercially available for indications other than MM that are 
under investigation for the treatment of MM. 
• Carfilzomib: Modakafusp alfa is contraindicated in combination with carfilzomib. See 
Section 4.2.4.4 for more information.  
• 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, if tumor flare is 
suspected, or as needed for other disease or treatment-related complications. 
• Live vaccines are excluded within 30 days before the first administration of study treatment 
and for 90 days after completion of study treatment.  
Please see Sections 8.2 and 8.7 and individual prescribing information for possible excluded 
medications, supplements, and dietary products for each combination agent. 
8.4 
List of European Union Auxiliary Medicinal Products Used in the Trial Other Than 
the Investigational Products  
Below are required concomitant medications essential to the assessment of safety or efficacy of 
the investigational medicinal product, required rescue medications, and required prophylaxis 
and/or required challenge medications.  
• 
Corticosteroids. 
• Analgesics and antipyretics. 
• Antihistamines. 
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• Leukotriene receptor antagonists. 
• Antivirals. 
• Antithrombotic agents.  
8.5 
DLTs 
Toxicity will be evaluated according to the NCI CTCAE, Version 5.0. 
Patients will be monitored through all cycles of therapy for treatment-related toxicities. DLTs 
will be evaluated at the end of Cycle 1. The DLT evaluation period may be increased as needed 
for safety reasons. Primarily, only toxicities that occur during Cycle 1 will be used for the 
purposes of defining DLT for future cohort expansion or dose modification decisions. If 
noncompliance with protocol defined requirements (eg, antiviral prophylaxis) results in Grade >3 
toxicities, these toxicities should not be considered DLTs. Use of platelet transfusions or growth 
factors to manage AEs that may represent DLTs, but are not yet clearly a DLT, should be 
discussed with the sponsor. TEAEs that are clearly not treatment related will not be defined as 
DLTs. 
A DLT will be defined as any of the following events that are considered by the investigator to 
be at least possibly related to modakafusp alfa:  
• Delay in the initiation of Cycle 2 by more than 14 days due to inadequate recovery of 
treatment-related hematological or nonhematologic toxicities. 
• Any Grade 5 AE. 
• Hematologic toxicity clearly unrelated to the underlying disease is defined as follows: 
– Nonfebrile Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 × 109/L; ANC 
<500 cells/mm3) lasting more than 7 consecutive days. 
– Febrile neutropenia: Grade ≥3 neutropenia (ANC <1.0 × 109/L; ANC <1000 cells/mm3) 
with fever and/or infection, where fever is defined as a body temperature >38.3°C or 
sustained temperature ≥38.0°C for more than 1 hour. 
– Grade 4 thrombocytopenia (platelets <25,000/mm3) lasting more than 14 consecutive 
days. 
– Grade 3 thrombocytopenia (25,000 <platelets< 50,000/mm3) with clinically significant 
bleeding. 
• Any other Grade ≥4 hematologic toxicity with the exception of Grade 4 lymphopenia. 
• Nonhematologic toxicity Grade ≥3 clearly unrelated to the underlying disease, with the 
exception of:  
– Asymptomatic laboratory changes (other than renal and hepatic laboratory values) 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. 
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– Grade 3 nausea and/or emesis that can be controlled to Grade ≤3 in ≤2 days with the use 
of optimal antiemetics (defined as an antiemetic regimen that employs both a serotonin 
receptor subtype 3 antagonist and a corticosteroid given in standard doses and according 
to standard schedules). 
– Grade 3 elevation in ALT, AST, and/or alkaline phosphatase that resolves to Grade ≤1 or 
baseline with supportive care within 7 days and is not associated with other clinically 
relevant consequences. 
– Grade 3 IRR that resolves with appropriate clinical treatment, without recurrence of 
Grade 3 symptoms. 
– Grade 3 fatigue lasting less than 72 hours. 
– Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs 
(NSAIDs) within 7 days. 
– Grade 3 diarrhea that can be controlled to Grade <3 in ≤3 days with appropriate 
treatment. 
– Grade 3 rash and pruritis that respond to standard treatment and resolve or improve to 
Grade <3 in ≤72 hours. 
8.5.1 Definition of DLT-Evaluable Patients 
The DLT-evaluable analysis set will include patients who experienced a DLT in Cycle 1 in the 
treatment phase of the study or patients who received a full dose of modakafusp alfa and at 
least 75% of the planned dose of the combination partners and completed evaluation for DLT in 
Cycle 1. The DLT-evaluable population will be used to determine the RP2D/MTD.  
Patients who withdraw before completing the DLT assessment period for reasons other than a 
DLT, or who do not fulfill either of the criteria above, will not be evaluable for assessment of 
DLT for dose review decisions and will be replaced in the cohort. 
8.5.2 Intrapatient Dose Escalation 
Intrapatient dose escalation will be permitted only when patients have completed assessments for 
Cycle 1. Patients eligible for intrapatient escalation can also be changed to a different schedule 
once the conditions described above are met. 
Patients who have tolerated treatment with modakafusp alfa well at the initially assigned dose 
may be allowed to increase their doses of modakafusp alfa in subsequent cycles of treatment 
following sponsor and investigator review of the available data. If the modakafusp alfa dose is to 
be increased, it may be increased to the highest dose that has been evaluated in the study and 
found to have an acceptable rate of DLT.  
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CONFIDENTIAL 
8.6 
Dose Modification Guidelines  
8.6.1 Modakafusp Alfa and Combination Agent(s) 
8.6.1.1 Criteria for Cycle 1 Day 1 
For initiating Cycle 1 Day 1 of treatment (modakafusp alfa and combination agents), the patient 
must meet the following criteria: 
• ANC ≥1000/mm3 without ongoing G-CSF for at least 3 days before Cycle 1 Day 1. 
• Platelet count must be ≥75,000/mm3 without ongoing transfusion support for at least 1 week 
before Cycle 1 Day 1. Platelet transfusions can be given any time as clinically indicated but 
should not be given for only the purpose of meeting the treatment criterion for platelet count.  
• Hb ≥8 g/dL. RBC transfusions can be given any time as clinically indicated. 
The above-cited criteria apply to modakafusp alfa and the combination agent(s).  
8.6.1.2 Criteria for Beginning or Delaying a Subsequent Treatment Cycle (Cycle 2 Day 1 and 
Beyond) 
For a new cycle of treatment (modakafusp alfa and combination agents) to begin, the patient 
must meet the following criteria: 
• ANC ≥1000/mm3. G-CSF can be used to reach this level. G-CSF can be used to reach this 
level. 
• Platelet count must be ≥50,000/mm3. Platelet transfusion can be applied any time it is 
clinically indicated, but it should not be applied for only the purpose of meeting the treatment 
criterion for platelet count. 
The aforementioned criteria apply to modakafusp alfa.  
For therapy to resume, toxicity considered 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 
investigator. If the patient fails to meet the previously 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 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. 
8.6.1.3 Modakafusp Alfa 
Dose modification guidelines for toxicities are described herein 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). 
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82 of 200 
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CONFIDENTIAL 
Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 of 
treatment will necessarily influence decisions regarding dose escalation, expansion of a dose 
level, or evaluation of intermediate dose levels. Dose modifications are not permitted during 
Cycle 1 of therapy unless the patient experiences a DLT. DLTs are defined in Section 8.5. If a 
patient experiences a DLT during Cycle 1, the event will be counted toward the assessment of 
tolerable combination agent doses for the given cohort. Patients experiencing DLTs in Cycle 1 
may continue in the study, but doses of lenalidomide, bortezomib, pomalidomide, daratumumab, 
or modakafusp alfa will be reduced as appropriate. Patients will be evaluated weekly for possible 
toxicities that may have occurred after the previous dose(s). 
Toxicities are to be assessed according to the NCI CTCAE, Version 5.0. Toxicities should be 
attributed to a specific drug, if possible, to allow appropriate dose modification(s). Reduction of 
1 agent and not the other is appropriate if toxicity is related primarily to 1 of the agents. 
Before beginning the next cycle of treatment, refer to the dose modification guidelines below. 
Further clarification can be obtained in consultation with the sponsor clinician (or designee). If 
multiple toxicities are noted, the dose adjustments and/or delays should be made according to the 
AE with the highest toxicity grade. The same dose modification guidelines will apply to 
subsequent cycles unless otherwise noted. Toxicities should be attributed to a specific study 
drug, if possible, to allow appropriate dose modification. If attribution to either drug is unclear, 
dose modification of modakafusp alfa should be considered first to allow full dosing of the 
combination agent if it is a reasonable approach for the particular situation. 
Dose modification of the combination drugs should be in accordance with the respective drug’s 
prescribing information. Alternative dose modifications may be recommended after discussion 
with the investigator and sponsor clinician/designee to maximize exposure of study treatment 
while protecting patient safety. 
8.6.1.4 Criteria for Dose Interruption 
All toxicities that occur during the study will be actively managed following the SOC unless 
otherwise specified in the protocol. Patients experiencing AEs attributed to modakafusp alfa may 
continue study treatment with the same dose, have modakafusp alfa treatment held, have the dose 
reduced, or 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. 
Table 8.a and Table 8.b provide general dose modification recommendations for nonhematologic 
and hematologic toxicities, respectively. Table 8.c provides dose modification recommendations 
for bleeding TEAEs to mitigate the risk of fatal hemorrhagic events. If the modakafusp alfa dose 
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. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
83 of 200 
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
Table 8.a 
Dose Modification Recommendations for Modakafusp Alfa 
Nonhematological Toxicities 
This table does not include guidance for management of bleeding TEAEs and IRRs. Refer to 
Table 8.c for the management of bleeding TEAEs and Table 8.e and Table 8.f 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. 
First 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 >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. 
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.c or for 
the management of IRRs, which is found in Table 8.e, Table 8.f, and Section 8.7.1.1. 
 
Table 8.b 
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.c for the management of bleeding TEAEs and Table 8.e and Table 8.f 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 
when clinically indicated. Please refer to Section 8.6.1 for the criteria of 
starting a new cycle of treatment. 
If the next cycle of modakafusp alfa is delayed for >14 days, study 
treatment should be discontinued unless the investigator considers that the 
patient will receive benefit continuing in the study. 
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.c or for 
the management of IRRs, which is found in Table 8.e, Table 8.f, and Section 8.7.1.1. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
84 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Table 8.c 
Dose Modification Recommendations for Modakafusp Alfa Bleeding 
TEAEs 
This table does not include guidance for management of IRRs. Refer to Table 8.e and Table 8.f 
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.e, Table 8.f, and 
Section 8.7.1.1. 
8.6.1.5 Criteria for Dose Reduction 
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 (Table 8.d). 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. 
Table 8.d 
Dose Reduction Levels for Modakafusp Alfa 
Starting Dose 
80 mg 
120 mg 
240 mg 
First dose level reduction 
60 mg 
80 mg 
120 mg 
Second dose level reduction 
Discontinue treatment 
60 mg 
80 mg 
Third dose level reduction 
NA 
Discontinue treatment 
60 mg 
NA: not applicable. 
 
8.6.1.6 Criteria for Discontinuation 
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 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 be evaluated approximately 
30 days after the last dose of treatment (end-of-treatment [EOT] visit) or right before the start of 
subsequent systemic anticancer therapy to permit the detection of any delayed TEAEs. 
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Study No. TAK-573-1502  
85 of 200 
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CONFIDENTIAL 
Patients who discontinue modakafusp alfa because of TEAEs assessed by the investigator as 
related only to modakafusp alfa may continue the combination agent(s) at the discretion of the 
investigator and with agreement by the sponsor. 
8.6.2 Combination Agents 
Dose modifications (dose change, interruption, discontinuation) of the combination drugs should 
be done in accordance with the respective drug’s local prescribing information. Alternative dose 
modifications may be recommended after discussion with the investigator and sponsor to 
maximize exposure of study treatment while protecting patient safety. 
8.7 
Management of Specific Adverse Reactions  
8.7.1 Modakafusp alfa 
8.7.1.1 Handling of IRRs Related to Modakafusp Alfa 
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 mandatory that all patients receive premedication, including corticosteroids, before 
modakafusp alfa dosing (Section 8.1.1.1). Recommendations for premedications for combination 
therapies are detailed in Section 8.11.2. On days on which combination agents are given on the 
same visit day as modakafusp alfa, administer the modakafusp alfa-specific premedication only. 
If a patient presents with an IRR at any dose level, the duration of the infusion of modakafusp 
alfa 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 and for at least 2 hours 
post infusion. Trained study 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, a serum sample for circulating biomarkers, a blood sample for flow 
cytometry, a blood sample for RNA, and a serum sample for immunogenicity (ADA/NAb) 
should be collected, if clinical management of the patient allows (as detailed in the SOEs in 
(Appendix A). 
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. All IRRs, including the signs and symptoms, will be reported in the 
eCRF per completion guidelines.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
86 of 200 
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CONFIDENTIAL 
Serious AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner. 
Grade 1 and 2 IRRs 
The recommendations for managing Grade 1 and Grade 2 IRRs are presented in Table 8.e. 
Table 8.e 
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. 
On 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.  
Grade 2 or higher event of laryngeal 
edema, or Grade 2 or higher 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. 
 
Grade 3 or Higher IRRs 
The recommendations for managing Grade ≥3 IRRs are presented in Table 8.f. 
Table 8.f 
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 events 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. Within 2 hours of restart, the infusion rate 
should be half 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. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
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CONFIDENTIAL 
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 
permanently discontinued. If at any time the platelet count is less than 10 × 109/L, after initiation 
of modakafusp alfa treatment, 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. Dose modification for bleeding TEAEs should 
follow the recommendations included in Table 8.c. 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. 
8.7.1.3 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. 
8.7.2 Combination Agents 
Please refer to the product labels for lenalidomide, pomalidomide, bortezomib and daratumumab 
for the management of product related clinical events.  
On days when both daratumumab SC and modakafusp alfa are administered, please refer to 
product label for daratumumab SC for the management of IRR events when they occur after 
daratumumab SC administration and before modakafusp alfa administration.  
8.8 
Precautions and Restrictions 
8.8.1 Contraception and Pregnancy Avoidance Procedures 
It is not known what effects modakafusp alfa has on human pregnancy or development of the 
embryo or fetus; therefore, patients participating in this study should avoid becoming pregnant or 
avoid impregnating a partner. Patients of reproductive potential should use effective methods of 
contraception through defined periods during and after study treatment as specified below. 
Adherence to the prescribing information and any guidelines for treatment-specific pregnancy 
prevention programs (eg, REMS or Pregnancy Prevention Program for lenalidomide or 
pomalidomide), if applicable, is mandatory, as appropriate in the country. 
Patients with a uterus and ovary(ies) must meet 1 of the following criteria: 
• Postmenopausal for at least 2 years before the screening visit, OR 
• Surgically sterile, OR  
• If they are of childbearing potential:  
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▫ Agree to practice 1 highly effective method and 1 additional effective (barrier) method of 
contraception (see Table 8.g) at the same time, from the time of signing of the ICF 
through 7 days after the last dose of modakafusp alfa, or through the period defined by 
the combination agent’s label, whichever is longer OR 
▫ Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (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) or breastfeed a baby during the study through 
7 days after the last dose of modakafusp alfa or through the period defined by the 
combination agent’s label, whichever is longer. 
Patients with a uterus and ovary(ies) must adhere to any applicable local (country-specified) 
treatment-specific pregnancy prevention guidelines. Specifically, lenalidomide and 
pomalidomide are similar to thalidomide and may cause severe life-threatening birth defects. 
Adherence to guidelines for any treatment-specific pregnancy prevention program, (eg, REMS or 
Pregnancy Prevention Program for lenalidomide or pomalidomide), if applicable, is mandatory, 
as appropriate in the country. 
Patients with testis(es), even if surgically sterilized (ie, status postvasectomy), must agree to 1 of 
the following: 
• Agree to practice effective barrier contraception (see Table 8.g) during the entire study 
treatment period and through 7 days after the last dose of modakafusp alfa, or through the 
period defined by the combination agent’s label, whichever is longer OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (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.) 
Patients with testis(es), even if surgically sterilized (ie, status postvasectomy), must: 
• Agree not to donate sperm during the study and for 7 days after the last dose of modakafusp 
alfa, or through the period defined by the combination agent’s label, whichever is longer. 
• Also adhere to any applicable local (country-specified) treatment-specific pregnancy 
prevention guidelines. 
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Study No. TAK-573-1502  
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Table 8.g 
Highly Effective and 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 
Cap, diaphragm, or sponge with spermicide 
Intrauterine hormone-releasing system 
Bilateral tubal occlusion 
Vasectomized partner 
Sexual abstinence 
8.8.2 Pregnancy 
Any participant who is found to be pregnant during the study should be withdrawn and 
modakafusp alfa should be immediately discontinued. In addition, any pregnancies in the partner 
of a study participant during the study should also be recorded, following authorization from the 
study participant’s partner.  
If a participant agrees to their primary care physician being informed, the investigator should 
notify the primary care physician that the participant was participating in a clinical study at the 
time of the pregnancy and provide details of the study drug the subject received. 
All pregnancies, including those in partners of study participants, will be followed to final 
outcome using the pregnancy form. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted. 
8.9 
Blinding 
This is an open-label study. 
8.10 Description of Investigational Agents 
Modakafusp alfa and combination agents used in this study are described in Sections 4.2 and 4.3. 
8.10.1 Packaging and Labeling 
Any sponsor-provided drugs will be labeled according to the current ICH guidelines on GCP and 
Good Manufacturing Practices and will include any locally required statements. 
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8.11 Clinical Study Storage, Handling, and Accountability  
8.11.1 Modakafusp Alfa 
Modakafusp alfa must be stored according to the manufacturer’s stipulation in a dry place at 2˚C 
to 8˚C (36˚F-46˚F). 
Any comparators (Section 8.11.2) provided by the sponsor must be stored in compliance with 
labeled storage conditions. 
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. Each site shipment will include a packing slip listing the 
contents of the shipment, or any applicable forms. 
The investigator is responsible for ensuring that deliveries of modakafusp alfa and other study 
materials from sponsor are correctly received, recorded, 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. 
Only subjects 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) in 
accordance with labeled storage conditions or appropriate instructions with access limited to the 
investigator and authorized staff at the investigational center. 
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. 
8.11.2 Combination Agents 
All the combination agents (lenalidomide, pomalidomide, bortezomib, daratumumab) should be 
stored in accordance with the instructions provided in the manufacturer’s product label. 
Additional details are provided in the respective package insert of the combination agent. 
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CONFIDENTIAL 
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 
other vendors such as the contract research organization (CRO) may be found in the ISF. 
For 24-hour contact information, please refer to the ISF. 
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/IEC.  
9.3 
Administrative Procedures 
Refer to Appendix A 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. 
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. 
9.4 
Informed Consent 
Each patient must provide written or electronic informed consent before any study-required 
procedures are conducted, unless those procedures are performed as part of the patient’s standard 
care. For further details, please see Section 15.2. 
Patients consenting electronically (eConsent), if available, will electronically sign consent forms. 
Paper consent forms will be used instead if required by local regulations. eConsent provides the 
same information as written consent forms, but in an electronic format that may include 
multimedia components. eConsent does not replace the important discussion between the study 
participant and site staff or investigator. Regardless of the consent format, the investigational site 
is responsible for the consenting process. 
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Study No. TAK-573-1502  
92 of 200 
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9.5 
Screening 
Eligibility criteria and associated screening study assessments must be confirmed during the 
screening period; this must take place after a patient has provided informed consent but before 
receiving study drug. 
Rescreening is permitted if in the opinion of the investigator, and upon consultation with the 
sponsor, a patient might meet all the eligibility criteria with the cause(s) of previous screening 
failure being resolved. The eligibility criteria for rescreening are the same as for initial screening. 
9.6 
Treatment Group Assignment 
Patient will be assigned into a treatment regimen in a nonrandomized manner based upon the 
recruitment status of the available cohort as communicated by the sponsor and defined in the 
cohort management plan. 
9.7 
Study Procedures 
9.7.1 Patient Demographics 
The date of birth (outside European Economic Area) or age (European Economic Area), race, 
ethnicity (optional depending on country), and sex of the patient are to be recorded during 
screening, as permitted by local regulations. 
9.7.2 Medical History 
During the screening period, a complete medical history will be compiled for each patient. This 
includes initial diagnosis date, MM staging at initial diagnosis using International Staging 
System. Known cytogenetic alterations should be also 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 following IMWG 
criteria. For patients who have received previous anti-CD38 treatment, the worst grade of IRR 
should be recorded. In addition, concomitant medications will be recorded. 
9.7.3 Physical Examination 
A complete physical examination will be completed per SOC at the times specified in the SOE 
(Appendix A). Physical examinations after the screening visit exam may be symptom directed. 
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. 
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9.7.4 Height and Weight 
Height will be measured during the screening visit only. Weight will be measured at the times 
specified in Appendix A. 
9.7.5 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 (BP) (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. 
BP will be measured every 30 minutes (±5 minutes) during the first 4 infusions, at the end of all 
infusions, and at any moment the patient complains of symptoms consistent with an IRR. If the 
patient experiences hypotension (with or without symptoms), intensive BP monitoring according 
to local practice should be instituted. The patient cannot be released from the site until BP blood 
pressure has returned to Grade 1 or baseline for at least 1 hour. During all infusions and for at 
least 2 hours postdose, patients must be observed.  
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 10.0. 
9.7.6 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 
test results before starting study drug.  
• A urine or serum pregnancy test will be required during screening (within 10-14 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 result.  
• For participants of childbearing potential in treatment arms with lenalidomide or 
pomalidomide, a pregnancy test is required weekly during the first 28 days of this study, 
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and a pregnancy test is required every 28 days if menstrual cycles are regular or every 
14 days if menstrual cycles are irregular. 
• Pregnancy tests may also be repeated during the study as per request of IRB or if required 
by local regulations. 
3) EOT: At EOT, a urine or serum pregnancy test is required in participants of childbearing 
potential. 
9.7.7 Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures (including any transfusion) 
completed by the patient will recorded in the eCRF from signing of the ICF through 
30 (+10) days after the last dose of treatment or the start of subsequent systemic anticancer 
therapy, whichever occurs first. Trade name and international nonproprietary name (if available), 
indication, and start and end dates of the administered medication(s) will be recorded. See 
Sections 8.2 and 8.3 regarding medications and therapies that are prohibited or allowed during 
the study. 
9.7.8 AE Monitoring 
Monitoring of AEs and TEAEs, serious and nonserious, will be conducted throughout the study 
as specified in Appendix A. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of TEAEs and SAEs. 
9.7.9 ECOG Performance Status 
ECOG performance status (Appendix H) will be evaluated and recorded as specified in the SOE 
(Appendix A). 
9.7.10 Enrollment 
Procedures for completing enrollment information are described in the Interactive Response 
Technology Systems User Guide. 
9.7.11 12-Lead ECG 
A 12-lead ECG will be administered at the time points specified in Appendix A. A qualified 
person will interpret the ECG locally. Additional ECGs may be obtained as clinically indicated 
at the discretion of the investigator. 
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 10.3.  
9.7.12 Pulmonary Function Testing  
A pulmonary function test (spirometry) will be administered during screening in treatment arms 
with daratumumab (Arm D). A qualified person will interpret the testing locally.  
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Spirometry will measure: 
• FVC (forced vital capacity; maximal volume of air exhaled with maximally forced 
expiratory effort from a position of maximal inspiration). 
• FEV1 (volume of air expressed in liters exhaled during the first second of performance of 
the FVC). 
9.7.13 Patient Cards 
9.7.13.1 PO Combination Agents Diary Card 
Patients will be provided a diary card or equivalent on which the date of PO combination agents 
(lenalidomide, pomalidomide) administration and missed doses will be recorded. Complete 
instructions are on the diary card. The diary card will be reviewed by the study site per the SOE 
(Appendix A). If extenuating circumstances prevent a patient from attending the study site 
(eg, the COVID-19 pandemic), dosing diary cards should be returned at the next available on-site 
clinic visit. 
9.7.13.2 Subject Identification Card 
Patients will be provided a subject identification card that includes emergency medical contact 
information regarding their participation in this study. Patients should carry this card with them 
at all times and must provide this card to healthcare providers before blood transfusion.  
9.7.14 Clinical Laboratory Procedures and Assessments 
Clinical laboratory evaluations will be performed locally as indicated in each section. Local 
hematology and chemistry laboratory results should be used for dosing decisions. 
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. 
Not all collections are applicable to all cohorts or patients within a cohort. 
 
 
 
9.7.14.1 Clinical Laboratory Tests 
Blood samples for analysis of the clinical chemistry and hematological parameters and urine 
samples for analysis of the urine parameters will be obtained as specified in Appendix A. They 
will be performed locally. 
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Hematology 
Hematology will consist of the following tests: 
Hematocrit 
Leukocytes with differential a 
Hemoglobin 
Neutrophils (ANC) 
Platelet (count) 
Schistocytes b 
ANC: absolute neutrophil count. 
a Differential to include basophils, eosinophils, lymphocytes, monocytes, and neutrophils. 
b Only for Arm 3 at timepoints defined in the schedules of events.  
 
Chemistry  
Chemistry evaluations will consist of the following standard chemistry panel: 
Albumin 
Standard C-reactive protein 
Alkaline phosphatase (ALP) 
Chloride 
Alanine aminotransferase (ALT) 
Glucose (nonfasting) 
Aspartate aminotransferase (AST) 
Lactate dehydrogenase (LDH) 
Bilirubin (total) 
Magnesium 
Blood urea nitrogen (BUN) or urea 
Phosphate 
Calcium 
Potassium 
Bicarbonate (HCO3-) or carbon dioxide (CO2) 
Sodium 
Creatinine 
Urate 
Ferritin a 
 
a Only for Arm 3 at time points defined in the schedules of events. 
 
If creatinine clearance is to be estimated, the Cockcroft-Gault formula will be employed as 
follows: 
Estimated creatinine clearance 
= [(1–0 - Age) × Mass (kg)] / [72 × serum creatinine (mg/dL)]. 
For female patients, the result of the formula above should be multiplied by 0.85. 
For transgender patients, use the sex at birth for patients not using hormone therapy or for 
patients who have used hormone therapy for <6 months; use the current gender for patients who 
have used hormone therapy for ≥6 months. 
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Urinalysis 
Urinalysis will consist of the following tests.  
Bilirubin 
pH 
Glucose 
Protein 
Ketones 
Specific gravity 
Leukocytes 
Turbidity and color 
Nitrites 
Urobilinogen 
Occult blood 
 
 
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of RBC/high-
power field, white blood cell/high-power field, casts, bacteria, and crystals. 
Other  
Hepatitis B serology (HBsAg, HBcAb, HBsAb) 
Serum β2 microglobulin 
HBV DNA test (polymerase chain reaction) 
Thyroid function tests (TSH, free T4) 
ABO blood group and Rh factor, direct and indirect 
antiglobulin tests (direct and indirect Coombs tests) 
 
HBsAg: hepatitis B surface antigen; HBcAb: hepatitis B core antibody; HBsAb: hepatitis B surface antibody; 
HBV: hepatitis B virus; T4: thyroxine; TSH: thyroid stimulating hormone/thyrotropin. 
 
Hepatitis B serology (HBsAg, hepatitis B core antibody, hepatitis B surface antibody) will be 
performed at screening. Patients with resolved hepatitis B infection (ie, patients who are HBsAg 
negative but positive for antibodies to anti–hepatitis B core antibody and/or antibodies to anti-
HBs) must be screened using real-time PCR measurement of HBV DNA levels. 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. 
 
9.8 
Study Compliance 
Study drug will be administered or dispensed 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. 
9.9 
Disease Assessment 
Disease assessments will be performed locally unless otherwise specified as detailed in the SOE 
(Appendix A) and evaluated according to IMWG criteria (Appendix G).  
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. 
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Serum and urine response assessments will be performed as indicated in the SOE (Appendix A). 
Imaging tests for qualifying patients are to be performed as indicated in the SOE (Appendix A). 
Investigators will assess disease response/status. Response and relapse categories are described 
in Appendix G.  
CR should be confirmed with follow-up assessments of bone marrow aspirate (BMA), SPEP, 
UPEP, immunofixation of blood and urine, and serum FLCs as outlined in Appendix A. One 
bone marrow assessment is required to document a 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. 
PD may be confirmed per standard clinical practice at the site. Local laboratories may be used to 
confirm PD. 
The disease assessments in Sections 9.9.1 through 9.9.7 will be performed as indicated in the 
SOE (Appendix A). 
9.9.1 Extramedullary Disease Imaging 
Patients with previously documented extramedullary disease or with suspicion of extramedullary 
progression will have a positron emission tomography–computed tomography (PET-CT) scan, 
computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan performed at 
screening (adequate imaging tests performed within 5 weeks of the planned first dose of study 
drug 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, repeat imaging using 
the same modality every 12 weeks (± 7 days) until a plateau or CR is reached, or as clinically 
indicated, and then at suspected progression (Hillengass et al. 2019). A plasmacytoma is 
considered measurable if the longest diameter is at least 1 cm and the product of the cross 
diameters is at least 1 cm2. Plasmacytomas of lesser size will be considered nonmeasurable. The 
requirement for bidirectional measurements applies only to plasmacytomas. Imaging tests for 
patients with extramedullary disease should be performed if new symptoms suggest PD. 
All follow-up scans should use the same imaging modality as used at screening. 
Images will be analyzed locally and reports will be maintained with the patient’s record for 
retrieval during monitoring visits. Deidentified copies of all imaging scans (including those from 
screening and any unscheduled scans) may be collected and transferred to the sponsor or 
designee for storage as needed.  
9.9.2 Bone Imaging 
Whole body bone imaging will be performed at screening (adequate imaging tests performed 
within 5 weeks of the planned first dose of study drug can be used as baseline and do not need to 
be repeated as part of screening). Whole body bone imaging can be done using either low-dose 
whole-body CT scan, PET-CT scan, or whole-body MRI (Hillengass et al. 2019). Low-dose 
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whole-body CT is recommended over conventional skeletal survey (series of radiographs) for the 
evaluation of MM bone disease. Therefore, conventional skeletal survey should be used only 
when whole-body CT or other novel imaging methods are not available. 
If symptoms or signs suggest increased or new bone lesions, either whole body bone imaging or 
localized imaging of symptomatic sites may be performed. Additional assessments for bone 
disease, either whole body bone imaging or localized imaging of symptomatic sites, can be done 
at the discretion of the investigator (ie, for suspected increased or new bone lesions or PD) 
during the study and at the EOT visit. 
The same assessment modality should be used throughout the study. 
Patients with no bone disease or only bone disease at baseline do not need to repeat imaging 
periodically unless clinically indicated. 
Images will be analyzed locally and reports will be maintained with the patient record for 
retrieval during monitoring visits. Deidentified copies of all imaging scans (including those from 
screening and any unscheduled scans) may be collected and transferred to the sponsor or 
designee for storage as needed. 
9.9.3 Quantification of Igs 
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. 
9.9.4 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 m≥200 mg/24 hours.  
M-protein in serum and urine will be quantified by SPEP and UPEP, respectively. These samples 
will be tested locally. 
9.9.5 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). Blood samples will be analyzed locally. 
9.9.6 Immunofixation of Serum and Urine 
Serum and urine samples will be obtained as specified in the SOE (Appendix A) at screening and 
to confirm a CR. Immunofixation of serum and/or urine may be omitted at screening if a 
previous local laboratory report for the SPEP and/or UPEP 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 locally. 
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9.9.7 BMA 
Bone marrow samples will be collected as detailed below and in Appendix B.  
9.9.7.1 Local Laboratory Evaluations 
9.9.7.1.1 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 B).  
9.9.7.1.2 Cytogenetics 
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). 
Cytogenetic results from samples taken within 5 weeks before the first dose are acceptable.  
9.9.7.2 Central Laboratory Evaluations 
9.9.7.2.1 BMA for MRD Assessment 
For patients enrolled in MM maintenance (Group 1), a BMA sample to evaluate MRD status 
should be collected at screening, 6 months, 1 year, and 2 years after the start of treatment and 
shipped in accordance with the procedures outlined in the laboratory manual. For patients to 
meet inclusion criteria for the MM maintenance arm, they must have a post-ASCT MRD positive 
assessment at a threshold of 10-5. If local methodologies do not meet the sensitivity threshold 
requirements or if the patient did not have a prior assessment, the sample collected for central 
analysis of MRD at screening can be used to confirm eligibility. 
For patients enrolled in the RRMM doublet and RRMM triplet groups, a BMA for MRD sample 
should be collected at the same time as the BMA/biopsy procedure is performed for local disease 
assessment purposes when a CR is suspected on laboratory values, as per routine clinical practice 
(Appendix B). Additional BMAs for MRD assessments will be collected at 6 months, 1 year, and 
2 years following CR confirmation. The BMA for MRD samples should be collected and 
shipped in accordance with the procedures outlined in the laboratory manual. 
9.9.7.2.2 Fresh BMA Sample 
For all RRMM patients, a BMA (first or second pull preferred) will be obtained at screening and 
optionally at relapse (for patients who have responded to treatment) 
 
. BMA samples should be collected and 
shipped in accordance with the procedures outlined in the laboratory manual. 
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9.10 Biomarker, PK, Pharmacodynamic, and Pharmacogenomics, Samples 
9.10.1 Primary Specimen Collection for PK, Pharmacodynamic, and Biomarker 
Assessments 
Blood samples will be collected via venipuncture or indwelling catheter at the time points 
detailed in the SOE (Appendix A) for serum concentration measurements of modakafusp alfa 
and biomarker assessments (with the exception of bone marrow biopsy and BMA). Other 
samples will be collected as detailed in the SOE. The primary specimen collection is presented in 
Table 9.a.  
 
 
 
Details on sample handling, storage, shipment, and analysis are provided in the laboratory 
manual. 
Table 9.a 
Primary Specimen Collections 
Specimen Name 
Primary Specimen 
Primary 
Specimen 
Derivative 
Description of Intended Use 
Sample 
Collection 
Serum sample for 
modakafusp PK 
Blood 
Serum  
Modakafusp alfa 
concentrations 
Mandatory 
Bone marrow aspirate 
for MRD 
BMA 
 
Biomarker measurements 
Mandatory 
Fresh bone marrow 
aspirate sample 
BMA 
DNA 
RNA 
Plasma 
Cells 
Biomarker measurements 
Mandatory 
Serum sample for 
immunogenicity and 
NAb 
Blood 
Serum  
Immunogenicity (ADA and 
NAb) against modakafusp alfa 
Mandatory 
Blood sample for flow 
cytometry 
Blood 
 
Biomarker measurements 
Mandatory 
Serum sample for 
circulating biomarkers 
Blood 
Serum 
Biomarker measurements  
Mandatory 
Blood sample for RNA 
Blood 
RNA 
Biomarker measurements 
Mandatory 
ADA: antidrug antibody; MRD: minimal/measurable residual disease; NAb: neutralizing antibody; 
PK: pharmacokinetic(s).  
 
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9.10.2 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. 
9.10.3 
 
 
 
 
 
 
 
 
 
9.10.3.1 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
9.10.3.2 
 
 
 
 
 
 
 
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9.10.4 
 
9.10.4.1 
 
 
 
 
 
 
 
 
 
 
9.10.5 Immunogenicity Sample Collection 
Serum samples prepared from blood for assessment of ADA and neutralizing ability (Nab) will 
be collected at the time points specified in the SOE (Appendix A) and 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 subject who 
experiences Grade ≥2 hypersensitivity/IRR (Section 8.7.1.1).  
If a patient experiences an IRR, blood samples should be collected for central evaluation of 
immunogenicity as clinical management of the patient permits (Section 8.7.1.1). 
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Confirmed positive ADA samples will be assayed for titer and domain specificity 
characterization and further assessed for NAb. These samples will be analyzed at a central 
laboratory. 
ADA-confirmed positive samples will be further assessed for NAb. These samples will be 
analyzed at a central laboratory. 
9.11 Criteria for Discontinuation or Withdrawal of a Subject 
Study drug must be permanently discontinued if the 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.  
• SAE or AE. 
• CR (after discussion with sponsor). 
• Protocol deviation (after discussion with sponsor). 
• PD (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.  
• Study terminated by sponsor. 
• Withdrawal by subject. 
• A participant has a confirmed pregnancy. 
• Lost to follow-up. 
• Other. 
A patient may 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. 
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9.12 Procedures for Discontinuation or Withdrawal of a Subject 
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. 
Patients who discontinue study drug for reasons other than PD before completing the full 
treatment course will remain in the study for posttreatment assessments as outlined in the SOE 
(Appendix A) until PD or withdrawal of consent. 
9.13 Subject Replacement 
Patients who have not received at least 75% of the combination agent dosing during Cycle 1 for 
reasons other than a DLT will be replaced. 
9.14 Completion of Study Treatment (for Individual Patients) 
Patients will be considered to have completed study treatment if they discontinued study drug for 
any reason outlined in Section 9.11. 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. 
9.15 Posttreatment Follow-up Assessments 
Patients who stop treatment for any reason other than PD will continue to have PFS visits. The 
PFS visits should occur Q4W from EOT 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. 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 10.1.4 for details regarding definitions, 
documentation, and reporting of SAEs.  
10.0 
ADVERSE EVENTS 
10.1 Definitions and Elements of AEs 
AE and SAE rates and frequency will be categorized by toxicity grades (severity) will be 
tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) and the NCI 
CTCAE Version 5.0. 
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10.1.1 Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient who has provided 
inform€(e)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 AESIs 
An 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 to characterize 
and understand them. In modakafusp alfa studies, IRRs are designated as AESIs. Instructions 
regarding how and when AESIs should be reported to the sponsor are provided in Section 10.2.1.  
10.1.4 SAEs 
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, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical 
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or surgical intervention to prevent one 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, Version 5.0, effective 27 November 2017 
(ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refe
ren ce_8.5x11.pdf).  
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 Reporting and Recording AEs and SAEs 
All AEs spontaneously reported by the patient 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 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as a single comprehensive event. 
Regardless of causality, SAEs must be reported by the investigator to the Takeda Global 
Pharmacovigilance department or designee within 24 hours of becoming aware of the 
event. This will be done by transmitting an EDC SAE report. If transmission of an EDC SAE 
report is not feasible, a facsimile of the completed Takeda paper-based SAE form will be sent. A 
sample of the paper based SAE form and processing directions are in the ISF. Information in the 
SAE report or form must be consistent with the data provided on the eCRF. 
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested. 
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All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
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 study; 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.  
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 5.0. The criteria are provided in the ISF. 
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 Reporting AESIs  
In modakafusp alfa studies, IRRs are designated as AESIs. An IRR can develop during or shortly 
after administration of a drug.  
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. Signs and symptoms may also include pruritus, urticaria, rigors, 
diaphoresis, bronchospasms, and cardiovascular collapse.  
Management guidelines are detailed in Section 8.7.1.1. 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.  
10.3 Monitoring AEs and Periods of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
• AEs will be reported from the signing of informed (e)consent through 30 days after 
administration of the last dose of study drug or start of subsequent anticancer therapy, 
whichever occurs first and recorded in the eCRFs. 
• SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed (e)consent 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 due to a patient’s stable or chronic condition or intercurrent illness(es). 
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10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a patient becomes pregnant or suspects pregnancy while participating in this study, the patient 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by sending a completed pregnancy form to the Takeda 
Global Pharmacovigilance department or designee. The pregnancy must be followed for the final 
pregnancy outcome. 
If a patient impregnates a partner during participation in this study, the sponsor must also be 
contacted immediately by sending a completed pregnancy form to the Takeda Global 
Pharmacovigilance department or designee. 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, device, or 
combination product. Individuals who identify a potential product complaint situation should 
immediately report this via the contact information provided in the ISF. 
A medication error is a preventable event that involves an identifiable patient and 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. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the contact information provided in the ISF. 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, the SAE should be reported. 
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 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 products administration or in the 
overall conduct of the trial. The investigational sites also will forward a copy of all expedited 
reports to their IRB or IEC in accordance with national regulations. 
11.0 
STUDY-SPECIFIC COMMITTEE 
No committees will be used in this study.  
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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, medical history, and concurrent conditions will be coded using the 
MedDRA. Drugs will be coded using the World Health Organization Drug Dictionary. 
12.1 eCRFs 
Completed eCRFs are required for each subject who signs €informed (e)consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will arrange training for 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 and regulatory 
authorities. Investigative sites must complete eCRFs in English. 
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 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. Reasons for significant corrections 
should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
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 patient’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 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, patient 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.  
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Furthermore, ICH E6 Section 4.9.5 requires investigators 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 and the head of the institution should contact and receive written approval from 
the sponsor before disposing of any such documents. 
13.0 
STATISTICAL METHODS 
13.1 Statistical and Analytical Plans 
A statistical analysis plan will be prepared and finalized before database lock. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
13.1.1 
Analysis Sets 
13.1.1.1 Safety Analysis Set 
The safety analysis set will include all patients who have received at least 1 dose, even if 
incomplete, of any study drug. 
13.1.1.2 PK Analysis Set 
Patients from the safety analysis set with sufficient dosing and PK data to reliably report 1 or 
more PK concentration will be used for PK analyses. 
13.1.1.3 DLT-Evaluable Analysis Set 
The DLT-evaluable analysis set will include patients who experienced a DLT in Cycle 1 in the 
treatment phase of the study or patients who received a full dose of modakafusp alfa and at 
least 75% of the planned dose of the combination partners and completed evaluation for DLT in 
Cycle 1. The DLT-evaluable population will be used to determine the RP2D/MTD.  
13.1.1.4 Response-Evaluable Analysis Set 
The response-evaluable analysis set is a subset of the safety analysis set including patients with 
measurable disease at baseline and at least 1 postbaseline efficacy evaluation. 
13.1.1.5 Immunogenicity-Evaluable Analysis Set 
Analysis will be based on available data from patients with a baseline assessment and at least 
1 postbaseline immunogenicity assessment. 
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13.1.1.6 MRD Analysis Set 
The MRD-evaluable analysis set for Group 1 (MM maintenance) will be all patients who are 
MRD+ on study entry, as determined by the required central analysis for MRD at screening. The 
MRD-evaluable analysis set for Group 2 (RRMM doublets) and Group 3 (RRMM triplets) will 
be a subset of the safety analysis set including all patients who are in CR and have at least 
1 evaluable postbaseline MRD assessment. 
13.1.2 
Analysis of Demography and Other Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized descriptively. Variables to 
be analyzed include sex, age, race, medical history, prior medications/therapies, ECG findings, 
and other parameters as appropriate. 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 as needed. 
13.1.3 
Efficacy Analysis 
13.1.3.1 Group 1: MM Maintenance 
No primary efficacy endpoint is included. Secondary efficacy endpoints include PFS; ORR 
(local assessment); DOR; rate of MRD[-] at a threshold of 10-5 in patients at 6 months, 1 year, 
and 2 years after the start of treatment; and duration of MRD[-] at a threshold of 10-5 in patients 
achieving MRD[-]. 
PFS is defined as the time from the date on which the first dose of study drug is administered to 
the date of first documentation of confirmed PD or death due to any cause, whichever occurs 
first. PD will be determined by IMWG criteria. Patients without documentation of PD or death 
will be censored at the date of last response assessment. 
DOR is defined as time from the date of first documentation of a confirmed PR or better to the 
date of first documentation of PD or death due to any cause. DOR will be calculated for 
responders only (PR or better). Responders without documentation of PD or death will be 
censored at the date of last response assessment that is stable disease or better. 
ORR is defined as the proportion of patients who achieved a confirmed PR or better (determined 
by the investigator) during the study based on IMWG criteria. 
Rate of MRD[-] is defined as the proportion of patients who have achieved MRD[-] status. 
Duration of MRD[-] is defined as the time from the date of first documentation of MRD[-] to the 
first documentation of MRD positivity or confirmed PD or death due to any cause, whichever 
occurs first. Patients without documentation of MRD positivity or confirmed PD will be 
censored at the date they were last known to be MRD[-]. 
PFS will be analyzed using the safety analysis set and summarized using the Kaplan-Meier (KM) 
method. ORR will be analyzed using the response-evaluable analysis set, and the rate of MRD[-] 
will be analyzed on the basis of the MRD analysis set. Both endpoints will be summarized with 
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2-sided 95% exact binomial CIs. Duration of MRD[-] will be analyzed in patients achieving 
MRD[-] by using the KM method.  
13.1.3.2 Group 2 and Group 3: RRMM Doublets and Triplets 
No primary efficacy endpoints are included. Secondary endpoints include OS, ORR, PFS, TTP, 
TTNT, DOR, DCR, EFS, TTR, rate of MRD[-] CR at a threshold of 10-5 with CR assessed by 
the investigator, rate of MRD[-] at a threshold of 10-5, and duration of MRD[-] at a threshold of 
10-5 in patients achieving MRD[-].  
DOR, ORR, PFS, rate of MRD[-], and duration of MRD[-] are defined the same as previously 
described for maintenance.  
OS is defined as the time from the first dose of administration to the date of death, due to any 
cause. Patients without documentation of death at the time of analysis will be censored at the 
date last known to be alive. 
TTP is defined as the time from the date of the first dose administration to the date of the first 
documentation of confirmed PD as defined by IMWG criteria. Patients without documentation of 
progression will be censored at the date of last response assessment. 
TTNT is defined as the time from the date of first dose administration to the date of the first dose 
initiation of the next line of antineoplastic therapy, for any reason. Patients who have not started 
a next line of therapy will be censored at the date last known to be alive before subsequent 
anticancer therapy.  
DCR is defined as the proportion of patients with a confirmed response sCR, CR, VGPR, PR, 
minimal response, or stable disease based on investigator’s disease assessment per IMWG 
criteria.  
EFS is defined as the time from the date on which the first dose of study drug is administered to 
the date of the first documentation of an event that may include confirmed PD, discontinuation of 
a treatment for an AE (related or not related), or death due to any cause, whichever occurs first. 
PD will be determined by IMWG criteria. Patients without documentation of PD, discontinuation 
of treatment, or death will be censored at the date of their last response assessment. 
TTR is defined as the time from the date of the first dose administration to the date of the first 
documentation of objective confirmed response as defined by IMWG criteria. 
ORR and DCR will be analyzed using the response-evaluable analysis set and summarized 
descriptively with 2-sided 95% exact binomial CIs. 
DOR and TTR will be analyzed for responders only. DOR will be summarized using KM 
method and descriptive summary will be provided for TTR as a continuous variable.  
OS, PFS, EFS, TTP, and TTNT will be analyzed using the safety analysis set and summarized 
descriptively using KM method for safety analysis set. 
Rate of MRD[-] CR is defined as the proportion of patients who have achieved MRD[-] CR 
status. 
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Rate of MRD[-] CR will be analyzed for both the MRD-evaluable analysis set and the safety 
analysis set and summarized with 2-sided 95% exact binomial CIs. Rate of MRD[-] will be 
analyzed for the safety analysis set and summarized with 2-sided 95% exact binomial CIs. 
Duration of MRD[-] will be analyzed in patients achieving MRD[-] using the KM method. 
13.1.4 
PK Analysis 
The PK of modakafusp alfa will be characterized in this study. 
The PK data collected in this study are intended to contribute to future population PK and 
exposure-response analyses of modakafusp alfa. These population PK and exposure-response 
analyses may include data collected in other modakafusp alfa clinical single or combination 
studies. The analysis plan for the population PK and exposure-response analyses will be 
separately defined, and the results of these analyses will be reported separately. 
13.1.5 
Immunogenicity Analyses 
The proportion of subjects with positive ADA (rate, titer and domain specificity) and NAb 
against modakafusp alfa in the study will be summarized. 
 
 
 
 
 
 
13.1.6 
Safety Analysis 
Safety will be evaluated by the frequency of AEs, severity, and types of AEs, and by changes 
from baseline in patients’ vital signs, weights, and clinical laboratory results using the safety 
analysis set. 
Exposure to study drug and reasons for discontinuation will be tabulated. 
TEAEs that occur after administration of the first dose of study drug and through 30 days after 
the last dose of study drug will be tabulated. 
13.1.6.1 TEAEs 
TEAE incidence rates and frequency of occurrence of overall toxicity, categorized by toxicity 
grades (severity) will be tabulated according to the MedDRA and the NCI CTCAE Version 5.0. 
These data will be presented in the following categories: 
• TEAEs. 
• Drug-related TEAEs. 
• Grade 3 or higher TEAEs. 
• Grade 3 or higher drug-related TEAEs. 
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• The most commonly reported TEAEs (ie, those reported by ≥10% of all patients). 
• SAEs (related and regardless of relationship). 
• TEAE leading to study drug modification and discontinuation. 
The incidence of DLTs will be tabulated using the DLT-evaluable analysis set. 
13.1.6.2 Clinical Laboratory Evaluation 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters. 
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the 
modakafusp alfa safety profile. 
13.1.6.3 Vital Signs 
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight will be tabulated by scheduled time point. ECOG performance status will be summarized 
using a shift table. 
13.1.6.4 Other Safety Parameters 
Physical examination findings will be presented in the data listings. 
Additional safety parameters may be performed to most clearly enumerate rates of toxicities and 
to further define the safety profile of modakafusp alfa. 
13.2 Interim Analysis and Criteria for Early Termination 
Although no formal interim analysis is planned, investigators and sponsor representatives will 
review accruing data to determine dose escalation and number of patients per cohort in the 
treatment phase. 
13.3 Determination of Sample Size 
The BOIN design will be implemented to guide the dose escalation/de-escalation. The target 
toxicity rate for MTD is set to 𝜙= 0.25 for MM maintenance as well as RRMM doublets and 
𝜙= 0.33 for RRMM triplets. Patients will be enrolled and treated in cohorts of size 
approximately 3. It is estimated that a total of approximately 120 DLT-evaluable patients will be 
enrolled: approximately 18 for MM maintenance (Arm 1), approximately 66 for RRMM doublet 
combinations, and approximately 36 for RRMM triplet combinations.  
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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. 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 study site 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 the 
sponsor’s designee, including but not limited to the Investigator’s Binder, trial drug, subject 
medical records, informed consent documentation, 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. 
14.2 Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial 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. 
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 the primary study 
assessments. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient 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 United States [US] Food and Drug 
Administration [FDA], the United Kingdom [UK] MHRA [Medicines and Healthcare products 
Regulatory Agency], the PMDA [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 guarantees access for quality assurance auditors to all study 
documents as described in Section 14.1. 
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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  
. 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 state and 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 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/notify site 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 drug/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. 
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Modakafusp alfa (TAK-573) 
 
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118 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
15.2 Subject Information, Informed (e)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 is 
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 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before 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, 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, 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 
before the subject is enrolled into 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 before the subject is enrolled into 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. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
119 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
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. 
Subjects who consented and provided a pharmacogenomics sample for DNA and RNA analysis 
can withdraw their consent and request disposal of a stored sample at any time before analysis. 
Sites must notify the sponsor of consent withdrawal. 
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, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 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 and Disclosure 
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 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
120 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
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 all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the 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 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 the sponsor providing this information to callers must provide 
the sponsor 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 or other publicly accessible 
websites, 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 study 
subjects. Refer to the 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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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
121 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
16.0 
REFERENCES 
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Aletaha, D., Landewe, R., Karonitsch, T., Bathon, J., Boers, M., Bombardier, C., et al. 2008. 
Reporting disease activity in clinical trials of patients with rheumatoid arthritis: 
EULAR/ACR collaborative recommendations. Arthritis Rheum, 59(10), 1371-7. 
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. 
Cook, J., Johnson, I., Higgins, A., Sidana, S., Warsame, R., Gonsalves, W., et al. 2021. 
Outcomes with different administration schedules of bortezomib in bortezomib, 
lenalidomide and dexamethasone (VRd) as first-line therapy in multiple myeloma. Am J 
Hematol, 96(3), 330-7. 
Cowan, A. J., Allen, C., Barac, A., Basaleem, H., Bensenor, I., Curado, M. P., et al. 2018. 
Supplement to: Global Burden of Multiple Myeloma: A Systematic Analysis for the 
Global Burden of Disease Study 2016. JAMA Oncol, 4(9), 1221-7. 
Darzalex (daratumumab) injection for intravenous use 2021. Prescribing Information. Horsham, 
PA 19044: Janssen Biotech, Inc. 
Darzalex Faspro (daratumumab and hyaluronidase-fihj) injection for subcutaneous use 2021. 
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. 
Deaglio, S., Mehta, K. and Malavasi, F. 2001. Human CD38: a (r)evolutionary story of enzymes 
and receptors. Leuk Res, 25(1), 1-12. 
Funaro, A., Horenstein, A. L., Calosso, L., Morra, M., Tarocco, R. P., Franco, L., et al. 1996. 
Identification and characterization of an active soluble form of human CD38 in normal 
and pathological fluids. International Immunology, 8(11), 1643-50. 
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. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
122 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
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. 
Grosicki, S., Simonova, M., Spicka, I., Pour, L., Kriachok, I., Gavriatopoulou, M., et al. 2020. 
Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week 
bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a 
randomised, open-label, phase 3 trial. Lancet, 396(10262), 1563-73. 
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. 
Holstein, S. A., Jung, S. H., Richardson, P. G., Hofmeister, C. C., Hurd, D. D., Hassoun, H., et 
al. 2017. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus 
placebo maintenance after single autologous stem-cell transplantation for multiple 
myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol, 4(9), e431-e42. 
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. 
Lacy, M. Q., Allred, J. B., Gertz, M. A., Hayman, S. R., Short, K. D., Buadi, F., et al. 2011. 
Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib 
and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood, 
118(11), 2970-5. 
Lacy, M. Q., Hayman, S. R., Gertz, M. A., Dispenzieri, A., Buadi, F., Kumar, S., et al. 2009. 
Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple 
myeloma. J Clin Oncol, 27(30), 5008-14. 
Lesinski, G. B., Raig, E. T., Guenterberg, K., Brown, L., Go, M. R., Shah, N. N., et al. 2008. 
IFN-alpha and bortezomib overcome Bcl-2 and Mcl-1 overexpression in melanoma cells 
by stimulating the extrinsic pathway of apoptosis. Cancer Res, 68(20), 8351-60. 
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. 
Liu, S. and Yuan, Y. 2015. Bayesian optimal interval designs for phase I clinical trials. J R Stat 
Soc Ser C Appl Stat, 64(3), 507-23. 
Markowitz, J., Luedke, E. A., Grignol, V. P., Hade, E. M., Paul, B. K., Mundy-Bosse, B. L., et 
al. 2014. A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma. J 
Immunother, 37(1), 55-62. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
123 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Moreau, P., Kumar, S. K., San Miguel, J., Davies, F., Zamagni, E., Bahlis, N., et al. 2021. 
Treatment of relapsed and refractory multiple myeloma: recommendations from the 
international myeloma working group. Lancet Oncol, 22(3), e105-e18. 
O'Donnell, E. K., Laubach, J. P., Yee, A. J., Chen, T., Huff, C. A., Basile, F. G., et al. 2018. A 
phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-
ineligible multiple myeloma. Br J Haematol, 182(2), 222-30. 
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. 
Pomalyst (pomalidomide) Capsules 2020. Prescribing Information. Summit, NJ: Celgene 
Corporation. 
Rajkumar, S. V. 2014. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and 
management. Am J Hematol Oncol, 89(10), 998-1009. 
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. 
Rajkumar, S. V. and Kumar, S. 2016. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin 
Proc, 91(1), 101-19. 
Revlimid (lenalidomide) 2021. Summary of Product Characteristics. Utrecht, Netherlands: 
Celgene Distribution B.V. 
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. 
Sarclisa (Isatuximab) 2020. Package Insert. Bridgewater, NJ: Sanofi-Aventis. 
Velcade (bortezomib) for Injection 2019. Prescribing Information. Cambridge, MA: Millennium 
Pharmaceuticals, Inc. 
Vogl, D. T., Kaufman, J. L., Holstein, S. A., Atrash, S., Nadeem, O., Janakiram, M., et al. 2021. 
Modakafusp alfa (TAK-573), an immunocytokine, shows clinical activity in patients with 
relapsed/refractory multiple myeloma; updated results from a first-in-human phase 1 
study. Abstract No. 898. Blood, 138, 898-9. 
Xpovio (selinexor) tablets for oral use 2021. Prescribing Information. Newton, MA: Karyopharm 
Therapeutics Inc. 
Zhou, Y., Lin, R., Kuo, Y. W., Lee, J. J. and Yuan, Y. 2021. BOIN suite: A software platform to 
design and implement novel early-phase clinical trials. JCO Clin Cancer Inform, 5, 91-
101. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
124 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
17.0 
APPENDICES 
17.1 Appendix A 
Schedules of Events 
Appendix A Table 1 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and Lenalidomide PO: Screening, Cycle 1, 
and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Informed consent b and subject identification 
card issued  
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior medication and treatment history 
X 
 
 
 
 
 
 
 
 
Height and weight c 
X 
 
 
 
 
X 
 
 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
 
12-lead ECG d 
X 
X 
 
X 
 
X 
 
X 
 
Physical examination e 
X 
X 
 
X 
 
X 
 
X 
 
Vital signs f 
X 
X 
 
X 
 
X 
 
X 
 
Diary card m 
 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and 
procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the 
patient starts nonprotocol therapy. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
125 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 1 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and Lenalidomide PO: Screening, Cycle 1, 
and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Dosing 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
 
X 
 
 
 
X 
 
 
 
Lenalidomide PO h 
 
→ a 
→ a 
→ a 
→ a 
→ a 
→ a 
→ a 
→ a 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
Bone imaging l, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9). 
Clinical assessment of imaging 
response/status 
 
Additional assessments to be done per the imaging schedule Section 9.9.  
Safety Laboratory Assessments (local 
analysis) 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
 
 
 
 
 
Viral serologies t 
X 
 
 
 
 
 
 
 
 
Urinalysis u 
X 
 
 
 
 
 
 
 
 
Pregnancy test v 
X 
X 
X 
X 
X 
X 
 
 
 
ABO blood group and Rh factor; direct and 
indirect Coombs tests  
X 
 
 
 
 
 
 
 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
126 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 1 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and Lenalidomide PO: Screening, Cycle 1, 
and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Disease Assessments 
 
Serum M-protein w 
X 
(X) 
 
X 
 
X 
 
X 
 
24-hour urine M-protein w, x 
 
X 
(X) 
 
(X) 
 
(X) 
 
(X) 
 
Serum FLC assay w 
X 
(X) 
 
X 
 
X 
 
X 
 
Immunofixation - serum and urine w, y 
(X) 
(X) 
 
X 
 
X 
 
X 
 
Quantification of Ig w, z 
X 
(X) 
 
 
 
X 
 
 
 
Serum β2 microglobulin 
X 
 
 
 
 
 
 
 
 
BMA/biopsy  
X 
Refer to Appendix B 
Investigator assessment of disease response/ 
status 
 
 
 
 
 
X 
 
 
 
Biologic Laboratory Assessments (central 
analysis) 
 
 
 
 
 
 
 
 
 
Serum sample for modakafusp alfa PK  
 
Refer to Appendix C 
Blood sample for flow cytometry g, aa  
 
X bb 
X 
X 
X 
X bb 
X 
X 
X 
Serum sample for circulating biomarkers g 
 
X ii 
X 
X 
X 
 
 
 
 
Serum sample for immunogenicity 
(ADA/NAb) g, cc 
 
X 
 
X 
 
X 
 
X 
 
Blood sample for RNA g 
 
X ii 
X 
X 
X 
 
 
 
 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
127 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 2 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and Lenalidomide PO: Cycle 3 and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3D1 
C4D1 
C5D1 
C6D1 
C7 and Beyond D1 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Weight c 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
12-lead ECG d 
 
X 
 
X 
X 
Physical examination e 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
X 
X 
Diary card m 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even 
if the patient starts nonprotocol therapy. 
Dosing 
 
 
 
 
 
Modakafusp alfa infusion g 
X 
X 
X 
X 
X 
Lenalidomide PO h 
→a 
→a 
→a 
→a 
→a 
Imaging Assessments (local) 
 
 
 
 
 
Bone imaging l, n 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1). 
Clinical assessment of imaging response/status 
Additional assessments to be done per the imaging schedule Section 9.9.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
128 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 2 Group 1 Arm 1 MM Maintenance Modakafusp Alfa IV and Lenalidomide PO: Cycle 3 and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3D1 
C4D1 
C5D1 
C6D1 
C7 and Beyond D1 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Safety Laboratory Assessments (local analysis) 
 
 
 
 
 
Chemistry q 
X 
X 
X 
X 
X 
Hematology r 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
X 
X 
Pregnancy test v 
X 
X 
X 
X 
X 
Disease Assessments 
 
Serum M-protein  
X 
X 
X 
X 
X 
24-hour urine M-protein x 
(X) 
(X) 
(X) 
(X) 
(X) 
Serum FLC assay  
X 
X 
X 
X 
X 
Immunofixation - serum and urine y  
X 
X 
X 
X 
X 
Quantification of Ig z 
X 
X 
X 
X 
X 
BMA/biopsy  
Refer to Appendix B. 
Investigator assessment of disease response/status 
X 
X 
X 
X 
X 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
Refer to Appendix C 
Serum sample for immunogenicity (ADA/NAb) cc 
X 
X 
X 
X 
X 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
129 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 3 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and Pomalidomide PO: Screening, Cycle 1, and 
Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Informed consent b and subject identification 
card issued  
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior medication and treatment history 
X 
 
 
 
 
 
 
 
 
Height and weight c 
X 
 
 
 
 
X 
 
 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
 
12-lead ECG d 
X 
X 
 
X 
 
X 
 
X 
 
Physical examination e 
X 
X 
 
X 
 
X 
 
X 
 
Vital signs f 
X 
X 
 
X 
 
X 
 
X 
 
Diary card m 
 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and 
procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the patient 
starts nonprotocol therapy. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
130 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 3 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and Pomalidomide PO: Screening, Cycle 1, and 
Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Dosing 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
 
X 
 
 
 
X 
 
 
 
Pomalidomide PO i 
 
→a 
→a 
→a 
 
→a 
→a 
→a 
 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
Bone imaging l, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1).  
Clinical assessment of imaging 
response/status 
 
Additional assessments to be done per the imaging schedule Section 9.9.  
Safety Laboratory Assessments (local 
analysis) 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Hematology r 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
 
 
 
 
 
Viral serologies t 
X 
 
 
 
 
 
 
 
 
Urinalysis u 
X 
 
 
 
 
 
 
 
 
Pregnancy test v 
X 
X 
X 
X 
X 
X 
 
 
 
ABO blood group and Rh factor, direct and 
indirect Coombs tests  
X 
 
 
 
 
 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
131 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 3 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and Pomalidomide PO: Screening, Cycle 1, and 
Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Disease Assessments 
 
Serum M-protein w 
X 
(X) 
 
X 
 
X 
 
X 
 
24-hour urine M-protein w, x 
X 
(X) 
 
(X) 
 
(X) 
 
(X) 
 
Serum FLC assay w 
X 
(X) 
 
X 
 
X 
 
X 
 
Immunofixation - serum and urine w, y  
(X) 
(X) 
 
X 
 
X 
 
X 
 
Quantification of Ig w, z  
X 
(X) 
 
 
 
X 
 
 
 
Serum β2 microglobulin 
X 
 
 
 
 
 
 
 
 
BMA/biopsy 
X 
Refer to Appendix B. 
Investigator assessment of disease 
response/status 
 
 
 
 
 
X 
 
 
 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
 
Refer to Refer to Appendix C. 
Blood sample for flow cytometry g, aa  
 
X bb 
X 
X 
X 
X bb 
X 
X 
X 
Serum sample for circulating biomarkers g 
 
X ii 
X 
X 
X 
 
 
 
 
Serum sample for immunogenicity 
(ADA/NAb) cc  
 
X 
 
X 
 
X 
 
X 
 
Blood sample for RNA g 
 
X ii 
X 
X 
X 
 
 
 
 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
132 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 4 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and Pomalidomide PO: Cycle 3 and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3D1 
C4D1 
C5D1 
C6D1 
C7 and Beyond D1 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Weight c 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
12-lead ECG d 
 
X 
 
X 
X 
Physical examination e 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
X 
X 
Diary card m 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, 
even if the patient starts nonprotocol therapy. 
Dosing 
 
 
 
 
 
Modakafusp alfa infusion g 
X 
X 
X 
X 
X 
Pomalidomide PO i 
→a 
→a 
→a 
→a 
→a 
Imaging Assessments (local) 
 
 
 
 
 
Bone imaging l, n 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1). 
Clinical assessment of imaging response/status 
Additional assessments to be done per the imaging schedule Section 9.9.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
133 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 4 Group 2 Arm 2 RRMM Doublet Modakafusp Alfa IV and Pomalidomide PO: Cycle 3 and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3D1 
C4D1 
C5D1 
C6D1 
C7 and Beyond D1 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Safety Laboratory Assessments (local analysis) 
 
 
 
 
 
Chemistry q 
X 
X 
X 
X 
X 
Hematology r  
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
X 
X 
Pregnancy test v 
X 
X 
X 
X 
X 
Disease Assessments 
 
Serum M-protein  
X 
X 
X 
X 
X 
24-hour urine M-protein x 
(X) 
(X) 
(X) 
(X) 
(X) 
Serum FLC assay  
X 
X 
X 
X 
X 
Immunofixation - serum and urine y 
X 
X 
X 
X 
X 
Quantification of Ig z  
X 
X 
X 
X 
X 
BMA/biopsy  
Refer to Appendix B. 
Investigator assessment of disease response/status 
X 
X 
X 
X 
X 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
Refer to Appendix C. 
Serum sample for immunogenicity (ADA/NAb) cc  
X 
X 
X 
X 
X 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
134 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 5 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and Bortezomib SC: Screening, Cycle 1, and 
Cycle 2 
Study Period 
Screening 
 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D11 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Informed consent b and subject 
identification card issued  
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Prior medication and treatment history 
X 
 
 
 
 
 
 
 
 
 
Height and weight c 
X 
 
 
 
 
 
X 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
X 
 
 
 
12-lead ECG d 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination e 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication 
and procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the patient 
starts nonprotocol therapy. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
135 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 5 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and Bortezomib SC: Screening, Cycle 1, and 
Cycle 2 
Study Period 
Screening 
 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D11 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Dosing 
 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
 
X 
 
 
 
 
X 
 
 
 
Bortezomib SC j 
 
 
X 
 
X 
X 
 
X 
X 
X 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
 
Bone imaging l, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1).  
Clinical assessment of imaging 
response/status 
 
Additional assessments to be done per the imaging schedule (Section 9.9).  
Safety Laboratory Assessments (local 
analysis) 
 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
(X) 
X 
X dd 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
(X) 
X 
X dd 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
 
 
 
 
 
 
Viral serologies t 
X 
 
 
 
 
 
 
 
 
 
Urinalysis u 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test v 
X 
X 
 
 
 
 
X 
 
 
 
ABO blood group and Rh factor, direct 
and indirect Coombs tests  
X 
 
 
 
 
 
 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
136 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 5 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and Bortezomib SC: Screening, Cycle 1, and 
Cycle 2 
Study Period 
Screening 
 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D11 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Disease Assessments 
 
Serum M-protein w 
X 
(X) 
 
 
X 
 
X 
 
X 
 
24-hour urine M-protein w, x  
X 
(X) 
 
 
(X) 
 
(X) 
 
(X) 
 
Serum FLC assay w 
X 
(X) 
 
 
X 
 
X 
 
X 
 
Immunofixation - serum and urine w, y  
(X) 
(X) 
 
 
X 
 
X 
 
X 
 
Quantification of Ig w, z  
X 
(X) 
 
 
 
 
X 
 
 
 
Serum β2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
BMA/biopsy  
X 
Refer to Appendix B. 
Investigator assessment of disease 
response/status 
 
 
 
 
 
 
X 
 
 
 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
 
Refer to Appendix C. 
Blood sample for flow cytometry g, aa  
 
X bb 
X  
 
X 
X  
X bb 
X  
X  
X  
Serum sample for circulating biomarkers 
g  
 
X ii 
X bb 
 
X bb 
X bb 
 
 
 
 
Serum sample for immunogenicity 
(ADA/NAb) cc 
 
X 
 
 
X 
 
X 
 
X 
 
Blood sample for RNA g 
 
X ii 
X bb  
 
X bb  
X bb 
 
 
 
 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
137 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 6 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and Bortezomib SC: Cycle 3 and Beyond 
Study Period 
 
Treatment Phase 
Cycle Day 
C3-C8  
D1 
C3-C8  
D8 
C3-C8  
D15 
C3-C8  
D22 
C9 and 
Beyond D1 
C9 and 
Beyond D8 
C9 and 
Beyond D22 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Weight c 
X 
 
 
 
X 
 
 
ECOG performance status 
X 
 
 
 
X 
 
 
12-lead ECG d 
X 
 
 
 
X 
 
 
Physical examination e 
X 
 
 
 
X 
 
 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the 
patient starts nonprotocol therapy. 
Dosing 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
X 
 
 
 
X 
 
 
Bortezomib SC j 
 
X 
X 
X 
 
X 
X 
Imaging Assessments (local) 
 
 
 
 
 
 
 
Bone imaging l, n 
 
Additional assessments for bone disease to be done at the discretion of the investigator 
(ie, for suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
 
Additional assessments for extramedullary disease per the imaging schedule 
(Section 9.9.1). 
Clinical assessment of imaging response/status 
 
Additional assessments to be done per the imaging schedule (Section 9.9).  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
138 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 6 Group 2 Arm 3 RRMM Doublet Modakafusp Alfa IV and Bortezomib SC: Cycle 3 and Beyond 
Study Period 
 
Treatment Phase 
Cycle Day 
C3-C8  
D1 
C3-C8  
D8 
C3-C8  
D15 
C3-C8  
D22 
C9 and 
Beyond D1 
C9 and 
Beyond D8 
C9 and 
Beyond D22 
Safety Laboratory Assessments (local analysis) 
 
 
 
 
 
 
 
Chemistry q 
X 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
X 
 
 
Pregnancy test v 
X 
 
 
 
X 
 
 
Disease Assessments 
 
Serum M-protein  
X 
 
 
 
X 
 
 
24-hour urine M-protein x 
(X) 
 
 
 
(X) 
 
 
Serum FLC assay  
X 
 
 
 
X 
 
 
Immunofixation - serum and urine y  
X 
 
 
 
X 
 
 
Quantification of Ig z 
X 
 
 
 
X 
 
 
BMA/biopsy  
Refer to Section Appendix B. 
Investigator assessment of disease response/status 
X 
 
 
 
X 
 
 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
Refer to Appendix C. 
Blood sample for flow cytometry (only at C3) g, aa, bb 
X  
X  
X  
X  
 
 
 
Serum sample for immunogenicity (ADA/NAb) cc 
X 
 
 
 
X 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
139 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 7 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV + Pomalidomide PO + Bortezomib SC: 
Screening, Cycle 1, and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Informed consent b and subject identification card issued 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior medication and treatment history 
X 
 
 
 
 
 
 
 
 
Height and weight c 
X 
 
 
 
 
X 
 
 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
 
12-lead ECG d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary card m 
 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even 
if the patient starts nonprotocol therapy. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
140 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 7 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV + Pomalidomide PO + Bortezomib SC: 
Screening, Cycle 1, and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Dosing 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
 
X 
 
 
 
X 
 
 
 
Bortezomib SC j 
 
 
X 
X 
X 
 
X 
X 
X 
Pomalidomide PO i 
 
→  
→ 
→ 
 
→ 
→ 
→ 
 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
Bone imaging l,, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the 
investigator (ie, for suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule 
(Section 9.9.1). 
Clinical assessment of imaging response/status 
 
Additional assessments to be done per the imaging schedule (Section 9.9.) 
Safety Laboratory Assessments (local) 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
 
 
 
 
 
Viral serologies t 
X 
 
 
 
 
 
 
 
 
Urinalysis u 
X 
 
 
 
 
 
 
 
 
Pregnancy test v 
X 
X 
X 
X 
X 
X 
 
 
 
ABO blood group and Rh factor, direct and indirect 
Coombs tests  
X 
 
 
 
 
 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
141 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 7 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV + Pomalidomide PO + Bortezomib SC: 
Screening, Cycle 1, and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Disease Assessments 
 
Serum M-protein w 
X 
(X) 
 
X 
 
X 
 
X 
 
24-hour urine M-protein w, x 
X 
(X) 
 
(X) 
 
(X) 
 
(X) 
 
Serum FLC assay w 
X 
(X) 
 
X 
 
X 
 
X 
 
Immunofixation - serum and urine w, y  
(X) 
(X) 
 
X 
 
X 
 
X 
 
Quantification of Ig w, z 
X 
(X) 
 
 
 
X 
 
 
 
Serum β2 microglobulin 
X 
 
 
 
 
 
 
 
 
BMA/biopsy  
X 
Refer to Appendix B. 
Investigator assessment of disease response/status 
 
 
 
 
 
X 
 
 
 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
 
Refer to Refer to Appendix C. 
Blood sample for flow cytometry g, aa 
 
X bb 
X  
X 
X  
X bb 
X  
X 
X  
Serum sample for circulating biomarkers g 
 
X ii 
X bb 
X bb 
X bb 
 
 
 
 
Serum sample for immunogenicity (ADA/NAb) cc 
 
X 
 
X 
 
X 
 
X 
 
Blood sample for RNA g 
 
X ii 
X bb 
X bb 
X bb 
 
 
 
 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
142 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 8 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV+ Pomalidomide PO + Bortezomib SC: Cycle 3 
and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3-C8 
D1 
C3-C8 
D8 
C3-C8 
D15 
C3-C8 
D22  
C9 and 
Beyond D1 
C9 and 
Beyond D8 
C9 and 
Beyond 
D22 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Weight c 
X 
 
 
 
X 
 
 
ECOG performance status 
X 
 
 
 
X 
 
 
12-lead ECG d 
X 
 
 
 
X 
 
 
Physical examination e 
X 
 
 
 
X 
 
 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
Diary card m 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and 
procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the 
patient starts nonprotocol therapy. 
Dosing 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
X 
 
 
 
X 
 
 
Bortezomib SC j 
 
X 
X 
X 
 
X 
X 
Pomalidomide PO i 
→ 
→ 
→ 
 
→ 
→ 
 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
Bone imaging l, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1). 
Clinical assessment of imaging 
response/status 
 
Additional assessments to be done per the imaging schedule Sections 9.9.1 and 9.9.2.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
143 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 8 Group 3 Arm A RRMM Triplet Modakafusp Alfa IV+ Pomalidomide PO + Bortezomib SC: Cycle 3 
and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3-C8 
D1 
C3-C8 
D8 
C3-C8 
D15 
C3-C8 
D22  
C9 and 
Beyond D1 
C9 and 
Beyond D8 
C9 and 
Beyond 
D22 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Safety Laboratory Assessments (local) 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
X 
 
 
Pregnancy test v 
X 
 
 
 
X 
 
 
Disease Assessments 
 
Serum M-protein  
X 
 
 
 
X 
 
 
24-hour urine M-protein x 
(X) 
 
 
 
(X) 
 
 
Serum FLC assay  
X 
 
 
 
X 
 
 
Immunofixation - serum and urine y  
X 
 
 
 
X 
 
 
Quantification of Ig z 
X 
 
 
 
X 
 
 
BMA/biopsy 
Refer to Appendix B. 
Investigator assessment of disease 
response/status 
X 
 
 
 
X 
 
 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
Refer to Appendix C. 
Blood sample for flow cytometry (only at C3) 
g, aa, bb 
X 
X 
X 
X 
 
 
 
Serum sample for immunogenicity 
(ADA/NAb) cc 
X 
 
 
 
X 
 
 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
144 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 9 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV + Daratumumab SC + Pomalidomide PO: 
Screening, Cycle 1, and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Informed consent b and subject identification 
card issued 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior medication and treatment history 
X 
 
 
 
 
 
 
 
 
Height and weight c 
X 
 
 
 
 
X 
 
 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
 
12-lead ECG d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary function testing 
X 
 
 
 
 
 
 
 
 
Physical examination e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary card m 
 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and 
procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the 
patient starts nonprotocol therapy. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
145 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 9 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV + Daratumumab SC + Pomalidomide PO: 
Screening, Cycle 1, and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Dosing 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
 
X 
 
 
 
X 
 
 
 
Pomalidomide i 
 
→ 
→ 
→ 
 
→ 
→ 
→ 
 
Daratumumab SC k 
 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
Bone imaging l, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, 
for suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1).  
Clinical assessment of imaging response/status 
 
Additional assessments to be done per the imaging schedule Section 9.9. 
Safety Laboratory Assessments (local) 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
 
 
 
 
 
Viral serologies t 
X 
 
 
 
 
 
 
 
 
Urinalysis u 
X 
 
 
 
 
 
 
 
 
Pregnancy test v 
X 
X 
X 
X 
X 
X 
 
 
 
Blood group and Rh, direct and indirect 
Coombs tests  
X 
 
 
 
 
 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
146 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 9 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV + Daratumumab SC + Pomalidomide PO: 
Screening, Cycle 1, and Cycle 2 
Study Period 
Screening 
Treatment Phase – Cycle 1 
Treatment Phase – Cycle 2 
Cycle Day 
 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Window Allowed 
≤21 d 
0 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Disease Assessments 
 
Serum M-protein w 
X 
(X) 
 
X 
 
X 
 
X 
 
24-hour urine M-protein w, x 
X 
(X) 
 
(X) 
 
(X) 
 
(X) 
 
Serum FLC assay w 
X 
(X) 
 
X 
 
X 
 
X 
 
Immunofixation - serum and urine w, y  
(X) 
(X) 
 
X 
 
X 
 
X 
 
Quantification of Ig w, z 
X 
(X) 
 
 
 
X 
 
 
 
Serum β2 microglobulin 
X 
 
 
 
 
 
 
 
 
BMA/biopsy  
X 
Refer to Appendix B. 
Investigator assessment of disease 
response/status 
 
 
 
 
 
X 
 
 
 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK 
 
Refer to Appendix C. 
Blood sample for flow cytometry g, aa  
 
X ii 
X bb 
X bb 
X bb 
X ii 
X bb 
X bb 
X bb 
Serum sample for circulating biomarkers g  
 
X ii 
X bb 
X bb 
X bb 
 
 
 
 
Serum sample for immunogenicity 
(ADA/NAb) cc 
 
X 
 
X 
 
X 
 
X 
 
Blood sample for RNA g  
 
X ii 
X bb 
X bb 
X bb 
 
 
 
 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
147 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 10 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV+ Daratumumab SC + Pomalidomide PO: 
Cycle 3 and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3D1 
C3D15 
C4D1 
C4D15 
C5D1 
C5D15 
C6D1 
C6D15 
C7 and 
Beyond D1 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Weight c 
X 
 
X 
 
X 
 
X 
 
X 
ECOG performance status 
X 
 
X 
 
X 
 
X 
 
X 
12-lead ECG d 
 
 
X 
 
 
 
X 
 
X 
Physical examination e 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary card m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medication and 
procedures 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
AE reporting 
Recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first. 
SAEs will be reported from signing of the ICF through 30 days after last dose of study drug, even if the patient 
starts nonprotocol therapy. 
Dosing 
 
 
 
 
 
 
 
 
 
Modakafusp alfa infusion g 
X 
 
X 
 
X 
 
X 
 
X 
Daratumumab SC k 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Pomalidomide i 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Imaging Assessments (local) 
 
 
 
 
 
 
 
 
 
Bone imaging l, n 
(X) 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) (Section 9.9.2). 
Extramedullary disease imaging l, o 
(X) 
Additional assessments for extramedullary disease per the imaging schedule (Section 9.9.1).  
Clinical assessment of imaging 
response/status 
 
Additional assessments to be done per the imaging schedule Section 9.9. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
148 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 10 Group 3 Arm D RRMM Triplet Modakafusp Alfa IV+ Daratumumab SC + Pomalidomide PO: 
Cycle 3 and Beyond 
Study Period 
Treatment Phase 
Cycle Day 
C3D1 
C3D15 
C4D1 
C4D15 
C5D1 
C5D15 
C6D1 
C6D15 
C7 and 
Beyond D1 
Window Allowed 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
Safety Laboratory Assessments (local) 
 
 
 
 
 
 
 
 
 
Chemistry q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology r  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function s 
X 
 
 
 
 
 
X 
 
X 
Pregnancy test v 
X 
 
X 
 
X 
 
X 
 
X 
Disease Assessments 
 
Serum M-protein  
X 
 
X 
 
X 
 
X 
 
X 
24-hour urine M-protein x 
(X) 
 
(X) 
 
(X) 
 
(X) 
 
(X) 
Serum FLC assay  
X 
 
X 
 
X 
 
X 
 
X 
Immunofixation - serum and urine y  
X 
 
X 
 
X 
 
X 
 
X 
Quantification of Ig z 
X 
 
X 
 
X 
 
X 
 
X 
BMA/biopsy  
Refer to Appendix B. 
Investigator assessment of disease 
response/status 
X 
 
X 
 
X 
 
X 
 
X 
Biologic Assessments (central) 
 
Serum sample for modakafusp alfa PK  
Refer to Appendix C. 
Blood sample for flow cytometry g, aa 
X ii 
X bb 
 
 
 
 
 
 
 
Serum sample for immunogenicity 
(ADA/NAb) cc 
X 
 
X 
 
X 
 
X 
 
X 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are after Footnotes for SOE Appendix A Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
149 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 11 All Groups: EOT and Follow-up 
Study Period 
EOT hh 
30 (+10) days after last dose or before the start of 
subsequent systemic anticancer therapy, whichever occurs 
first 
Follow-up 
(PFS) gg 
Every 4±1 weeks  
Follow-up 
(OS) jj 
Every 12±1 weeks  
Visit Name 
 
ECOG performance status 
X 
 
 
12-lead ECG  
X 
 
 
Physical examination e 
X 
 
 
Vital signs 
X 
 
 
Monitoring of concomitant 
medication and procedures  
Recorded from signing of the ICF through 30 (+10) days 
after last dose of study drug or the start of subsequent 
systemic anticancer therapy, whichever occurs first 
 
 
AE reporting  
Recorded from signing of the ICF through 30 (+10) days 
after last dose of study drug or the start of subsequent 
systemic anticancer therapy, whichever occurs first 
 
 
SAEs will be reported from signing of the ICF through 30 
(+10) days after last dose of study drug, even if the patient 
starts non protocol therapy 
Only study drug-related 
SAEs will be reported 
 
Imaging Assessments (local) 
 
 
 
Bone imaging l, n 
Additional assessments for bone disease to be done at the discretion of the investigator (ie, for 
suspected increased or new bone lesions or PD) 
 
Extramedullary disease imaging l, o, p 
Additional assessments for extramedullary disease per the imaging schedule  
 
Laboratory Assessments  
 
 
 
Chemistry q 
X 
 
 
Hematology r 
X 
 
 
Urinalysis u 
X 
 
 
Pregnancy test v 
X 
 
 
Thyroid function s 
X 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
150 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix A Table 11 All Groups: EOT and Follow-up 
Study Period 
EOT hh 
30 (+10) days after last dose or before the start of 
subsequent systemic anticancer therapy, whichever occurs 
first 
Follow-up 
(PFS) gg 
Every 4±1 weeks  
Follow-up 
(OS) jj 
Every 12±1 weeks  
Visit Name 
 
Disease Assessments 
 
 
 
Serum M-protein  
(X) ff 
X 
X 
24-hour urine M-protein x 
(X) ff 
(X) 
(X) 
Serum FLC assay 
(X) ff 
X 
X 
Immunofixation - serum and urine y 
(X) ff 
X 
X 
Investigator assessment of disease 
response/status 
X 
X 
 
Quantification of Ig z 
(X) ff 
X 
X 
BMA/biopsy  
Refer to Appendix B. 
 
Blood sample for flow cytometry aa 
X 
 
 
Serum sample for circulating 
biomarkers  
X 
 
 
PK collection  
Refer to Appendix C. 
 
 
Serum sample for immunogenicity 
(ADA/NAb) cc  
X 
X 
 
Survival 
 
 
X 
Subsequent therapy 
 
 
X 
Footnotes for all SOE tables (Treatment Arms 1, 2, 3, A, and D; EOT; and follow-up) are on after last page of SOE tables Footnotes for SOE Appendix A 
Tables 1-11. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
151 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Footnotes for SOE Appendix A Tables 1-11 
ADA: antidrug antibody; AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMA: bone marrow aspiration; BP: blood 
pressure; C: cycle; CO2: carbon dioxide; CR: complete response; CT: computed tomography; D, d: day; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EOT: end of treatment; FLC: free light chain; HBcAb: hepatitis B core antibody; HBsAb: hepatitis B surface antibody; HBsAg: hepatitis B 
surface antigen; HBV: hepatitis B virus; HCO3-: bicarbonate; ICF: informed consent form; ID: identification; Ig: immunoglobulin; IRR: infusion-related 
reaction; IV: intravenous(ly); MM: multiple myeloma; MRI: magnetic resonance imaging; NAb: neutralizing antibody; OS: overall survival; PCR: polymerase 
chain reaction; PD: progressive disease; PET-CT: positron emission tomography–computed tomography; PFS: progression-free survival; PK: 
pharmacokinetic(s); PO: oral(ly); QD: once daily; RBC: red blood cell; RRMM: relapsed/refractory multiple myeloma; SAE: serious adverse event; SC: 
subcutaneous(ly); SOE: schedule of events; T4: thyroxine; 
; TSH: thyroid stimulating hormone; 
WBC: white blood cell.  
Cross in parentheses “(X)” indicates test is to be performed only under certain circumstances as indicated in the associated footnote(s). 
a 
Denotes continuously during each cycle. Lenalidomide will be taken PO QD continuously (D1-D28). Pomalidomide will be taken PO on Days 1-21.  
b 
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. 
c 
Height will be measured only at the screening visit. 
d 
Standard local safety ECGs will be collected and read locally at screening, on dosing days during C1 and C2 (depending on the arms), and beyond every 
other cycle (ie, C4D1, C6D1, C8D1, etc). 
e 
Physical examinations may be performed up to 1 day before treatment infusions. After screening, targeted physical examinations (symptom directed) may be 
performed. 
f 
Vital signs are to be measured before starting the infusion and at completion of the infusion. Vital signs include temperature, pulse, respiratory rate, oxygen 
saturation, and BP. BP will be measured every 30 minutes (±5 minutes) during the first 4 infusions, at the end of all infusions, and at any moment the patient 
complains of symptoms consistent with an IRR.  
g 
In case of an IRR, collect serum samples for circulating biomarkers, blood samples for flow cytometry, and blood samples for RNA.  
h 
Lenalidomide dose will be 10 mg PO QD continuously (D1-D28) per Section 6.2.1.1. Participants with a uterus/ovary(ies) must avoid pregnancy for at least 
4 weeks before beginning lenalidomide therapy, during therapy, during dose interruptions, and for at least 4 weeks after completing therapy. Participants 
must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control beginning 4 weeks before 
initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing for 4 weeks after discontinuation of lenalidomide therapy. 
Two negative pregnancy tests must be obtained before initiating therapy. The first test should be performed within 10-14 days and the second test 
within 24 hours before prescribing lenalidomide therapy; pregnancy tests should then be obtained weekly during the first month, and monthly 
thereafter in participants with regular menstrual cycles, or every 2 weeks in participants with irregular menstrual cycles. Lenalidomide should be 
taken at about the same time each day. When both modakafusp alfa and lenalidomide are given on the same visit day, lenalidomide should not be 
administered at the same time as modakafusp alfa. (At least 30 minutes should elapse between the administration of the 2 drugs.) 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
152 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
i 
Pomalidomide dose will be 4 mg PO on Days 1-21 of each 28-day cycle per Section 6.2.2.1. Participants with a uterus/ovary(ies) must avoid pregnancy for 
at least 4 weeks before beginning pomalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. 
Participants must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks 
before initiating treatment with pomalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of 
pomalidomide therapy. Two negative pregnancy tests must be obtained before initiating therapy. The first test should be performed within 10-14 
days and the second test within 24 hours before prescribing pomalidomide therapy; pregnancy tests should then be obtained weekly during the first 
month, and monthly thereafter in participants with regular menstrual cycles, or every 2 weeks in participants with irregular menstrual cycles. 
Pomalidomide should be taken at about the same time each day. When both modakafusp alfa and pomalidomide are given on the same visit day, 
pomalidomide should not be administered at the same time as modakafusp alfa. (At least 30 minutes should elapse between the administration of the 2 
drugs.) 
j 
Bortezomib dose will be 1.3 mg/m2 SC on Days 8, 15 and 22 of each 28-day cycle for the first 8 cycles and subsequently on Days 8 and 22 per Section 
6.2.2.2.  
k 
Daratumumab dose will be 1800 mg SC on Days 1, 8, 15, and 22 of Cycles 1 and 2; on Days 1 and 15 of Cycles 3 to 6; and then on Day 1 thereafter, per 
Section 6.2.3.2.  
l 
The same assessment modality should be used throughout the study. Adequate imaging test(s) performed within 5 weeks of the planned first dose of study 
drug can be used as the screening evaluation and do not need to be repeated. 
m 
Patients receiving PO combination agents (lenalidomide or pomalidomide) will record doses taken in a diary provided by the site. The diary card will be 
given to patients on C1D1. The diary card will be reviewed by the study site per Section 9.7.12 
n 
Imaging to assess bone disease is required for all patients 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. Low-dose whole-body CT is 
recommended over conventional skeletal survey for the evaluation of MM bone disease. Conventional skeletal survey can be used for the diagnosis of MM 
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 or PD). The same modality for assessment should be used throughout the study.  
o 
Imaging to assess extramedullary disease is required for all patients at screening by PET-CT, MRI, or CT scan. 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 extramedullary disease is documented at screening, repeat imaging using the same modality every 12 weeks until a plateau or CR 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. 
p 
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. 
q 
Chemistry will consist of albumin, alkaline phosphatase, ALT, AST, bilirubin (total), blood urea nitrogen or urea, calcium, HCO3- or CO2, creatinine, 
chloride, glucose (nonfasting), lactate dehydrogenase, magnesium, phosphate, potassium, sodium, standard C-reactive protein, and urate. It is not necessary 
to repeat these tests on C1D1 predose if screening tests were done ≤4 days earlier.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
153 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
r 
Hematology will consist of hemoglobin, hematocrit, platelet count, leukocytes with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils) and ANC. See footnote dd for additional tests. It is not necessary to repeat these tests on C1D1 predose if screening tests were done ≤4 days 
earlier. 
s 
Thyroid function tests will consist of TSH and free T4. These tests will be performed at screening, and every 3 cycles thereafter (ie, C3D1, C6D1, C9D1, 
etc) until EOT. 
t 
Viral serologies will consist of hepatitis B serology (HBsAg, HBcAb, HBsAb) and will be performed at screening. For hepatitis B: patients with resolved 
infection (ie, patients who are HBsAg negative but positive for antibodies to anti-HBc and/or antibodies to anti-HBs) must be screened using real-time PCR 
measurement of HBV DNA levels. 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.  
u 
Urinalysis (dipstick) will include bilirubin, glucose, ketones, leukocytes, nitrites, occult blood, pH, protein, specific gravity, turbidity and color, and 
urobilinogen. Microscopic analysis only if clinically indicated: bacteria, RBCs, WBCs, casts, bacteria and crystals.  
v 
Pregnancy testing (refer to Section 8.8.1).  
– 
Screening: Participants of childbearing potential must have 2 negative pregnancy tests before starting study drug. A negative urine or serum pregnancy 
test will be required at screening (within 10 to 14 days before the start of study drug). A negative urine or serum pregnancy test is required at baseline 
(within 24 hours before the start of study drug).  
– 
On-treatment: 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. If menstrual period is delayed, absence of pregnancy in patients of childbearing potential must be confirmed by a negative urine or serum 
pregnancy test.  
– 
A urine or serum pregnancy test is required at EOT in participants of childbearing potential. 
– 
Participants of childbearing potential in treatment arms with lenalidomide or pomalidomide must have negative pregnancy tests as defined in the 
prescribing information (2 negative tests must be obtained before initiating therapy). The first test should be performed within 10-14 days and the 
second test within 24 hours before therapy; pregnancy tests should then be obtained weekly during the first month, and monthly thereafter in participants 
with regular menstrual cycles, or every 2 weeks in participants with irregular menstrual cycles. 
w 
Repeat at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
x 
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). 
y 
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. 
z 
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 should occur 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). 
aa Blood sample to be collected for centralized flow cytometry, 
. 
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bb Samples are to be collected predose (before administration of parenteral agents). 
cc Blood samples for immunogenicity (ADA/NAb) testing will be collected before the dose on indicated visits while the patient remains in treatment, and at the 
EOT visit and follow-up visits for up to 1 year after EOT. In case of an IRR, blood draws should be performed for central evaluation of immunogenicity (see 
Section 9.10.5). 
dd Ferritin and blood smear. Arm 3: At screening and C1D11, ferritin will be obtained in addition to the chemistry and hematology laboratory tests defined in 
footnotes q and r, respectively. At C1D11, schistocytes will be obtained in addition to the chemistry and hematology laboratory tests defined in footnotes q 
and r, respectively.  
 
 
 
ff Repeat tests in parentheses only 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. 
gg 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.  
hh EOT laboratory assessments are to be performed before the patient starts a new treatment or a maximum of 30 days (±10 days) after the last dose. 
ii Samples to be collected predose (prior to administration of parenteral agents) and at 4 hours (±30 minutes) after the end of infusion of modakafusp alfa. 
jj OS follow-up continues every 12 weeks until death, study termination, or patient withdrawal. 
 
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17.2 Appendix B 
Bone Marrow Collection and Assessment Schedules  
Appendix B Table 1 
Bone Marrow Collection and Assessment Schedule for Group 1: MM Maintenance Modakafusp Alfa 
and Lenalidomide 
Study Period 
Screening 
Treatment Phase 
Follow-up 
Cycle Day 
 
 
EOT 
PFS Follow-up 
Window Allowed 
≤21 d 
±2 d 
30 (+10) days after last dose 
of study drug or the start of 
subsequent systemic 
anticancer therapy, 
whichever occurs first 
Every 4 weeks  
±1 week 
BMA/biopsy for disease assessment (local 
analysis) a, b 
X 
Sample to be collected at susCR to confirm response, optional at the 
time of progression, and EOT.  
 
BMA for MRD (central analysis)  
X 
Sample to be collected 6 months, 1 
year, and 2 years from start of study 
treatment. 
 
 
Fresh BMA sample (central analysis) a 
 
 
(X) 
 
Footnotes follow Appendix B Table 2. 
 
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Appendix B Table 2 
Bone Marrow Collection and Assessment Schedule for Group 2: RRMM Doublet Combinations 
Study Period 
Screening 
Treatment Phase 
Follow-up 
Cycle Day 
 
 
Suspected CR 
EOT 
PFS Follow-up 
Window Allowed 
≤21 d 
 
30 (+10) days after last 
dose of study drug or 
the start of subsequent 
systemic anticancer 
therapy, whichever 
occurs first 
Every 4 weeks ±1 
week 
 
BMA/biopsy for disease assessment (local 
analysis) a, b 
X 
Sample to be collected at susCR to confirm response, optional at 
the time of progression and EOT. 
 
BMA/biopsy for cytogenetics (local 
analysis) a 
X 
 
 
 
BMA for MRD (central analysis) c 
 
Sample to be collected at susCR and 6 
months, 1 year, and 2 years following 
CR confirmation. Yearly sample 
collection if the patient had an MRD[-
] result.  
 
 
Fresh BMA sample (central analysis) b 
X 
 
 
(X) 
 
Footnotes follow Appendix B Table 3. 
 
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Appendix B Table 3 
Bone Marrow Collection and Assessment Schedule for Group 3: RRMM Triplet Combinations 
Study Period 
Screening 
Treatment Phase 
Follow-up 
Cycle Day 
 
Suspected CR 
EOT 
PFS Follow-up 
Window Allowed 
≤21 days  
 
30 (+10) days after last 
dose of study drug or the 
start of subsequent 
systemic anticancer 
therapy, whichever occurs 
first 
Every 4 weeks 
±1 week 
BMA/biopsy for disease assessment (local 
analysis) a, b 
X 
Sample to be collected at susCR to confirm response, optional at the time 
of progression and EOT. 
(X) 
BMA/biopsy for cytogenetics (local 
analysis) a 
X 
 
 
 
BMA for MRD 
(central analysis) c 
X 
Sample to be collected at susCR and at 6 
months, 1 year, and 2 years following CR 
confirmation. Yearly sample collection if 
the patient had an MRD[-] result.  
 
 
Fresh BMA sample (central analysis) a 
X 
 
(X) 
 
BMA: bone marrow aspirate, bone marrow aspiration; CR: complete response; EOT: end of treatment; MRD: measurable/minimal residual disease; 
MRD[-]: measurable/minimal residual disease negative; PFS: progression-free survival; susCR: suspected complete response. 
For local analysis of disease assessment and cytogenetics at screening, a standard BMA biopsy drawn before consent is acceptable provided that the sample is 
collected within 5 weeks of the first dose. 
a 
A BMA (1st or 2nd pull preferred) will be obtained at screening and optionally at relapse (for patients who have responded to treatment) 
 
 
b 
Optional BMA to be collected at EOT visit for central analysis for patients who have responded to therapy and progressed.  
c 
If a patient has an MRD[-] result for any of the on-treatment assessments, this will trigger yearly evaluations of MRD until the patient progresses. However, if a patient 
does not have an MRD[-] result for any of the planned on-treatment assessments, no additional BMA for MRD will be required. 
 
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17.3 Appendix C PK Sampling  
 
Time Point 
Modakafusp Alfa PK 
(Cycle 1 and Cycle 2) 
Day 1 a 
Day 8 
Day 15 
Day 22 
Predose (within 30 min before administration 
of any SC or IV combination agent)  
X 
 
 
 
End of infusion (±10 min)  
X 
 
 
 
2 to 4 hours after end of infusion (±30 min) 
X 
 
 
 
During the clinic visit  
 
X b 
X b 
X b 
IV: intravenous(ly); PK: pharmacokinetic(s); SC: subcutaneous(ly). 
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. 
b. 
Blood samples for Day 8, 15, and 22 modakafusp alfa PK measurement will be collected during the clinic 
visit within 30 minutes before administration of any subcutaneous or IV combination agent.  
 
Time Point 
Modakafusp PK 
(Cycle 3 and Beyond) a 
Day 1 b 
EOT 
End of infusion 
X 
 
2 to 4 hours after end of infusion (±30 min)  
X 
 
During the clinic visit 
 
X 
PK: pharmacokinetic(s); EOT: end of treatment. 
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.  
b. 
Starting with Cycle 12, PK sampling will be performed every 3 cycles (C12D1, C15D1, C18D1, etc) until 
EOT. 
 
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17.4 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 responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
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, before 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 
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contact and receive written approval from the sponsor before disposing of any such 
documents. 
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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17.5 Appendix E 
Elements of Informed Consent 
In seeking informed consent, the following information shall be provided to each participant:  
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of participation.  
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of participants involved in the study. 
7. A description of the participant’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment. 
10. A description of the possible side effects of the treatment that the participant may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the participant or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the participant, the participant 
should be made aware of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the participant and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the 
participant will be maintained, and a note of the possibility that regulatory agencies, 
auditor(s), IRB/IEC, and the monitor may inspect the records. By signing a written ICF, the 
participant or the participant’s legally acceptable representative is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the participant for participating in the study. 
17. The anticipated expenses, if any, to the participant for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the participant. 
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the participant otherwise is entitled, and that the participant or the 
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subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the participant is otherwise entitled. 
20. The consequences of a participant’s decision to withdraw from the research and procedures 
for orderly termination of participation by the participant. 
21. A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study. 
22. A statement that results of pharmacogenomics analysis will not be disclosed unless 
prevailing laws require the sponsor to do so. 
23. The foreseeable circumstances or reasons under participation in the study may be terminated. 
24. A written participant authorization (either contained within the ICF or provided as a separate 
document) describing to the participant the contemplated and permissible uses and 
disclosures of the participant’s personal information (including personal health information) 
for purposes of conducting the study. The authorization must contain the following 
statements regarding the uses and disclosures of the participant’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) that participants agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the participant’s identity will remain confidential in the event that study results are 
published. 
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It is not known what effects modakafusp alfa has on human pregnancy or development of the 
embryo or fetus; therefore, patients participating in this study should avoid becoming pregnant or 
avoid impregnating a partner. Patients of reproductive potential should use effective methods of 
contraception through defined periods during and after study treatment as specified below. 
Patients with a uterus and ovary(ies) must meet 1 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 and 
1 additional effective (barrier) method of contraception (see Table 8.g) at the same time, 
from the time of signing of the ICF through 7 days after the last dose of modakafusp alfa, or 
through the period defined by the combination agent’s label, whichever is longer OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (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.) 
• Patients with a uterus and ovary(ies) must adhere to any applicable local (country-specified) 
treatment-specific pregnancy prevention guidelines. 
• Agree not to donate an egg or eggs (ova) or breastfeed a baby during the study through 
7 days after the last dose of modakafusp alfa or through the period defined by the 
combination agent’s label, whichever is longer. 
Patients with testis(es), even if surgically sterilized (ie, status postvasectomy), must agree to 1 of 
the following: 
• Agree to practice effective barrier contraception (see Table 8.g) during the entire study 
treatment period and through 7 days after the last dose of modakafusp alfa, or through the 
period defined by the combination agent’s label, whichever is longer OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (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.) 
Patients with testis(es), even if surgically sterilized (ie, status postvasectomy), must: 
• Agree not to donate sperm during the study and for 7 days after the last dose of modakafusp 
alfa, or through the period defined by the combination agent’s label, whichever is longer. 
• Also adhere to any applicable local (country-specified) treatment-specific pregnancy 
prevention guidelines. 
A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 
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17.6 Appendix F 
Investigator Consent to the 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 
UK, US, 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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17.7 Appendix G 
IMWG Definition of MM and Response Criteria 
IMWG criteria will be used for evaluating patient eligibility and response. Based on IMWG 
diagnostic criteria, MM is defined by the following (both criteria must be met): 
1. Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma* and  
2. 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 >2 g/dL below the lower limit of normal or a 
hemoglobin value <10 g/dL. 
– 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 lesion on MRI studies (at least 5 mm in size). 
CT: computed tomography; FLC: free light chain; IMWG: International Myeloma Working Group; MM: multiple 
myeloma; MRI: magnetic resonance imaging; PET-CT: [18F]ﬂuorodeoxyglucose positron emission tomography with 
computed tomography. 
* 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 (Rajkumar 2014). 
 
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Response Category  Response Criteria 
sCR 
Criteria for CR, as defined below, with the addition of a normal FLC ratio, and an absence 
of clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometry; 
2 consecutive assessments of laboratory parameters are needed a. 
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. 
Immunophenotypic 
CR 
sCR as defined, plus absence of phenotypically aberrant plasma cells (clonal) in bone 
marrow with minimum of 1 million total bone marrow cells analyzed by multiparametric 
ﬂow cytometry (with >4 colors). 
Molecular CR 
CR as deﬁned, plus negative allele-speciﬁc oligonucleotide polymerase chain reaction 
(sensitivity 10-5). 
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. 
MR b 
• 
≥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; IMWG: International Myeloma Working Group; 
MR: minimal response; ORR: objective response rate; PD: progression of disease; PR: partial response; 
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 study, 2 consecutive 
BM assessments are not required. 
b For relapsed/refractory myeloma only. 
c These categories do not contribute to the ORR. 
(Kumar et al. 2016)  
 
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CONFIDENTIAL 
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 do not need to be conﬁrmed. 
PD is defined as an increase of ≥25% from lowest response value in any of the following: 
• 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 
• Urine M-protein (absolute increase must be ≥200 mg/24 hour), and/or 
• 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). 
• 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 
• Definite development of new bone lesions or soft tissue plasmacytomas OR ≥50% increase 
from nadir in sum of product of diameters of >1 soft tissue plasmacytoma OR ≥50% increase 
in the longest diameter of a previous soft tissue plasmacytoma >1 cm in its short axis or an 
unequivocal increase in the size of existing bone lesions.  
• Development of hypercalcemia (corrected serum calcium >11.5 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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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
168 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
17.8 Appendix H 
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 et al. 1982).  
ECOG: Eastern Cooperative Oncology Group.  
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
169 of 200  
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
17.9 Appendix I 
BOIN Design for Dose Escalation/De-escalation 
The BOIN design will be implemented for dose escalation/de-escalation. The target toxicity rate 
for MTD is set to be 𝜙= 0.25 for MM maintenance and RRMM doublets and 𝜙= 0.33 for 
RRMM triplets, unless otherwise specified. Approximately 120 total patients will be enrolled to 
evaluate the dose escalation for a total of 6 arms (Zhou et al. 2021). 
The operating characteristics of the BOIN design are evaluated with 1000 simulations (assuming 
various distributions of toxicity across dose levels) and presented in the following tables.  
Group 1: MM - Maintenance Therapy 
Appendix I Table 1 
Simulation Settings for Arm 1: Modakafusp Alfa With 
Lenalidomide 
 
Dose 1 Dose 2 Dose 3 Dose 4 
Average 
sample 
size 
Correct 
selection 
% 
Overdose 
% 
% 
patients 
at MTD 
% 
patients 
overdosed 
% 
early 
stop 
Scenario 1 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.25 
0.42 
0.50 
0.59 
 
 
 
 
 
 
Selection % 
69.8 
22.4 
3.2 
0.2 
13.4 
69.8 
25.8 
44.7 
55.3 
4.4 
% pts treated 
44.7 
44.9 
9.2 
1.2 
 
 
 
 
 
 
Scenario 2 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.10 
0.25 
0.40 
0.62 
 
 
 
 
 
 
Selection % 
21.1 
55.7 
21.0 
1.9 
16.3 
55.7 
22.9 
47.5 
27.1 
0.3 
% pts treated 
25.4 
47.5 
23.0 
4.1 
 
 
 
 
 
 
Scenario 3 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.02 
0.10 
0.25 
0.42 
 
 
 
 
 
 
Selection % 
0.10 
24.9 
56.8 
18.2 
17.1 
56.8 
18.2 
39.8 
14.3 
0 
% pts treated 
7.3 
38.6 
39.8 
14.3 
 
 
 
 
 
 
Scenario 4 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.05 
0.08 
0.12 
0.25 
 
 
 
 
 
 
Selection % 
1.0 
8.2 
32.1 
58.7 
16.3 
58.7 
0 
26.4 
0 
0 
% pts treated 
5.8 
30.9 
36.9 
26.4 
 
 
 
 
 
 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients. 
 
Group 2: RRMM - Doublet Combinations 
Arms 2-4 in the doublet combinations for RRMM will have the same simulation settings as 
Arm 1 and therefore the same operating characteristics. 
Group 3: RRMM - Triplet Combinations  
Simulation settings for Arms A and D in the triplet combinations for RRMM are in 
Appendix I Table 2, Appendix I Table 3, Appendix I Table 4, and Appendix I Table 5. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
170 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix I Table 2 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 1 as the Starting Dose 
 
Dose 1 Dose 2 Dose 3 Dose 4 
Average 
sample 
size 
Correct 
selection 
% 
Overdose 
% 
% 
patients 
at MTD 
% patients 
overdosed 
% 
early 
stop 
Scenario 1 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.33 
0.50 
0.58 
0.67 
 
 
 
 
 
 
Selection % 
68.0 
16.5 
2.2 
0.1 
12.1 
68.0 
18.8 
67.6 
32.4 
13.2 
% pts treated 
67.6 
28.1 
4.1 
0.2 
 
 
 
 
 
 
Scenario 2 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.14 
0.33 
0.50 
0.70 
 
 
 
 
 
 
Selection % 
26.2 
52.7 
19.9 
0.7 
16.2 
52.7 
20.6 
43.1 
17.7 
0.5 
% pts treated 
39.2 
43.1 
16.2 
1.5 
 
 
 
 
 
 
Scenario 3 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.02 
0.15 
0.33 
0.50 
 
 
 
 
 
 
Selection % 
0.8 
25.0 
56.9 
17.3 
17.5 
56.9 
17.3 
33.3 
11.3 
0 
% pts treated 
20.6 
34.8 
33.3 
11.3 
 
 
 
 
 
 
Scenario 4 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.05 
0.11 
0.18 
0.33 
 
 
 
 
 
 
Selection % 
1.0 
7.3 
38.3 
53.4 
17.7 
53.4 
0 
24.4 
0 
0 
% pts treated 
20.9 
25.8 
28.8 
24.4 
 
 
 
 
 
 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients; 
RRMM: relapsed/refractory multiple myeloma. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
171 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix I Table 3 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 2 as the Starting Dose 
 
Dose 1 Dose 2 Dose 3 Dose 4 
Average 
sample 
size 
Correct 
selection 
% 
Overdose 
% 
% 
patients 
at MTD 
% 
patients 
overdosed 
% 
early 
stop 
Scenario 1 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.33 
0.50 
0.58 
0.67 
 
 
 
 
 
 
Selection % 
61.2 
27.8 
2.6 
0 
14.3 
61.2 
30.4 
44.3 
55.6 
8.4 
% pts treated 
44.3 
46.6 
8.5 
0.5 
 
 
 
 
 
 
Scenario 2 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.14 
0.33 
0.50 
0.70 
 
 
 
 
 
 
Selection % 
21.9 
59.3 
17.3 
1.3 
15.4 
59.3 
18.6 
53.9 
25.8 
0.2 
% pts treated 
20.3 
53.9 
22.7 
3.1 
 
 
 
 
 
 
Scenario 3 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.02 
0.15 
0.33 
0.50 
 
 
 
 
 
 
Selection % 
0.7 
26.5 
53.8 
19.0 
16.4 
53.8 
19.0 
42.4 
16.3 
0 
% pts treated 
2.3 
38.9 
42.4 
16.3 
 
 
 
 
 
 
Scenario 4 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.05 
0.11 
0.18 
0.33 
 
 
 
 
 
 
Selection % 
0.2 
7.0 
29.4 
63.4 
16.6 
63.4 
0 
35.6 
0 
0 
% pts treated 
1.3 
28.0 
35.0 
35.6 
 
 
 
 
 
 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients; 
RRMM: relapsed/refractory multiple myeloma. 
 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
172 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Appendix I Table 4 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 3 as the Starting Dose 
 
Dose 1 Dose 2 Dose 3 Dose 4 
Average 
sample 
size 
Correct 
selection 
% 
Overdose 
% 
% 
patients 
at MTD 
% 
patients 
overdosed 
% 
early 
stop 
Scenario 1 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.33 
0.50 
0.58 
0.67 
 
 
 
 
 
 
Selection % 
51.7 
28.2 
11.8 
0.3 
16.2 
51.7 
40.3 
30.8 
69.2 
8.0 
% pts treated 
30.8 
33.5 
32.1 
3.6 
 
 
 
 
 
 
Scenario 2 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.14 
0.33 
0.50 
0.70 
 
 
 
 
 
 
Selection % 
15.5 
55.4 
28.1 
0.8 
15.7 
55.4 
28.9 
39.0 
48.9 
0.2 
% pts treated 
12.1 
39.0 
42.8 
6.1 
 
 
 
 
 
 
Scenario 3 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.02 
0.15 
0.33 
0.50 
 
 
 
 
 
 
Selection % 
0.4 
21.1 
60.6 
17.9 
15.3 
60.6 
17.9 
55.2 
24.1 
0 
% pts treated 
1.1 
19.5 
55.2 
24.1 
 
 
 
 
 
 
Scenario 4 
 
 
 
 
 
 
 
 
 
 
True DLT rate 
0.05 
0.11 
0.18 
0.33 
 
 
 
 
 
 
Selection % 
0.1 
2.7 
32.0 
65.2 
14.6 
65.2 
0 
49.4 
0 
0 
% pts treated 
0.2 
4.8 
45.6 
49.4 
 
 
 
 
 
 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients; 
RRMM: relapsed/refractory multiple myeloma. 
 
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Modakafusp alfa (TAK-573) 
Study No. TAK-573-1502  
173 of 200 
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
CONFIDENTIAL 
Appendix I Table 5 
Simulation Settings for Arms A and D in the Triplet Combinations 
for RRMM: Dose 4 as the Starting Dose 
Dose 1 Dose 2 Dose 3 Dose 4 
Average 
sample 
size 
Correct 
selection 
% 
Overdose 
% 
% 
patients 
at MTD 
% 
patients 
overdosed 
% 
early 
stop 
Scenario 1 
True DLT rate 
0.33 
0.50 
0.58 
0.67 
Selection % 
46.0 
31.9 
12.7 
3.4 
17.1 
46.0 
48.0 
19.6 
80.3 
6.0 
% pts treated 
19.6 
27.2 
28.6 
24.5 
Scenario 2 
True DLT rate 
0.14 
0.33 
0.50 
0.70 
Selection % 
15.3 
52.0 
29.7 
2.6 
16.8 
52.0 
32.3 
31.0 
61.0 
0.4 
% pts treated 
8.0 
31.0 
36.2 
24.8 
Scenario 3 
True DLT rate 
0.02 
0.15 
0.33 
0.50 
Selection % 
0.2 
16.9 
53.7 
29.2 
15.0 
53.7 
29.2 
41.3 
44.7 
0 
% pts treated 
0.6 
13.4 
41.3 
44.7 
Scenario 4 
True DLT rate 
0.05 
0.11 
0.18 
0.33 
Selection % 
0 
1.3 
22.9 
75.8 
12.2 
75.8 
0 
71.1 
0 
0 
% pts treated 
0 
2.2 
26.6 
71.1 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients; 
RRMM: relapsed/refractory multiple myeloma. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
174 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
17.10 Appendix J 
Protocol History 
Date 
Amendment Number 
Amendment Type 
Region 
03 April 2024 
Amendment 4 v2 
Substantial 
Global 
28 February 2024 
Amendment 4 v1 (not implemented) 
Substantial 
Global 
13 June 2023 
Amendment 3 
Substantial 
Global 
17 August 2022 
Amendment 2 
Substantial 
Global 
27 May 2022 
Amendment 1 
Substantial 
Global 
13 May 2022 
Initial protocol EU v1 
Nonsubstantial; Regional  
European Union 
01 April 2022 
Initial protocol 
Not applicable 
Global 
 
Protocol Amendment 1 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 1. The 
primary reasons for this amendment are to:  
• Revise and/or clarify several procedures in the Schedules of Events (SOEs).  
• Add an exclusion criterion for patients who have previously received modakafusp alfa. 
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.  
Protocol Amendment 1 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1.  
Cover page 
EudraCT number added. 
Number was not present. 
2.  
Section 5.1.3 
 
 
Table 9.a Primary Specimen 
Collections 
Section 13.1.5 Immunogenicity 
Analyses 
Appendix A Table 9 
Appendix A Table 10 
 
 
 
 
Assay not available.  
3.  
Section 6.2.3.2 Arm B MKP in 
RRMM 
Section 6.2.3.3 Arm C MDK in 
RRMM 
Text regarding carfilzomib 
20/56 intravenous (IV) mg/m2 once 
weekly dosing schedule revised to 
include a full description of the 
carfilzomib dosing schedule in 
Group 3 (Arms B and C) within 
each modakafusp alfa IV dose level.  
Revised for clarity and 
consistency. 
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Study No. TAK-573-1502  
175 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
4.  
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
An exclusion criterion was added 
for previous modakafusp alfa 
treatment. 
Update. 
5.  
Section 8.1.1.2 Postinfusion 
Medication 
Section 9.6.5 Vital Signs 
Harmonized monitoring period 
procedures during infusions and 
postdose. 
Update. 
6.  
Section 8.2.1 Definition of DLT-
Evaluable Patients 
Section 13.1.1.3 DLT-Evaluable 
Analysis Set 
Definition changed from “The DLT-
evaluable analysis set will include 
patients who experienced a DLT in 
Cycle 1 in the treatment phase of the 
study or have completed Cycle 1 
dose of modakafusp alfa and at least 
75% of the planned dose of the 
combination partners.” to “The 
DLT-evaluable analysis set will 
include patients who experienced a 
DLT in Cycle 1 in the treatment 
phase of the study or patients who 
received a full dose of modakafusp 
alfa and any amount of the planned 
dose of the combination partners 
and completed evaluation for DLT 
in Cycle 1.” 
Update to include patient 
with any dose of combination 
partners in the DLT-
evaluable patient set. 
7.  
Section 9.6.12 Pulmonary 
Function Testing  
Section added to describe the 
pulmonary function testing 
procedure to be used. 
Correction. 
8.  
Section 9.6.13 Echocardiogram 
Section added to describe the 
echocardiogram procedure to be 
used. 
Correction. 
9.  
Section 9.8.2 Bone Imaging  
Text regarding bone imaging 
updated. 
Correction. 
10.  
Appendix A Schedules of Events 
Tables 1 to 19 
Changed the term “Skeletal survey” 
to “Bone imaging” in all Schedule 
of Event (SOE) tables. 
Changed the term “CT, PET-CT, or 
MRI scan” to “Extramedullary 
imaging” in all SOE tables. 
Editorial update. 
11.  
Appendix A Schedules of Events 
Removed “if possible” from 
footnote ee. 
Clarification. 
12.  
Appendix A Schedules of Events 
Removed redundant footnote nn. 
Correction. 
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Study No. TAK-573-1502  
176 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
13.  
Appendix A Table 3 
• 
Pomalidomide dispensation 
removed at Cycle (C)1 
Day (D)22. 
• 
Serum free light chain (FLC) 
assay added at screening, 
C1D1, C1D15, and C2D15. 
• 
Immunofixation serum - urine 
added at C1D15, and C2D15.  
• 
Quantification of 
immunoglobulin (Ig) added at 
screening. 
• 
Quantification of Ig removed at 
C1D8, C1D15, C1D22, C2D8, 
C2D15, and C2D22. 
• 
Flow cytometry added at C2D1, 
C2D8, C2D15, and C2D22. 
• 
Investigator assessment of 
disease response removed at 
screening.  
Corrections. 
14.  
Appendix A Table 5 
Removed pregnancy test at C2D1. 
Correction. 
15.  
Appendix A Table 9 
Added pregnancy test at C1D1. 
Removed thyroid function at C1D1 
and C2D1. 
Correction. 
16.  
Appendix A Table 11 
Removed pregnancy test at C2D8, 
C2D15, and C2D22. 
Correction. 
17.  
Appendix A Schedules of Events 
Tables 11 to 19 
“Serum sample for immunogenicity 
(ADA)” changed to “Serum sample 
for immunogenicity (ADA/NAb).”  
Editorial update for 
consistency. 
18.  
Appendix A Schedules of Events 
Tables 1 to 19 
Added row titles “Disease 
Assessments” and “Biologic 
Assessments” in all SOE tables. 
Editorial update. 
19.  
Appendix A Schedules of Events 
Tables 1 to 19 
Added row for serum β2 
microglobulin at screening. 
Editorial update. 
20.  
Appendix A Schedules of Events 
Tables 1 to 19 
 
 
 
Correction. 
21.  
Appendix A Schedules of Events 
Tables 1 to 19 
Timing of screening assessments 
clarified in footnote a. 
Clarification. 
22.  
Appendix C Table 2 PK 
Sampling: Cycles 3 and Beyond  
Pharmacokinetics (PK) at end of 
treatment (EOT), which is already in 
Appendix A Table 19, added in 
Appendix C Table 2. 
Editorial update for 
consistency. 
 
 
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177 of 200  
Protocol Incorporating Amendment No. 5 US v1 
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CONFIDENTIAL 
 
Protocol Amendment 2 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are to:  
• Remove modakafusp alfa and daratumumab arm (Arm 5 in Group 2 relapsed and refractory 
multiple myeloma [RRMM] Doublets). 
• Remove secondary objectives relating to daratumumab pharmacokinetics (PK). 
• Reduce the modakafusp alfa starting dose.  
• Revise the prior therapy inclusion criterion.  
• Update pregnancy testing timepoints and modalities, and contraception language (period of 
contraception and method). 
• Update imaging assessment schedules. 
• Remove baseline human immunodeficiency (HIV) and hepatitis C virus (HCV) testing. 
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.  
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1.  
2.0 STUDY SUMMARY 
Removed all references to 
daratumumab doublet arm. 
Removed secondary objective 
regarding daratumumab PK. 
Number of subjects and arms 
updated. 
Modakafusp alfa dose updated. 
Food and Drug 
Administration (FDA) 
comment and harmonization 
with inclusion criteria in 
Study TAK-573-2001. 
2.  
3.4 Corporate Identification  
Section added per new template 
New template 
3.  
4.4.1.1 Rationale for Modakafusp 
Alfa Dose 
Added rationale for starting dose at 
80 mg.  
Per FDA feedback on Study 
TAK-573-2001. 
4.  
4.2.4.3 TAK-573-2001 
Added section on Study TAK-573-
2001. 
Update.  
5.  
4.5.1.2 Clinical Safety Summary 
Updated safety information 
Update.  
6.  
5.1.2 Secondary Objectives 
Removed secondary objective 
regarding daratumumab PK for 
Group 2 RRMM Doublets. 
Arm 5 was removed from 
protocol (Modakafusp alfa-
Daratumumab arm). This arm 
will be included in another 
study (TAK-573-2001). 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
178 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
7.  
6.2 Overview of Combination 
Therapy Groups and Dose 
Regimens 
Added tables for combination 
regimens. 
Clarification.  
8.  
6.1 Overview of Study Design  
Appendix A Schedules of Events 
Removed Arm 5: Modakafusp alfa + 
daratumumab (MD) in RRMM. 
This arm will be included in 
another study 
(TAK-573-2001). 
9.  
6.1 Overview of Study Design  
6.3.1 Group 1: NDMM 
Maintenance 
6.3.2 Group 2: RRMM Doublets 
6.3.3 Group 3: RRMM Triplets 
6.4 Number of Patients  
13.3 Determination of Sample 
Size 
Appendix I BOIN Design for 
Dose Escalation/De-escalation 
Sample size increased.  
New dose cohort was added.  
10.  
6.2 Overview of Combination 
Therapy Groups and Dose 
Regimens 
Changed modakafusp alfa starting 
dose to 80 mg in all arms and added 
1 dose level (modakafusp alfa 60 
mg). 
Per FDA feedback on study 
TAK-573-2001. 
11.  
6.4 Number of Patients 
 
Clarified replacement of non-dose-
limiting toxicity (DLT) evaluable 
patients. 
Clarification. 
12.  
6.5.4 Definition of End of 
Study/Study Completion and 
Planned Reporting 
Details added regarding termination 
of the study. 
Update. 
13.  
7.1 Inclusion Criteria 
Changed inclusion Criterion 3c to 
“For Group 2 RRMM doublet arms 
only: Patients who have received at 
least 3 prior lines of antimyeloma 
therapy including at least 1 PI, 1 
IMiD and 1 anti-CD38 mAb drug, 
or who are triple refractory to a PI, 
an IMiD and an anti-CD38 mAb 
drug regardless of the number of 
prior line(s) of therapy.” 
Changed inclusion Criterion 3d to 
“For Group 3 RRMM triplet arms 
only: Patients who have received 1 
to 3 prior lines of antimyeloma 
therapy including at least 1 PI and 1 
IMiD, and who are not refractory to 
the combination partners.” 
FDA comment and 
harmonization with inclusion 
criteria in TAK-573-2001. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
179 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
14.  
7.1 Inclusion Criteria  
Serum creatinine was removed from 
laboratory tests required at 
enrollment. 
Update. 
15.  
 
Electronic consent was added. 
Update. 
16.  
7.1 Inclusion Criteria 
Criterion regarding nonsecretory 
multiple myeloma (MM) was 
removed. 
Update. 
17.  
9.4 Informed (e)Consent 
Criterion regarding usage of drugs 
that prolong the QT interval was 
removed.  
Update.  
18.  
 
Criterion regarding current/prior use 
of immunosuppressive medications 
was removed. 
Update.  
19.  
7.2 Exclusion Criteria 
Two criteria regarding 
cardiovascular history were revised. 
Update. 
20.  
8.1.1.3 Prophylaxis Against Risk 
of Infection 
“…or as recommended with specific 
agents as described below.:” was 
added.  
Update. 
21.  
8.3 Prohibited Medications and 
Procedures 
Heading added to separate 
prohibited from permitted 
medications. 
Clarification. 
22.  
8.4 List of European Union 
Auxiliary Medicinal Products 
Used in the Trial Other Than the 
Investigational Products 
Section added per new template 
New template. 
23.  
8.5.2 Intrapatient Dose Escalation Text added regarding potential 
modakafusp alfa dose escalation. 
Clarification. 
24.  
8.8.1 Contraception and 
Pregnancy Avoidance Procedures 
Time frames and safety language 
were updated. 
Update. 
25.  
9.7.15.1 Clinical Laboratory Tests Details regarding transgender 
patients added.  
Update. 
26.  
9.7.6 Pregnancy Test  
Appendix A Schedules of Events 
Updated pregnancy testing by 
adding monthly pregnancy tests for 
all arms. Updated pregnancy testing 
to either serum or urine tests for all 
pregnancy testing.  
Monthly pregnancy testing 
was required by health 
authorities on another 
TAK-573 study. 
Harmonization of the 
timepoints and methods 
through TAK-573 studies.  
27.  
9.7.15.1 Clinical Laboratory Tests 
Appendix A Schedules of Events 
Remove HIV and HCV. 
Harmonization with the 
TAK-573-2001 study. 
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
180 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
28.  
9.9.1 Extramedullary Disease 
Imaging  
Appendix A Schedules of Events 
Updated schedule of assessment 
from every 2 cycles to every 3 
cycles if lesion at baseline. 
Harmonization with standard-
of-care (SOC) and other 
TAK-573 studies. 
29.  
9.9.2 Bone Imaging 
Appendix A Schedules of Events 
Updated schedule of assessment 
from every 2 cycles to at the 
investigator’s discretion. 
Harmonization with SOC and 
other TAK-573 studies. 
30.  
Table 9.a Primary Specimen 
Collections 
13.1.4 PK Analysis  
Appendix C PK Sampling 
Remove daratumumab PK analysis 
for RRMM Doublets. 
Arm 5 was removed from 
protocol (modakafusp alfa-
daratumumab arm). This arm 
will be included in another 
study (TAK-573-2001). 
31.  
AE Definition 
Definition revised to comply with 
new template. 
Update. 
32.  
10.1.4 SAEs 
Definition revised and text 
streamlined to comply with new 
template. 
Update. 
33.  
10.2 Procedures for Reporting and 
Recording AEs and SAEs 
Section revised and text streamlined 
to comply with new template. Fax 
numbers removed. 
Update. 
34.  
Prior Section 10.2.8.5 Reporting 
of Abnormal Liver Function Tests 
Section removed as no longer 
applicable. 
Update. 
35.  
10.5 Procedures for Reporting 
Product Complaints or Medication 
Errors (Including Overdose) 
Section added  
Update. 
36.  
14.2 Protocol Deviations 
Clarification added regarding 
assessment of protocol deviations. 
Update. 
37.  
Appendix A Schedules of Events 
Removed urinalysis after CxD1 
from all arms. 
Harmonization with TAK-
573-2001. 
38.  
Appendix A Schedules of Events 
Removed thyroid function at C1D1 
from Group 3 Arm A. 
Correction. 
39.  
Previous Appendix I removed. 
Examples of QT Interval Prolonging 
Agents. 
Update.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
181 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reasons for this amendment are to: 
• Revise the study design. 
• Update clinical data from ongoing modakafusp alfa studies. 
• Close the combination arm with carfilzomib and add contraindications to concurrent 
carfilzomib and modakafusp alfa treatment. 
• Add event-free survival (EFS) as a secondary endpoint. 
• Revise the pomalidomide and bortezomib dosing schedules. 
• Clarify instructions for the administration of combination agents. 
• Clarify the collection of biomarker, pharmacodynamic, and immunogenicity samples.  
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. 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
1. 
Cover page 
2.0 STUDY SUMMARY 
Added ClinicalTrials.gov identifier. Regulatory update.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
182 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
2. 
2.0 STUDY SUMMARY  
5.3.2 Secondary Endpoints 
5.3.3 
 
6.0 STUDY DESIGN 
7.1 Inclusion Criteria  
13.0 STATISTICAL 
METHODS 
Appendix A Schedules of 
Events 
Group 1 was modified. 
Eligibility changes: 
• 
Requirement for newly 
diagnosed multiple myeloma 
(MM) was removed.  
• 
Patients must not have started 
lenalidomide maintenance 
before enrollment.  
• 
Measurable disease at diagnosis 
no longer required.  
• 
Achievement of major clinical 
response no longer required. 
• 
Tandem transplant allowed. 
• 
Patients may start maintenance 
therapy as early as 60 days after 
transplantation and up to 180 
days after transplantation or 
consolidation. 
NDMM (newly diagnosed multiple 
myeloma) maintenance was changed 
to MM maintenance throughout the 
protocol. 
Per investigator assessment was 
added to the secondary endpoint of 
overall response rate. 
 
 
 
 
  
Study design revision per 
investigator feedback.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
183 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
3. 
2.0 STUDY SUMMARY  
4.5.2 Benefit-Risk Profile of 
the Combination Agents 
6.1 Overview of Study Design 
6.2.2.3 Arm 4 MK in RRMM 
(Closed to Enrollment) 
6.2.3 Group 3: RRMM Triplets 
7.1 Inclusion Criteria 
8.1.2.4 Daratumumab 
Administration, 
Premedications and 
Prophylaxis 
13.3 Determination of Sample 
Size 
Appendix A Schedules of 
Events  
Appendix I 
BOIN 
Design for Dose 
Escalation/De-escalation 
Carfilzomib was removed as a 
combination agent, and treatment 
arms that included carfilzomib were 
closed. 
• 
Arm 4 was closed to 
enrollment. 
• 
Arms B and C were removed 
from the protocol. 
• 
Content describing or related to 
carfilzomib and Arms 4, B, and 
C was removed. (Previous 
Sections 4.3.4, 4.4.2.4, and 
9.7.13 were deleted.) 
• 
Study schema was revised. 
Concurrent modakafusp alfa and 
carfilzomib treatment is 
contraindicated due to safety 
events.  
4. 
2.0 STUDY SUMMARY 
5.1 Objectives 
5.3 Endpoints 
13.1.3.2 Group 2 and Group 3: 
RRMM Doublets and Triplets 
Secondary 
 
objectives and endpoints for Groups 
2 and 3 were combined.  
The clinical benefit rate endpoint 
was removed as a secondary 
endpoint for Groups 2 and 3. 
Event-free survival (EFS) was added 
as a secondary endpoint for Groups 
2 and 3. 
Clarification and revision of 
study design.  
5. 
2.0 STUDY SUMMARY 
6.1 Overview of Study Design 
6.3 Dose Escalation/De-
escalation 
6.4 Number of Patients 
13.3 Determination of Sample 
Size 
Appendix I 
BOIN 
Design for Dose 
Escalation/De-escalation  
Sample size was updated to align 
with changes in study arms. Total 
sample size is approximately 120 
patients: approximately 18 patients 
in Arm 1, 66 patients in the RRMM 
doublet arms, and 36 patients in the 
RRMM triplet arms.  
Harmonization with 
aforementioned study design 
changes.  
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Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
184 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
6. 
2.0 STUDY SUMMARY 
6.2.2 Group 2: RRMM 
Doublets  
6.2.3 Group 3: RRMM Triplets 
6.3.2 Group 2: RRMM 
Doublets 
New doses for pomalidomide (2 and 
3 mg) were added. 
Exploration of other dosing in 
the arm with pomalidomide. 
7. 
4.2.1 Mechanism of Action 
Text describing the mechanism of 
action of modakafusp alfa was 
modified. 
Update. 
8. 
4.2.4.1 TAK-573-1501 
4.2.4.2 TAK-573-1001 
4.4.1.1 Rationale for 
Modakafusp Alfa Dose  
4.5.1 Benefit-Risk Profile of 
Modakafusp Alfa 
4.5.1.2 Clinical Safety 
Summary 
Text was updated with more-recent 
clinical data from Study TAK-573-
1501 and Study TAK-573-1001. 
Clinical update.  
9. 
4.2.4 Clinical Experience 
4.2.4.3 TAK-573-2001 
4.4.1.1 Rationale for 
Modakafusp Alfa Dose 
Updated status of Study TAK-573-
2001. 
Update. 
10. 
4.2.4.4 TAK-573-1502 Arm 4 Safety events with concurrent 
modakafusp alfa and carfilzomib 
treatment were described in a new 
section. 
Concurrent modakafusp alfa and 
carfilzomib treatment is 
contraindicated due to safety 
events.  
11. 
4.4.1.1 Rationale for 
Modakafusp Alfa Dose 
Guidelines for the use of 
modakafusp alfa with concurrent 
anticoagulation were added.  
Safety update.  
12. 
4.4.2.2 Pomalidomide 
Text detailing the starting dose for 
pomalidomide was added as well as 
a literature reference for the lower 
pomalidomide dose.  
Update.  
13. 
4.5.2 Benefit-Risk Profile of 
the Combination Agents 
7.1 Inclusion Criteria 
Instructions and precautions for 
pomalidomide were expanded.  
Clinical update.  
14. 
6.3.1 Group 1: MM 
Maintenance  
6.3.2 Group 2: RRMM 
Doublets 
6.3.3 Group 3: RRMM Triplets 
Bayesian Optimal Interval decision 
tables to guide escalation and de-
escalation decisions and descriptions 
were added. 
Statistical update.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
185 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
15. 
6.2.2.2 Arm 3 MV in RRMM 
8.1.2.3 Bortezomib 
Administration, 
Premedications and 
Prophylaxis 
Appendix A Schedules of 
Events 
Bortezomib dosing schedule was 
revised.  
 
Harmonization with 
aforementioned study design 
changes and safety update. 
16. 
6.2.2.2 Arm 3 MV in RRMM 
 
Staged enrollment was added for 
Arm 3.  
Study design update. 
17. 
6.5.1 Duration of an Individual 
Patient’s Study Participation 
Patients in Group 2 and Group 3 
may receive modakafusp alfa in 
combination with associated agents 
until disease progression, 
unacceptable toxicity, or until any 
other discontinuation criterion is 
met, whichever occurs first.  
Clarification.  
18. 
7.1 Inclusion Criteria #9 
Prohibited prior treatments and 
washout periods were revised as 
follows.  
The minimal interval between the 
last dose of any of the following 
treatments/procedures and the first 
dose of study treatment must be at 
least:  
Bispecific antibodies 
28 days 
Any investigational anticancer 
therapy product  
28 days 
 
Clarified other inclusion criteria.  
Clinical update and clarification. 
19. 
7.1 Inclusion Criteria 
6.2.2 Group 2: RRMM 
Doublets 
The eligibility requirement for 
estimated creatinine clearance is 
≥60 mL/min (Cockcroft-Gault 
formula) for the first 3 patients in 
Arm 3.  
Safety update.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
186 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
20. 
7.1 Inclusion Criteria 
8.1.2.1 Lenalidomide 
Administration, 
Premedications and 
Prophylaxis 
8.1.2.2 Pomalidomide 
Administration, 
Premedications and 
Prophylaxis 
8.8 Precautions and 
Restrictions 
9.7.6 Pregnancy Testing 
Contraception guidelines were 
expanded to include mandatory 
adherence to any treatment-specific 
pregnancy prevention program  
Regulatory and safety update.  
21. 
7.2 Exclusion Criteria 
Clarified exclusion criteria.  
For the criterion related to history of 
treatment discontinuation related to 
treatment-related toxicity, added 
“For the lenalidomide arm: The 
patient is intolerant to 
lenalidomide.”  
Clarification. 
22. 
8.1 Study Drug Administration Timing of administration of 
pomalidomide and lenalidomide 
added. 
Clarification. 
23. 
8.1.1.1 Premedications  
Appendix A Schedules of 
Events 
Time frames for premedication were 
removed, and the timing of 
premedications was clarified.  
Update based on ongoing clinical 
experience with modakafusp 
alfa. 
24. 
8.1.2.1 Lenalidomide 
Administration, 
Premedications and 
Prophylaxis 
Inserted “Lenalidomide may 
increase digoxin plasma levels.” 
Update. 
25. 
8.1.2.4 Daratumumab 
Administration, 
Premedications and 
Prophylaxis 
Appendix A Schedules of 
Events 
Section 8.1.2.4, previously 
Carfilzomib Administration, 
Premedications and Prophylaxis, 
was deleted. Section 8.1.2.4 is now 
as shown. Text added: No dose 
reduction is permitted for 
daratumumab. 
Clinical update.  
26. 
8.3 Prohibited Medications and 
Procedures 
Live vaccines are prohibited 30 days 
before the first administration of 
study drug and for 90 days after the 
completion of study treatment.  
Response to a European Union 
health authority. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
187 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
27. 
8.3 Prohibited Medications and 
Procedures 
Carfilzomib was added to the list of 
prohibited medications. 
Concurrent modakafusp alfa and 
carfilzomib treatment is 
contraindicated due to safety 
events. 
28. 
8.5 DLTs  
The evaluation period for dose-
limiting toxicity (DLT) may be 
increased as needed for safety 
reasons.  
Because of the safety events with 
carfilzomib, flexible language 
was added for the DLT 
evaluation period. 
29. 
8.5.1 Definition of 
DLT-Evaluable Patients  
13.1.1.3 DLT-Evaluable 
Analysis Set 
The DLT-evaluable analysis set will 
include patients who experienced a 
DLT in Cycle 1 in the treatment 
phase of the study or patients who 
received a full dose of modakafusp 
alfa and at least 75% of the planned 
dose of the combination partners and 
completed evaluation for DLT in 
Cycle 1.  
Clarification. 
30. 
8.6.1 Modakafusp Alfa and 
Combination Agent(s) 
Dose modification and laboratory 
value requirements for treatment 
cycle guidelines were expanded.  
Clinical update. 
31. 
9.10.5 Immunogenicity 
Sample Collection 
Text describing handling of 
infusion-related reactions was 
expanded.  
Clinical update. 
32. 
9.7.3 Physical Examination 
Appendix A Schedules of 
Events 
Physical examinations after the 
screening visit can be symptom 
directed.  
In Group 3 For Cycle 3 and beyond, 
weight assessment, Eastern 
Cooperative Oncology Group 
assessment, and physical 
examination were removed from all 
days except Day 1 of each cycle. 
Per input from an investigator, a 
comprehensive physical 
examination is not necessary at 
each visit. 
33. 
9.7.5 Vital Signs 
Appendix A Schedules of 
Events 
Timing of blood pressure 
measurements was clarified. 
Clinical update.  
34. 
9.7.13.2 Subject Identification 
Card 
Appendix A Schedules of 
Events 
Patient identification cards will be 
provided to all patients.  
Information for healthcare 
providers in the event a patient 
requires a blood transfusion.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
188 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
35. 
9.7.14 Clinical Laboratory 
Procedures and Assessments 
 
Hepatitis testing was clarified. 
Previous text was imprecise. 
Text related to hepatitis testing 
was in only the exclusion 
criteria. It was added in this 
section for clarification.  
36. 
9.7.14 Clinical Laboratory 
Procedures and Assessments 
Appendix A Schedules of 
Events 
ABO blood group, Rh factor, and 
direct and indirect antiglobulin tests 
were added.  
 
Modakafusp alfa has been shown 
to interfere with serological 
testing due to binding to CD38 
on red blood cells, which results 
in positive direct and indirect 
antiglobulin tests. 
37. 
9.7.14 Clinical Laboratory 
Procedures and Assessments 
Appendix A Schedules of 
Events 
Collection was changed to free 
thyroxine (T4) instead of T4 and T3 
(triiodothyronine). 
Clinical clarification.  
38. 
9.7.14 Clinical Laboratory 
Procedures and Assessments 
Appendix A Schedules of 
Events 
Ferritin and schizocytes tests were 
added for Arm 3. 
Safety laboratory tests were added at 
Cycle 1 Day 1 and Cycle 1 Day 11.  
Clinical safety update.  
39. 
9.9.1 Extramedullary Disease 
Imaging 
9.9.2 Bone Imaging 
Language was added to describe 
future imaging central collection/ 
analysis if needed. 
Internal committee request.  
40. 
9.9.7.2.1 BMA for MRD 
Assessment 
Appendix A Schedules of 
Events 
Condensed information about time 
points for bone marrow aspiration. 
Clarification. 
41. 
9.10.1 Primary Specimen 
Collection for PK, 
Pharmacodynamic, and 
Biomarker Assessments 
9.10.3 
 
  
Appendix A Schedules of 
Events 
Collection of biomarker samples 
was clarified. 
 
 
 
 
 
 
42. 
9.10.3 
 
 
9.10.3.2 
 
 
Appendix A Schedules of 
Events 
 
 
  
 
 
 
Administrative clarification.  
43. 
9.10.3.2 
 
  
 
.  
 
. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
189 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
44. 
9.10.1 Primary Specimen 
Collection for PK, 
Pharmacodynamic, and 
Biomarker Assessments 
9.10.4 
 
  
Appendix A Schedules of 
Events 
Collection of 
 
 immunogenicity samples was 
clarified. 
 
 
 neutralizing 
antibody was added to 
immunogenicity collections.  
45. 
2.0 STUDY SUMMARY 
13.1.1.6 MRD Analysis Set 
13.1.3 Efficacy Analysis  
Analysis set for minimal/measurable 
residual disease was clarified. 
 
Statistical update. 
46. 
13.1.3.2 Group 2 and Group 3: 
RRMM Doublets and Triplets 
Clinical benefit rate (CBR) was 
replaced by event-free survival 
(EFS), and EFS was defined.  
Clarification of a new endpoint. 
47. 
Appendix A Schedules of 
Events 
Appendix B Bone Marrow 
Collection and Assessment 
Schedules 
Appendix C PK Sampling 
Footnotes were streamlined, 
clarified, or updated.  
Clarification and update. 
48. 
Appendix A Schedules of 
Events 
Visit schedule was clarified.  
For the arm with daratumumab, 
visits for Cycle 3 and beyond are as 
follows: Cycle 3 through Cycle 6 on 
Days 1 and 15 and Cycle 7 and 
beyond on Day 1. 
For the arms with bortezomib, visits 
for Cycle 3 and beyond are as 
follows: Cycle 3 through Cycle 8 on 
Days 1, 8, 15, and 22 and Cycle 9 
and beyond on Days 1, 8, and 22.  
Aligned with the dosing schedule 
of bortezomib and daratumumab. 
49. 
Appendix C PK Sampling  
The pharmacokinetics sampling 
schedule was updated to every 3 
cycles starting with Cycle 12 instead 
of every cycle. 
Study design update.  
50. 
Appendix G 
IMWG 
Definition of MM and 
Response Criteria 
Definitions were updated. 
Update.  
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
190 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 Summary and Rationale (Not Implemented) 
This section describes the changes in reference to the protocol incorporating Amendment 4 v1 
(not implemented). As of 20 November 2023, Takeda decided to discontinue the development of 
modakafusp alfa, including Study TAK-573-1502. These decisions were made due to strategic 
reasons and not due to any safety concerns with modakafusp alfa. Following the implementation 
of Amendment 4, the majority of study assessments will be discontinued to ease the burden of 
protocol-mandated assessments on patients.  
Upon implementation of this amendment, 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 (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 are 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. 
Pharmacokinetic assessments will no longer be performed or recorded. Local laboratory 
assessments should be performed per local standard of care, and recording of AEs in the 
electronic case report form will be limited to AEs leading to dose modification or discontinuation 
of study drug. See the updated Schedule of Events—Amendment 4 and beyond (Appendix A 
Table 1) for more detailed information. 
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. 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
1.  2.0 STUDY SUMMARY 
The purpose and rationale for 
Protocol Amendment 4 was added. 
Clarification 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
191 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
2.  2.0 STUDY SUMMARY 
5.1.2 Secondary Objectives 
5.1.3 
 
 
5.3.2 Secondary Endpoints 
5.3.3 
 
“Following the implementation of 
Protocol Amendment 4 (see Section 
1.3), data collection will be limited 
to the safety assessments outlined in 
the updated Schedule of Events—
Protocol Amendment 4 and Beyond 
(Appendix A Table 1).” was added 
to the Secondary 
 
Objectives and Endpoints for use 
after the implementation of Protocol 
Amendment 4. 
Updated objectives and 
endpoints to note that data 
collected for them would no 
longer be collected after 
implementation of Protocol 
Amendment 4. 
3.  6.1 Overview of Study Design The purpose and rationale for the 
implementation of Protocol 
Amendment 4 was added.  
“Prior to Implementation of Protocol 
Amendment 4:” was added before 
text characterizing the Overview of 
Study Design for use prior to 
implementation of Protocol 
Amendment 4. 
Clarification. 
4.  6.2 Overview of Combination 
Therapy Groups and Dose 
Regimens 
6.3 Dose Escalation/De-
escalation 
6.4 Number of Patients 
6.5 Duration of the Study 
“Following the implementation of 
Protocol Amendment 4 (see Section 
1.3), data collection will be limited 
to the safety assessments outlined in 
the updated Schedule of Events—
Protocol Amendment 4 and Beyond 
(Appendix A Table 1).” was added 
throughout the Study Design 
section. 
Clarification. 
5.  6.5.3 Posttrial Access 
“After the data cutoff date, ongoing 
patients must transition to the 
Posttrial Access program once it 
becomes available in their country.” 
Was added to the Posttrial Access 
section. 
Clarification. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
192 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
6.  6.5.4 Definition of End of 
Study/Study Completion and 
Planned Reporting 
“Following the implementation of 
Protocol Amendment 4 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 Definition of End of Study for 
use after the implementation of 
Protocol Amendment 4. 
Language about premature 
termination of the study was added 
to match other trials in the program. 
Clarification. 
7.  8.0 STUDY DRUG 
Section “8.4 
List of European 
Union Auxiliary Medicinal Products 
Used in the Trial Other Than the 
Investigational Products” was 
removed. 
As per the latest EU CTR 
guidance from EMA, all EU-
CTR specific protocol changes 
will be made in the substantial 
modification step after EU CTR 
transition (as needed). 
8.  9.0 STUDY CONDUCT 
A description of the data collection 
requirements was added that will be 
implemented in Protocol 
Amendment 4.  
Clinical updates. 
9.  9.7 Study Procedures 
A description of the data collection 
requirements and changes to study 
procedures was added that will be 
implemented in Protocol 
Amendment 4. 
Clinical updates. 
10.  9.7.3 Physical Examination 
9.7.5 Vital Signs 
9.7.6 Pregnancy Testing 
9.7.9 ECOG Performance 
Status 
9.7.11 12-Lead ECG 
9.7.14 Clinical Laboratory 
Procedures and Assessments 
9.7.14.1 Clinical Laboratory 
Tests 
“Following the implementation of 
Protocol Amendment 4 (see Section 
1.3), data collection will be limited 
to the safety assessments outlined in 
the updated Schedule of Events—
Protocol Amendment 4 and Beyond 
(Appendix A Table 1).” was added 
to the relevant Study Procedure 
section for use after the 
implementation of Protocol 
Amendment 4. 
Clinical updates. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
193 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
11.  9.7.7 Concomitant 
Medications and Procedures 
“Upon implementation of Protocol 
Amendment 4, concomitant 
medications and procedures will not 
be recorded in the eCRF.” was 
added for use after the 
implementation of Protocol 
Amendment 4. 
Clinical updates. 
12.  9.7.8 AE Monitoring 
“Upon implementation of Protocol 
Amendment 4 (see Section 1.3), AE 
data collection will be limited to the 
following: all SAEs, 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). Refer to the Updated 
SOE - Amendment 4 (Appendix A 
Table 1) for details.” was added for 
use after the implementation of 
Protocol Amendment 4. 
Clinical updates. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
194 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
13.  9.7.14 .Clinical Laboratory 
Procedures and Assessments 
9.7.14.1 Clinical Laboratory 
Tests 
“Following the implementation of 
Protocol Amendment 4 (see Section 
1.3), data collection will be limited 
to the safety assessments outlined in 
the updated Schedule of Events—
Protocol Amendment 4 and Beyond 
(Appendix A Table 1). 
Per Protocol Amendment 4, 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 SOC (ie, for acute 
management of TEAEs), per the 
investigator’s judgment of SOC.” 
was added for use after the 
implementation of Protocol 
Amendment 4. 
Clinical updates. 
14.  9.9 Disease Assessment 
9.9.1 Extramedullary Disease 
Imaging 
9.9.2 Bone Imaging 
9.9.3 Quantification of Igs 
9.9.4 Quantification of M-
Protein in Serum and Urine 
9.9.5 Serum FLC Assay 
9.9.6 Immunofixation of 
Serum and Urine 
9.9.7 BMA 
9.9.7.1.1 Disease Assessment 
9.9.7.1.2 Cytogenetics 
9.9.7.2 Central Laboratory 
Evaluations 
“Following the implementation of 
Protocol Amendment 4 (see Section 
1.3), all laboratory and investigator 
assessments of response and 
progression for protocol purposes 
are discontinued. Patients should 
otherwise be treated by the 
investigator according to SOC.” was 
added for use after the 
implementation of Protocol 
Amendment 4. 
Clinical updates. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
195 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
15.  9.10 Biomarker, PK, 
Pharmacodynamic, and 
Pharmacogenomics, Samples 
Indicated that with implementation 
of Protocol Amendment 4: 
-“…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.” 
-“BMA, 
 serum, and blood 
samples for biomarker, PK, 
pharmacodynamic and 
pharmacogenomic measurements 
will no longer be collected.” 
-“…centralized clinical laboratory 
evaluations 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 
SOC (ie, for acute management of 
TEAEs), per the investigator’s 
judgment of SOC.” 
Clinical Updates. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
196 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
16.  9.10.1 Primary Specimen 
Collection for PK, 
Pharmacodynamic, and 
Biomarker Assessments 
9.10.2 PK Measurements 
9.10.3 
 
 
9.10.3.1 
 
 
9.10.3.2 
 
 
9.10.4 
 
 
9.10.5 Immunogenicity 
Sample Collection 
“Upon implementation of Protocol 
Amendment 4 (see Section 1.3), 
BMA, 
, serum, and blood 
samples for biomarker, PK, 
pharmacodynamic and 
pharmacogenomic measurements 
will no longer be collected.” was 
added for use after implementation 
of Protocol Amendment 4. 
Clinical Updates. 
17.  9.15 Posttreatment Follow-up 
Assessments 
“Upon implementation of Protocol 
Amendment 4, patients will not be 
followed for the PFS or OS follow-
up periods. See the SOE for 
appropriate assessments after the 
implementation of Protocol 
Amendment 4 in (Appendix A 
Table 1).” was added for use after 
implementation of Protocol 
Amendment 4. 
Clinical Updates 
18.  10.2 Procedures for Reporting 
and Recording AEs and SAEs 
10.3 Monitoring AEs and 
Periods of Observation 
10.4 Procedures for Reporting 
Drug Exposure During 
Pregnancy and Birth Events 
“Upon implementation of Protocol 
Amendment 4, 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 during pregnancy 
and pregnancy outcomes, product 
complaints, and medication errors 
(including overdose) are to be 
reported.” was added for use after 
implementation of Protocol 
Amendment 4. 
Clinical Updates. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
197 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
19.  10.2 Procedures for Reporting 
and Recording AEs and SAEs 
“Please note that while the types of 
AEs recorded and reported may 
differ dependent upon the 
implementation of Protocol 
Amendment 4, procedures for 
reporting AEs and SAEs will remain 
the same as stipulated here in 
Section 10.2.”” was added for use 
after implementation of Protocol 
Amendment 4. 
SAE reporting contact information 
was added to match other protocols 
in the program. 
Clarifications. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
198 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
20.  13.0 STATISTICAL 
METHODS 
13.1 Statistical and Analytical 
Plans 
Indicated that with implementation 
of Protocol Amendment 4: 
-“…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.” 
-“All central laboratory and 
investigator assessments of response 
and progression for protocol 
purposes are 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.” 
-“Pharmacokinetic (PK) assessments 
will no longer be performed or 
recorded.” 
-“Patients should otherwise be 
treated by the investigator according 
to local SOC. Local laboratory 
assessments should be performed 
per local SOC, and recording of AEs 
in the electronic case report form 
(eCRF) will be limited to AEs 
leading to dose modification or 
discontinuation of study drug.” 
Clinical updates. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
199 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 4 v1 (Not Implemented) 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number Sections Affected by Change 
Description of Each Change and Rationale 
21.  Appendix A 
Schedules of 
Events 
Provided rationale for the 
implementation of the Updated 
Schedule of Events—Protocol 
Amendment 4 and Beyond. 
Added a new schedule of events for 
use with the implementation of 
Protocol Amendment 4 (Appendix 
A Table 1) and updated all other 
Schedules of Events for use prior to 
the implementation of Protocol 
Amendment 4 (Appendix A Table 2 
through Appendix A Table 12). 
Updated the titles for the Schedules 
of Events (Appendix A Table 2 
through Appendix A Table 12 to be 
used Prior to Protocol Amendment 4 
with text indicating as such. 
Clinical Updates 
22.  Appendix B 
Bone 
Marrow Collection and 
Assessment Schedules 
Provided text to indicate that 
“IMPORTANT NOTE: Bone 
marrow sample collection and 
assessment are no longer required as 
of the implementation of Protocol 
Amendment 4. 
Refer to Section 1.3 for a description 
of the changes to study conduct as a 
result of the implementation of 
Protocol Amendment 4.” 
Clinical updates and 
clarifications. 
23.  Appendix C PK Sampling 
Provided text to indicate that 
“IMPORTANT NOTE: 
Pharmacokinetic sample collection 
and assessment are no longer 
required as of the implementation of 
Protocol Amendment 4. 
Refer to Section 1.3 for a description 
of the changes to study conduct as a 
result of the implementation of 
Protocol Amendment 4.” 
Clinical updates and 
clarifications. 
 
Protocol Amendment 4 v2 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 4 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 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-1502  
200 of 200  
Protocol Incorporating Amendment No. 5 US v1 
19 September 2024 
 
CONFIDENTIAL 
mitigate the risk of fatal hemorrhagic events in response to the observation of a suspected 
unexpected serious adverse reaction (SUSAR) in the ongoing Study TAK-573-1501. 
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. 
Protocol Amendment 4 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.  
8.2 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. 
2.  
8.6.1.4 Criteria for Dose Interruption Addition of Table 8.c with the dose modifications 
for modakafusp alfa bleeding TEAEs. 
Updated to 
mitigate the 
risk of fatal 
hemorrhagic 
events. 
3.  
8.6.1.6 Criteria for Discontinuation 
Removal of criteria related to Grade 4 
life-threatening TEAEs. 
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.c with 
the dose modifications for modakafusp alfa 
bleeding TEAEs 
Updated to 
mitigate the 
risk of fatal 
hemorrhagic 
events. 
 
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Signature Page for TAK-573-1502 Protocol Amend 05 US v1 2024-09-19
Title: Amend 05 US v1 to A Phase 1b Open-label Study to Evaluate the Safety and 
Document Number: TDN-000443416 v1.0
Approval
Clinical
25-Sep-2024 21:52:55 GMT+0000
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Number: TAK-573-1502
Study Title: A Phase 1b Open-label Study to Evaluate the Safety and Tolerability of 
Intravenous Modakafusp Alfa as Part of Combination Therapy in Adult Patients With 
Multiple Myeloma 
Phase: Phase 1b
Version: 1.0
Date: 09-May-2022
Prepared by: 
 MS, PhD,
 Statistics
Based on:
Protocol Version: 1.0
Protocol Date: 01-Apr-2022
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.
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TAK-573-1502
Page 2 of 35
Statistical Analysis Plan
09-May-2022
CONFIDENTIAL
REVISION HISTORY
Version
Approval Date
Primary Rationale for Revision
N/A
N/A
N/A
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TAK-573-1502
Page 3 of 35
Statistical Analysis Plan
09-May-2022
CONFIDENTIAL
TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................6
1.1
Objectives..................................................................................................................6
1.1.1
Primary Objectives ............................................................................................6
1.1.2
Secondary Objectives ........................................................................................6
1.1.3
......................................................................................7
1.2
Endpoints...................................................................................................................8
1.2.1
Primary Endpoints .............................................................................................8
1.2.2
Secondary Endpoints .........................................................................................8
1.2.3
.......................................................................................9
1.3
Estimands ................................................................................................................10
2.0
STUDY DESIGN..........................................................................................................10
3.0
STATISTICAL HYPOTHESES AND DECISION RULES...........................................14
4.0
SAMPLE-SIZE DETERMINATION.............................................................................14
5.0
ANALYSIS SETS.........................................................................................................15
5.1
Safety Analysis Set..................................................................................................15
5.2
PK Analysis Set.......................................................................................................15
5.3
DLT-Evaluable Analysis Set....................................................................................15
5.4
Response-Evaluable Analysis Set ............................................................................15
5.5
Immunogenicity-Evaluable Analysis Set..................................................................15
5.6
MRD Analysis Set ...................................................................................................15
6.0
STATISTICAL ANALYSIS..........................................................................................16
6.1
General Considerations............................................................................................16
6.2
Disposition of Subjects ............................................................................................16
6.3
Demographic and Other Baseline Characteristics.....................................................16
6.3.1
Demographics..................................................................................................16
6.3.2
Medical History and Concurrent Medical Conditions.......................................16
6.3.3
Baseline Characteristics...................................................................................17
6.4
Medication History and Concomitant Medications...................................................17
6.4.1
Prior Medications ............................................................................................17
6.4.2
Concomitant Medications ................................................................................17
6.5
Efficacy Analysis.....................................................................................................17
6.5.1
Primary Endpoints Analysis.............................................................................17
6.5.2
Secondary Endpoints Analysis.........................................................................17
6.5.2.1
Derivation of Endpoints...........................................................................18
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TAK-573-1502
Page 4 of 35
Statistical Analysis Plan
09-May-2022
CONFIDENTIAL
6.5.2.2
Main Analytical Approach.......................................................................19
6.6
Safety Analysis........................................................................................................22
6.6.1
DLTs ...............................................................................................................22
6.6.2
Adverse Events................................................................................................22
6.6.3
Clinical Laboratory Evaluations.......................................................................24
6.6.4
Vital Signs.......................................................................................................25
6.6.5
12-Lead ECGs.................................................................................................26
6.6.6
ECOG..............................................................................................................26
6.6.7
Extent of Exposure and Compliance ................................................................27
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses................................27
6.7.1
Pharmacokinetic/Pharmacodynamic Analyses .................................................27
6.7.2
Immunogenicity Analysis ................................................................................27
6.7.3
Interim Analyses..............................................................................................28
6.8
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] ............................................................................................................28
7.0
REFERENCES..............................................................................................................29
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................30
9.0
APPENDIX...................................................................................................................31
9.1
Changes From the Previous Version of the SAP.......................................................31
9.2
Data Handling Conventions .....................................................................................31
9.2.1
Definition of Baseline......................................................................................31
9.2.2
Definition of Visit Windows............................................................................31
9.2.3
Date Imputation Rules .....................................................................................31
9.3
Analysis Software....................................................................................................33
9.4
BOIN Design for Dose Escalation/De-escalation .....................................................33
LIST OF IN-TEXT TABLES AND FIGURES
Figure 2.a
Study Schema ....................................................................................................11
Figure 2.b
Flowchart for Study Conduct Using the BOIN design ........................................11
Table 6.a
Progression and Censoring Date for PFS and DOR Analyses .............................20
Table 6.b
Progression and Censoring Date for TTP Analyses ............................................20
Table 6.c
Clinical Laboratory Tests...................................................................................25
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TAK-573-1502
Page 5 of 35
Statistical Analysis Plan
09-May-2022
CONFIDENTIAL
ABBREVIATIONS
ADA
Antidrug antibody
AE
Adverse event
AESI
Adverse event of special interest
ASCT
Autologous stem cell transplant
C1D1
Cycle 1 day 1
CBR
Clinical benefit rate
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DLT
Dose-limiting toxicity
DOR
Duration of response
ECG
Electrocardiogram
IRR
Infusion-related reaction
KM
Kaplan-Meier
MedDRA
MM
Medical Dictionary for Regulatory Activities
Multiple myeloma
MRD
MTD
Minimal/measurable residual disease
Maximum tolerated dose
NAb
Neutralizing antibody
NDMM
Newly diagnosed multiple myeloma
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression free survival
PK
Pharmacokinetic
PR
Partial response
PT
Preferred Term (MedDRA)
QTcF
QT interval with Fridericia correction method
RP2D
Recommended phase 2 dose
RRMM
Relapsed/refractory multiple myeloma
SAE
Serious adverse event
sCR 
Stringent CR
SOC
System Organ Class
TEAE 
Treatment-emergent adverse event
TTNT
Time to next treatment
TTP
Time to progression
TTR
Time to response
VGPR
Very good partial response
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TAK-573-1502
Page 6 of 35
Statistical Analysis Plan
09-May-2022
CONFIDENTIAL
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objectives
The primary objectives of the study are:
Group 1: Newly Diagnosed Multiple Myeloma (NDMM) Maintenance

To determine the safety and tolerability of modakafusp alfa and lenalidomide combination
therapy as maintenance in adult patients with NDMM after autologous stem cell transplant
(ASCT).

To determine the recommended phase 2 dose (RP2D) of the combination therapy with
modakafusp alfa.
Group 2: Relapsed Refractory Multiple myeloma (RRMM) Doublet Combinations (Doublets)

To determine the safety and tolerability of modakafusp alfa as part of 2-drug combination
therapy in adult patients with RRMM.

To determine the RP2D of the combination therapy with modakafusp alfa (recommended
doses of the doublet combinations).
Group 3: RRMM Triplet Combinations (Triplets)

To determine the safety and tolerability of modakafusp alfa as part of 3-drug combination
therapy in adult patients with RRMM.

To determine the RP2D of the combination therapy with modakafusp alfa (recommended
doses of the triplet combinations).
1.1.2
Secondary Objectives
The secondary objectives of the study are:
Group 1: NDMM Maintenance

To evaluate the preliminary efficacy of modakafusp alfa and lenalidomide combination
therapy as maintenance in adult patients with NDMM after ASCT.

To evaluate the rate and duration of minimal/measurable residual disease (MRD) negativity.

To collect PK data to support population PK and exposure-response analysis of modakafusp
alfa when given in combination therapy.

To characterize the immunogenicity profile of modakafusp alfa when given in combination
therapy.
Group 2: RRMM Doublets
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TAK-573-1502
Page 8 of 35
Statistical Analysis Plan
09-May-2022
CONFIDENTIAL
1.2
Endpoints
1.2.1
Primary Endpoints
The primary endpoints of the study for Groups 1, 2, and 3 (NDMM Maintenance, RRMM 
doublets, and RRMM triplets) are:

Occurrence of dose-limiting toxicities (DLTs) in Cycle 1.

Frequency and severity of treatment-emergent adverse events (TEAEs).
1.2.2
Secondary Endpoints
Secondary endpoints are:
Group 1: NDMM Maintenance

Progression free survival (PFS).

Overall response rate (ORR) (local assessment).

Duration of response (DOR).

MRD negative rate at a sensitivity of 10-5 in patients 6 months, 1 year, and 2 years after 
treatment in the MRD analysis set. 

Duration of MRD negativity at a sensitivity of 10-5 for patients achieving MRD negativity.

Antidrug antibody (ADA) incidence and characteristics (eg, titer and specificity) and 
neutralizing antibody (NAb).
Group 2: RRMM Doublets

Overall survival (OS).

ORR.

PFS.

Time to progression (TTP).

Time to next treatment (TTNT).

DOR.

Disease control rate (DCR).

Clinical benefit rate (CBR).

Time to response (TTR).

ADA incidence and characteristics (eg, titer and specificity) and NAb.
Group 3: RRMM Triplets

OS.
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Arm D: Modakafusp alfa + daratumumab + pomalidomide (MDP) in RRMM
The overall study schema is shown in Error! Reference source not found..
Figure 2.a
Study Schema
After the doublet RP2D is determined in RRMM doublets, dose escalation of modakafusp alfa in triplet 
combinations will begin.
ASCT: autologous stem cell transplant; MD: modakafusp alfa and daratumumab; MDK: modakafusp alfa, 
daratumumab, and carfilzomib (Kyprolis®); MDP: modakafusp alfa, daratumumab, and pomalidomide; MK: 
modakafusp alfa and carfilzomib (Kyprolis®); MKP: modakafusp alfa, carfilzomib (Kyprolis®), and 
pomalidomide; MP: modakafusp alfa and pomalidomide; MPV: modakafusp alfa, pomalidomide, and 
bortezomib (Velcade®); MV: modakafusp alfa and bortezomib (Velcade®); NDMM: newly diagnosed multiple 
myeloma; RRMM: relapsed or refractory multiple myeloma.
Patient participation will include a screening phase, a treatment phase, and a follow-up phase. 
The screening phase will be up to approximately 21 days before Cycle 1 Day 1. 
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Patients will be evaluated approximately 30 days after the last dose of modakafusp alfa (EOT
visit) or right before the start of subsequent systemic anticancer therapy to permit the detection 
of any delayed TEAEs. The follow-up phase of the study begins once a patient discontinues 
study treatment and completes the EOT visit; study follow-up continues until the study ends or 
the patient completes OS follow-up.
Patients who discontinue for reasons other than progressive disease (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 until death, study termination, or patient withdrawal.
The BOIN design (Liu & Yuan, 2015) will be implemented for dose escalation/de-escalation
(Figure 2.b). Patients will be enrolled and treated in cohort sizes of approximately 3. The starting 
dose will need to treat at least 3 evaluable patients.
Group 1: NDMM Maintenance
The target toxicity rate for maximum tolerated dose (MTD) is set to be ϕ = 0.25. For the purpose 
of overdose control, doses  and higher levels will be eliminated from further examination if 
Pr( > 0.25 | data) >0.95 and at least 3 evaluable patients have been treated at dose level , 
where  is the true DLT rate of dose level . When the lowest dose is eliminated, the study will 
be stopped for safety. It is estimated that approximately 12 DLT-evaluable patients will be 
enrolled.
The BOIN design will be implemented following the steps described below:
1. Patients in the first cohort are treated at a starting dose with at least 3 evaluable patients.
2. A dose is assigned to the next cohort of patients according to the rule below:

If the observed DLT rate at the current dose is ≤ = 0.197, escalate the dose to the 
next higher level.

If the observed DLT rate at the current dose is >  = 0.298, de-escalate the dose to the 
next lower dose level.

Otherwise, stay at the current dose.
3. Repeat step 2 until the maximum sample size of 12 is reached or stop the study if the number 
of evaluable patients treated at the current dose reaches 6 and the decision is made to stay at 
the current dose.
Group 2: RRMM Doublets
The BOIN design will be implemented in the same way as Group 1. It is estimated that 
approximately 48 DLT-evaluable patients will be enrolled for RRMM doublet combinations, 
with approximately 12 for each of Arms 2-5.
Group 3: RRMM Triplets
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After the doublet RP2D is determined in Group 2, dose escalation of modakafusp alfa in Group 3 
will begin. The target toxicity rate for MTD is set to be ϕ = 0.33. 
For the purpose of overdose control, doses  and higher levels will be eliminated from further 
examination if Pr( > 0.33 | data) > 0.95 and at least 3 evaluable patients have been treated at 
dose level , where  is the true DLT rate of dose level . When the lowest dose is eliminated, 
stop the study for safety. It is estimated that approximately 60 DLT-evaluable patients will be 
enrolled, with approximately 15 for each of 4 arms A-D. 
The escalation/de-escalation will be conducted in steps as follows:
4. Patients in the first cohort are treated at the starting dose level with at least 3 evaluable 
patients.
5. Assign a dose to the next cohort of patients according to the rule below:

If the observed DLT rate at the current dose is ≤ = 0.260, escalate the dose to the 
next higher level.

If the observed DLT rate at the current dose is >  = 0.395, de-escalate the dose to the 
next lower dose level.

Otherwise, stay at the current dose.
6. Repeat step 2 until the maximum sample size of 15 is reached or stop the study if the number 
of evaluable patients treated at the current dose reaches 9 and the decision is to stay at the 
current dose.
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Figure 2.b
Flowchart for Study Conduct Using the BOIN design
BOIN: Bayesian Optimal Interval; DLT: dose-limiting toxicity; MTD: maximum tolerated dose; λd: DLT rate de-
escalation boundary; λe: DLT rate escalation boundary.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
Not applicable.
4.0
SAMPLE-SIZE DETERMINATION
The BOIN design will be implemented for dose escalation/de-escalation. The target toxicity rate 
for MTD is set to be ϕ = 0.25 for NDMM maintenance (Group 1) and RRMM doublets (Group 2) 
and ϕ = 0.33 for RRMM triplets (Group 3). Approximately 120 patients will be enrolled into the 
following groups:

Group 1 (NDMM maintenance; Arm 1) A total of approximately 12 patients will be enrolled.
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
Group 2 (RRMM doublets): A total of approximately 48 patients will be enrolled (12 for 
each of 4 cohorts: Arms 2 to 5).

Group 3 (RRMM triplets): Approximately 60 patients will be enrolled (15 for each of 4 
cohorts: Arms A to D).
The operating characteristics of the BOIN design evaluated with 1000 simulations assuming 
various distributions of toxicity across dose levels are presented in Appendix 9.4.
5.0
ANALYSIS SETS
5.1
Safety Analysis Set
The safety analysis set will include all patients who have received at least 1 dose, even if 
incomplete, of any study drug.
5.2
PK Analysis Set
Patients from the safety analysis set with sufficient dosing and PK data to reliably report 1 or 
more PK concentration will be used for PK analyses.
5.3
DLT-Evaluable Analysis Set 
The DLT-evaluable analysis set will include patients who experienced a DLT in Cycle 1 in the 
treatment phase of the study or have completed Cycle 1 procedures and have received Cycle 1 
dose of modakafusp alfa and at least 75% of the planned dose of the combination partners. The 
DLT-evaluable population will be used to determine the RP2D/MTD.
5.4
Response-Evaluable Analysis Set 
The response-evaluable analysis set is a subset of the safety analysis set including patients with 
measurable disease at baseline and at least 1 post-baseline efficacy evaluation.
5.5
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.
5.6
MRD Analysis Set 
The MRD-evaluable analysis set for Group 1 (NDMM Maintenance) will be all patients who are 
MRD+ upon study entry, as determined by the required central analysis for MRD at screening. 
The MRD-evaluable analysis set for Group 3 (RRMM Triplets) will be a subset of the safety
analysis set including all patients who are in CR and have at least 1 evaluable post-baseline
MRD assessment.
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6.0
STATISTICAL ANALYSIS
6.1
General Considerations
Where applicable, variables will be summarized descriptively by study visit. For categorical 
variables, the count and proportions of each possible category value will be tabulated by 
treatment group. The denominator for the proportion will be based on the number of subjects 
who provided non-missing responses to the categorical variable. For continuous variables, the 
number of subjects with non-missing values, mean, median, SD, minimum, and maximum values 
will be tabulated for all patients in the relevant analysis set. Means and medians will be 
presented to 1 more decimal place than the recorded data. The SDs will be presented to 2 more 
decimal places than the recorded data. CIs will be presented using the same number of decimal 
places as the parameter estimate. 
6.2
Disposition of Subjects
Reasons for screen failures will be generated in a summary table.
Subjects disposition including subjects in each of the study populations, subjects who have 
completed the study, subjects who are off treatment, the primary reasons for discontinued 
treatment, subjects who are ongoing (if applicable at the time of database lock/data cut-off), 
subjects participating in PFS follow-up, subjects who discontinued from the study, as well as 
primary reasons discontinued from the study, will be generated in a summary table by safety
analysis set.
6.3
Demographic and Other Baseline Characteristics
6.3.1
Demographics
Demographics will be summarized using safety analysis set. Demographics variables include age
at the date of informed consent, race, ethnicity, sex, height, and weight.
6.3.2
Medical History and Concurrent Medical Conditions
Medical History and concurrent medical conditions will be summarized using safety analysis set. 
Medical history and concurrent medical conditions will be coded using the latest MedDRA 
dictionary. Concurrent medical conditions are the ones ongoing or started on or after the day 
informed consent was signed. Medical history and concurrent medical conditions will be 
summarized separately by safety analysis set. 
If both start date and stop date are missing, medical condition will be assumed to start before 
informed consent and continue after treatment discontinuation. If only start date is missing, then 
medical condition will be assumed to start before informed consent. If stop date is missing, then 
medical condition will be assumed to continue after treatment discontinuation.
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6.3.3
Baseline Characteristics
Baseline characteristics will be summarized using safety analysis set.
Variables include disease characteristics, imaging assessments, laboratory assessments, baseline 
bone marrow assessment, cytogenetics, and prior therapy.
6.4
Medication History and Concomitant Medications 
Medication history and concomitant medications will be coded using the latest WHO Drug 
Dictionary.
If both start date and stop date are missing, medication will be assumed to start before the first 
dosing date of the study drug and continue after treatment discontinuation. If only start date is 
missing, then medication will be assumed to start before the first dosing date of the study drug. If 
only stop date is missing, then medication will be assumed to continue after treatment 
discontinuation.
6.4.1
Prior Medications
Medication history is defined as the medication stopped before the first dosing date of the study 
drug. Medication history will be summarized using safety analysis set.
6.4.2
Concomitant Medications
Concomitant medication is defined as the medication ongoing or started on or after the first 
dosing date of the study drug. Concurrent medications will be summarized using safety analysis 
set by WHO standardized medication name.
6.5
Efficacy Analysis
Efficacy endpoints will be derived for all patients enrolled into the study and listed as 
appropriate. Efficacy analyses will be summarized by treatment arms.
6.5.1
Primary Endpoints Analysis
No primary efficacy endpoints are included.
6.5.2
Secondary Endpoints Analysis
Group 1: NDMM Maintenance
Secondary endpoints include PFS, ORR, DOR, MRD negative rate, duration of MRD negativity, 
and MRD negative rate at 6 months, 1 year, and 2 years after treatment.
Group 2: RRMM Doublets
Secondary endpoints include OS, PFS, ORR, DOR, TTP, TTNT, DCR, CBR, and TTR.
Group 3: RRMM Triplets
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Secondary endpoints include OS, PFS, ORR, DOR, TTP, TTNT, DCR, CBR, TTR, and MRD
negative rate in patient achieving CR.
6.5.2.1
Derivation of Endpoints
Group 1: NDMM Maintenance
PFS is defined as the time from the date of the first dose administration to the date of first 
documentation of confirmed PD or death due to any cause, whichever occurs first. PD will be 
determined by IMWG criteria. Patients without documentation of PD or death will be censored 
at the date of last response assessment.
ORR is defined as the proportion of patients who achieved a partial response (PR) or better 
(determined by the investigator) during the study based on IMWG criteria.
DOR is defined as time from the date of first documentation of a confirmed PR or better to the 
date of first documentation of PD or death due to any cause. Responders without documentation 
of PD or death will be censored at the date of last adequate response assessment that is stable 
disease or better. The DOR will be calculated only for those patients with a confirmed PR or 
better.
MRD negative rate at a sensitivity of 10-5 is defined as the proportion of patients who have 
achieved MRD negative status.
Duration of MRD negativity is defined as the duration from the start of MRD negative status to 
the time of reappearance of detectable MRD (MRD positive), PD, or death. Patients who achieve 
MRD negative status, but have no documentation of reappearance of detectable MRD, PD, or 
death will be censored at the date of last assessment that is MRD negative.
Group 2: RRMM Doublets
OS is defined as the time from the first dose of administration to the date of death, due to any 
cause. Patients without documentation of death at the time of analysis will be censored at the
date last known to be alive.
PFS, ORR, and DOR are defined same as in Group 1.
TTP is defined as the time from the date of the first dose administration to the date of the first 
documentation of PD as defined by IMWG criteria. Patients without documentation of 
progression will be censored at the date of last response assessment.
TTNT is defined as the time from the date of first dose administration to the date of the first dose 
initiation of the next line of antineoplastic therapy, for any reason. Patients who have not started 
the next-line therapy will be censored at the date last known to be alive before subsequent 
anticancer therapy.
DCR is defined as the proportion of patients with a response of stringent complete response 
(sCR), CR, very good partial response (VGPR), PR, minimal response, or stable disease based 
on investigator's disease assessment per IMWG criteria.
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CBR is defined as the proportion of patients who had a response of sCR, CR, VGPR, PR, or 
minimal response based on investigator’s disease assessment per IMWG criteria.
TTR is defined as the time from the date of the first dose administration to the date of the first 
documentation of objective response as defined by IMWG criteria.
Group 3: RRMM Triplets
The definitions are defined same as in Group 1 and Group 2.
6.5.2.2
Main Analytical Approach
Group 1: NDMM Maintenance

PFS will be analyzed using the safety analysis set. 
The PFS in months [(earliest date of progression or death or censor – date of first dose + 
1)/30.4375], and the status (death, PR, or censored) will be presented in listing. Refer to 
Table 6.a for detailed censoring rules.
The Kaplan-Meier method will be used to estimate the 25th, 50th (median), and 75th 
percentiles, along with associated 2-sided 95% CIs based on Brookmeyer and Crowley 
method.

ORR will be analyzed using the response-evaluable analysis set. 
The frequencies, percentages, and the exact two-sided 95% CIs will be summarized.

DOR will be analyzed for the responders only (PR or better).
DOR in months [(date of progression/death or censor – date of confirmed response + 
1)/30.4375], and the status (death, PD, or censored) will be presented in listing. Refer to 
Table 6.a for detailed censoring rules.
The Kaplan-Meier method will be used to estimate the 25th, 50th (median), and 75th 
percentiles, along with associated 2-sided 95% CIs based on Brookmeyer and Crowley 
method.

MRD negativity rate at a sensitivity of 10-5 will be analyzed based on MRD-evaluable 
analysis set. The denominator would be all patients who are MRD+ based on the central 
analysis during screening who have a subsequent on-treatment MRD evaluation. The 
number and percentage of subjects who have achieved MRD negativity rate at a 
sensitivity of 10-5 will be presented in listing by dose level. The corresponding exact 95% 
CI for MRD negativity (10-5) rate will also be provided. The rate of maintaining MRD 
negativity (10-5) will be reported in patients who achieve CR and MRD negativity (10-5).

Duration of MRD negativity at a sensitivity of 10-5 will be analyzed for patients who 
reach MRD negative status only. The Kaplan-Meier method will be used to estimate the 
25th, 50th (median), and 75th percentiles, along with associated 2-sided 95% Cis based on 
Brookmeyer and Crowley method.
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Table 6.a
Progression and Censoring Date for PFS and DOR Analyses
Scenarios
Event date/censoring date
Event 
status
No (or inadequate) baseline
tumor assessments
Date of the first dose
Censored
No post-baseline assessments
Date of the first dose
Censored
Confirmed progression documented 
without extended loss-to-follow-up 
time (two or more missed cycles)
Date of assessment of the earliest date of 
the confirmed progression
Event
No confirmed progression or death
Date of last adequate assessment of 
response
Censored
Subsequent anti-cancer therapy
started (before documented 
confirmed progression or death)*
Date of last adequate assessment of 
response2 (prior to the initiation of the 
subsequent anti-cancer therapy)
Censored
Death without extended loss-to-
follow-up time
Death date
Event
Death or progression after an 
extended loss-to-follow-up time (two 
or more missed cycles)4
Date of last adequate assessment of 
response2 (prior to missed assessments)
Censored
*If PD or death and the subsequent anti-cancer therapy occur on the same day, it is assumed that the 
progression or death was documented first (e.g., event status is an event, and the date of event is the date of 
progression or death). If the subsequent anti-cancer therapy is initiated prior to any adequate assessment, 
censoring date should be the date of the first dose.
Group 2: RRMM Doublets

OS will be analyzed using the safety analysis set. 
The OS in months [(death or censored – date of first dose + 1)/30.4375], and the status 
(death or censored) and the status (death, or censored) will be presented in listing by dose 
level.
The Kaplan-Meier method will be used to estimate the 25th, 50th (median), and 75th 
percentiles, along with associated 2-sided 95% CIs based on Brookmeyer and Crowley 
method.

PFS will be analyzed the same way as in Group 1.

ORR will be analyzed the same way as in Group 1.

DOR will be analyzed the same way as in Group 1.
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
TTP will be analyzed using the safety analysis set.
The Kaplan-Meier method will be used to estimate the 25th, 50th (median), and 75th 
percentiles, along with associated 2-sided 95% CIs based on Brookmeyer and Crowley 
method by dose level. A Kaplan-Meier plot of TTP time will be provided. Refer to Table 
6.b for detailed censoring rules. 

TTNT will be analyzed using the safety analysis set.
The Kaplan-Meier method will be used to estimate the 25th, 50th (median), and 75th 
percentiles, along with associated 2-sided 95% CIs based on Brookmeyer and Crowley 
method by dose level. A Kaplan-Meier plot of TTNT time will be provided. 

DCR will be analyzed using the response-evaluable analysis set. 
The frequencies, percentages, and the exact two-sided 95% CIs will be summarized.

CBR will be analyzed using the response-evaluable analysis set. 
The frequencies, percentages, and the exact two-sided 95% CIs will be summarized.

TTR will be analyzed as a continuous variable for the responders only (PR or better).
Mean, median, standard deviation, minimum, maximum, 25th, and 75th percentiles will 
be summarized.
Table 6.b
Progression and Censoring Date for TTP Analyses
Scenarios
Event date/censoring date
Event 
status
No (or inadequate) baseline
tumor assessments
Date of the first dose
Censored
No post-baseline assessments
Date of the first dose
Censored
Confirmed progression 
documented without extended 
loss-to-follow-up time (two or 
more missed cycles)
Date of assessment of the earliest date of the 
confirmed progression
Event
No confirmed progression or 
death
Date of last adequate assessment of response
Censored
Subsequent anti-cancer therapy
started (before documented 
confirmed progression or 
death)*
Date of last adequate assessment of response
(on or prior to the initiation of the subsequent 
anti-cancer therapy)
Censored
Death due to progression 
without extended loss-to-
Death date
Event
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follow-up time
Death from causes other than 
progression without extended 
loss-to-follow-up time
Date of last adequate assessment of response2 
prior to death
Censored
Death or progression after an 
extended loss-to-follow-up time 
(two or more missed cycles)
Date of last adequate assessment of response2
(prior to missed assessments)
Censored
*If PD or death and the subsequent anti-cancer therapy occur on the same day, it is assumed that the 
progression or death was documented first (e.g., event status is an event, and the date of event is the date of 
progression or death). If the subsequent anti-cancer therapy is initiated prior to any adequate assessment, 
censoring date should be the date of the first dose.
Group 3: RRMM Triplets
The main analytical approach will be the same as in Group 1 and Group 2 except for MRD 
negativity rate in patients achieving CR, the denominator would be the number of patients in CR 
that have an evaluable MRD test.
6.6
Safety Analysis
Safety will be evaluated by the frequency of AEs, severity, and types of AEs, and by changes 
from baseline in patients’ vital signs, weights, and clinical laboratory results.
6.6.1
DLTs
DLT will be analyzed in the DLT-evaluable analysis set. A by-patient listing of DLTs as 
identified by the investigator that occur during cycle 1 will be presented by dose schedule and 
dose levels. Patients will be grouped by the dose level to which they were originally assigned, 
including those who receive subsequent treatment at a lower or higher dose level.
6.6.2
Adverse Events
Adverse events (AEs) will be analyzed using safety analysis set.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
24.0 or later (based on version at time of database lock). 
Treatment-emergent AE is defined as any AE that occurs after administration of the first dose of 
any study treatment through 30 days after the last dose of any study treatment. Treatment-
emergent AEs will be summarized by MedDRA system organ class (SOC), and preferred term
(PT). For summary tabulations the following hematologic abnormalities coded to MedDRA 
preferred terms in the Investigations SOC will be pooled with the appropriate clinical terms in 
the Blood and lymphatic system disorders SOC:
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MedDRA Preferred Term 
(Investigation SOC)
Mapped to 
(Blood and lymphatic system disorders SOC)
Neutrophil count decreased
Neutropenia
Platelet count decreased
Thrombocytopenia
Hemoglobin decreased
Anemia
While blood cell count decreased
Leukopenia
TEAEs will also be summarized by the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) Version 5.0 or later.
On-study death is defined as deaths that occur between the first dose of study drug and up to 30 
days after the last dose of study drug and deaths that occur after 30 days after the last dose of 
study drug but are assessed as related to treatment. The following tables will be presented with 
the number and percentage of subjects by MedDRA SOC and PT. All summaries will be by
group and dose levels. Patients with multiple occurrences of same AEs of the same PT and SOC 
will be counted once for each PT or SOC. Patients with multiple occurrences of same AEs will 
have only the maximum intensity of that AE event counted once for each PT or SOC. These 
tables will be ordered in descending order of overall SOC incidence and overall PT incidence 
within each SOC.

All DLTs (in the DLT Evaluable Population); 

All treatment-emergent AEs (TEAEs);

All TEAEs by maximum CTCAE severity grade; 

All TEAEs CTCAE severity Grade 3 or 4; 

All TEAEs CTCAE severity Grade 5;

Drug-related TEAEs; 

Drug-related TEAEs by maximum CTCAE severity grade; 

Drug-related TEAEs CTCAE severity Grade 3;

Drug-related TEAEs CTCAE severity Grade 4; 

Drug-related TEAEs CTCAE severity Grade 3 or 4;

Drug-related TEAEs CTCAE severity Grade 5;

Serious TEAEs (SAEs) ; 

SAEs by maximum CTCAE severity grade; 

SAEs CTCAE severity Grade 3 or 4; 
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
SAEs CTCAE severity Grade 5; 

Drug-related SAEs (any related serious TEAEs); 

Drug-related SAEs by maximum CTCAE severity grade; 

Drug-related SAEs and CTCAE severity Grade 3 or 4; 

Drug-related SAEs and CTCAE severity Grade 5; 

TEAEs leading to dose delays;

TEAEs leading to dose reduction; 

TEAEs leading to infusion rate reduction;

TEAEs leading to dose interruption;

TEAEs leading to drug infusion interruptions;

TEAEs leading to drug discontinuation; 

All TE AESIs, e.g. infusion-related reactions (IRR)

TE AESIs (IRRs) CTCAE severity Grade 3 or 4;

TE AESIs (IRRs) CTCAE severity Grade 5;

All Serious TE AESIs (IRRs);TEAEs leading to on-study death or treatment related death. 
The following summary tables will display the number and percentage of patients by PT only 
and will be ordered in descending order of PT: 

All TEAEs; 

Drug-related TEAEs; 

SAEs (any serious TEAEs);

Drug-related SAEs (any related serious TEAEs);

All TE AESIs, e.g. infusion-related reactions (IRR)

The most commonly reported TEAEs (i.e. those events reported by >= 10% of all 
patients)
6.6.3
Clinical Laboratory Evaluations
All laboratory values (e.g. hematology, chemistry, urinalysis, etc) will be converted to 
standardized units. If a lab value is reported using a non-numeric qualifier (eg, less than (<) a 
certain value, or greater than (>) a certain value), the given numeric value will be used in the 
summary statistics, ignoring the non-numeric qualifier. If a patient has repeated laboratory values 
for a given time point, the value from the last evaluation will be used.
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Laboratory test results will be summarized according to the scheduled sample collection time 
point. Change from baseline will be presented by dose level. Scheduled laboratory along with 
unscheduled lab test results will be listed.
Lab parameters to be analyzed are as follows:
Table 6.c Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Standard C-reactive 
protein
Bilirubin
Serology Hepatitis B
(HBsAg, HBcAb, 
HBsAb)
Hemoglobin
Alkaline phosphatase
Chloride
Glucose
Serology Hepatitis C 
(HCV Ab)
Platelet count
Alanine 
aminotransferase
Glucose (nonfasting)
Ketones
Serology HIV
Leukocytes with 
differential
Aspartate 
aminotransferase
Lactate dehydrogenase
Leukocytes
Serum β2 macroglobulin
Neutrophils 
(ANC)
Bilirubin (total)
Magnesium
Nitrites
Thyroid function test 
(TSH, T4, T3)
Plasma cells and 
blasts
Blood urea nitrogen
Phosphate
Occult blood
Calcium
Potassium
pH
Bicarbonate (HCO3
-) or 
carbon dioxide (CO2)
Sodium
Protein
Creatinine
Urate
Specific gravity
Turbidity and 
color
Urobilinogen
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
Version 5.0 or later. Shift tables will be constructed for laboratory parameters either using 
CTCAE grade or based on low/medium/high compared to normal ranges on patients who have 
both baseline and at least one post-baseline assessment. Individual platelet and ANC profiles will 
be generated for each schedule/dose level.
6.6.4
Vital Signs
Vital sign results (temperature, pulse, respiratory rate, oxygen saturation, diastolic blood pressure, 
systolic blood pressure) will be summarized by schedules and dose levels as follows:

Baseline value (C1D1 or screening if C1D1 is not available).

Minimum post-baseline value.
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
Change to Minimum post-baseline value.

Maximum post-baseline value.

Change to Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value.
For blood pressure values collected during the infusion, the number and percentage of patients 
with changes from pre-infusion blood pressure values will be summarized in the following 
categories:

Increase of diastolic blood pressure of at least 10 mm Hg during any infusion.

Decrease of diastolic blood pressure of at least 10 mm Hg during any infusion.

Increase of systolic blood pressure of at least 20 mm Hg during any infusion.

Decrease of systolic blood pressure of at least 20 mm Hg during any infusion.
Shifts from baseline to the worst post-baseline ECOG score will be tabulated. 
6.6.5
12-Lead ECGs
ECG data (ventricular rate, RR interval, PR interval, QT interval, and QTcF interval) will be 
summarized by schedules and dose levels as follows:
Baseline value (C1D1 or screening if C1D1 is not available).

Minimum post-baseline value.

Change to Minimum post-baseline value.

Maximum post-baseline value.

Change to Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value.
In addition, a categorical analysis of QTcF intervals will be performed for each time point. The 
number and percentage of patients in each QTcF interval (<450 msec, 450-480 msec, >480-
<500 msec, and ≥500msec) will be summarized at baseline and each of the subsequent time 
points. Categories of changes from baseline (≥30 msec and ≥60 msec) will be summarized as 
well.
6.6.6
ECOG
Shifts from baseline to the worst post-baseline ECOG score will be tabulated.
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6.6.7
Extent of Exposure and Compliance
The exposure to study drugs (modakafusp alfa and combinations agents) characterized by 
summaries and descriptive statistics of duration of treatment in weeks [(Date of last study drug
exposure – date of first study drug dose + 1)/7], number of treated cycles (1, 2, 3, 4, 5, 6, 7-
12, >12), and relative dose intensity will be summarized using the safety analysis set. 

A treated cycle is defined as a cycle in which any amount of study drug for at least one of 
the dosing days in the cycle;

Cumulative dose is defined as the sum of all doses of the study drug administered to a 
subject during the treatment period. For example, cumulative dose of modakafusp alfa is 
defined as the sum of all doses of modakafusp alfa administered to a subject during the 
treatment period; Cumulative dose of each agent is defined as the sum of all doses of the 
agent administered to a subject during the treatment period.

Relative dose intensity = (actual dose per week / planned dose per week) × 100. The 
actual dose per week adjusts for delays in the start of a cycle and assumes the last cycle is 
fixed at the intended duration.
o
Actual dose per week: cumulative dose / treatment interval in weeks;
o
Planned dose per week: starting dose on C1D1 / treatment interval in weeks.
Action on Study Drug
The reason for dose modification (e.g. dose increased, dose reduced, interrupted, withdrawn, 
delayed, rate increased, rate reduced, drug infusion interrupted) of study drugs (modakafusp alfa 
and combination agents) will be summarized by cycles for the safety analysis set.
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
6.7.1
Pharmacokinetic/Pharmacodynamic Analyses
The pharmacokinetic and pharmacodynamic analyses will be performed using PK analysis set 
and described in a separate analysis plan.
6.7.2
Immunogenicity Analysis
The immunogenicity analysis will be performed using immunogenicity-evaluable analysis set. 
The immunogenicity of modakafusp alfa will be assessed by determining anti–modakafusp alfa
antibody (ADA) incidence and characteristics and by determining neutralizing antibody (NAb) 
incidence. All ADA and NAb data will be listed. Proportion of subjects with positive ADA (rate, 
titer at each timepoint, and domain specificity) or Nab against modakafusp alfa will be 
summarized. 
 
 Percent of patients with positive ADA
and NAb at baseline and positive ADA (final result and by domain specificity) and NAb at any 
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post-baseline time point during the study will be summarized. Summaries will be provided 
separately by dose level.
 
. ADA titer distribution over time will be presented 
through a box-plot on a logarithmic scale.
6.7.3
Interim Analyses
Not applicable.
6.8
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
Not applicable.
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7.0
REFERENCES
Liu, S., & Yuan, Y. (2015). Bayesian Optimal Interval Designs for Phase I Clinical Trials. J R 
Stat Soc Ser C Appl Stat, 64(3):507-523.
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8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Not applicable.
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Statistical Analysis Plan
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9.0
APPENDIX 
9.1
Changes From the Previous Version of the SAP
Not applicable.
9.2
Data Handling Conventions 
9.2.1
Definition of Baseline 
Baseline is defined as the last non-missing evaluation prior to or on the date that the first dose of 
the study drug is taken.
9.2.2
Definition of Visit Windows 
A window of ±2 days will be permitted from the study visit schedule.
9.2.3
Date Imputation Rules 
Incomplete Dates in the Screening Period
1. If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used.
2. If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used.
3. If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used.
Incomplete Adverse Event Onset Date
Assumption: For on-study Adverse Events.
If year is missing (or completely missing): set to the date of first dose.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year = year of first dose: set the date to the first dose date.
If year < year of first dose: set month and day to December 31st.
If year > year of first dose: set month and day to January 1st.
If month and year are present and day is missing:
If year = year of first dose, and:
If month = month of first dose: set day to day of first dose.
If month < month of first dose: set day to last day of month.
If month > month of first dose: set day to 1st day of month.
If year < year of first dose: set day to last day of month.
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If year > year of first dose: set day to 1st day of month.
For all other cases: set to date of first dose.
Incomplete Adverse Event Resolution Date
Assumption: For on-study Adverse Events.
If day is missing but month and year are non-missing, impute as the earliest of:
o
Last day of the month
o
Data cutoff date
o
Death date
If day and month are missing, impute as the earliest of:
o
December 31st
o
Data cutoff date
o
Death date
If date is completely missing (i.e. AE is ongoing), impute as earliest of:
o
Data cutoff date
o
Treatment discontinuation date (i.e. last dose date) + 30 days  
o
Death date
Incomplete Concomitant Medication Start Date/Prior Therapy Start Date/Progression Date 
during Prior Therapy
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to January 1st.
If year and month are present and day is missing:
Set day to 1st day of month.
Incomplete Concomitant Medication End Date
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to December 31st.
If year and month are present and day is missing:
Set day to last day of the month.
Incomplete Subsequent Anti-Cancer Therapy Start Date
If year is missing (or completely missing): set to date of last dose of study treatment + 1
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If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year > year of the last dose: Set month and day to January 1st.
If year = year of the last dose: Set month and day to date of last dose of study 
treatment +1.
If year and month are present and day is missing:
Set day to 1st day of month if the resulting imputed date is greater than date of last 
dose.
Otherwise set the imputed date to date of last dose + 1.
9.3
Analysis Software 
Analyses will be conducted using SAS® Version 9.4 or higher (SAS® Institute, Inc., Cary, North 
Carolina, United States).
9.4
BOIN Design for Dose Escalation/De-escalation
Group 1: NDMM - Maintenance Therapy
Dose 1
Dose
2
Dose 3
Average 
sample 
size
Correct 
selection 
%
Overdose 
%
% 
patients at 
MTD
% patients 
overdosed
% early 
stop
Scenario 1
True DLT rate
0.05
0.10
0.25
Selection %
3.4
34.1
62.5
11.1
62.5
0
43.3
0
0
% pts treated
10.3
46.3
43.3
Scenario 2
True DLT rate
0.10
0.25
0.39
Selection %
29.9
51.7
18.3
11.5
51.7
18.3
48.3
23.7
0.1
% pts treated
27.9
48.3
23.7
Scenario 3
True DLT rate
0.25
0.43
0.62
Selection %
72.4
23.1
0.8
10.8
72.4
23.9
45.6
54.4
3.7
% pts treated
45.6
45.5
8.9
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients.
Group 2: RRMM - Doublet Combinations
The operating characteristics of Group 2 are the same as those of Group 1.
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Statistical Analysis Plan
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Group 3: RRMM - Triplet Combinations
Dose 1 as the Starting Dose
Dose 1
Dose 2
Dose 3
Average 
sample 
size
Correct 
selection 
%
Overdose 
%
% 
patients at 
MTD
% patients 
overdosed
% early 
stop
Scenario 1
True DLT 
rate
0.05
0.16
0.33
Selection %
1.4
35.6
63.0
14.9
63.0
0
36.8
0
0
% pts treated
25.8
37.4
36.8
Scenario 2
True DLT 
rate
0.15
0.33
0.51
Selection %
24.8
56.8
17.7
14.1
56.8
17.7
41.9
14.8
0.7
% pts treated
43.3
41.9
14.8
Scenario 3
True DLT 
rate
0.33
0.51
0.6
Selection %
67.0
18.2
2.6
11.4
67.0
20.8
69.6
30.3
12.2
% pts treated
69.6
27.1
3.2
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients.
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Dose 2 as the Starting Dose
Dose 1
Dose 2
Dose 3
Average 
sample 
size
Correct 
selection %
Overdose 
%
% 
patients at 
MTD
% patients 
overdosed
% early 
stop
Scenario 1
True DLT rate
0.05
0.16
0.33
Selection %
0.8
27.5
71.7
13.5
71.7
0
50.2
0
0
% pts treated
3.6
46.2
50.2
Scenario 2
True DLT rate
0.15
0.33
0.51
Selection %
18.8
60.9
20.0
13.9
60.9
20.0
56.6
23.1
0.3
% pts treated
20.2
56.6
23.1
Scenario 3
True DLT rate
0.33
0.51
0.6
Selection %
59.9
28.3
2.7
13.3
59.9
31.0
46.1
53.9
9.1
% pts treated
46.1
47.2
6.7
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients.
Dose 3 as the Starting Dose
Dose 1
Dose 2
Dose 3
Average 
sample 
size
Correct 
selection 
%
Overdose 
%
% 
patients at 
MTD
% patients 
overdosed
% early 
stop
Scenario 1
True DLT 
rate
0.05
0.16
0.33
Selection %
0.9
19.6
79.5
11.4
79.5
0
74.2
0
0
% pts treated
1.3
24.5
74.2
Scenario 2
True DLT 
rate
0.15
0.33
0.51
Selection %
17.2
51.8
30.9
13.4
51.8
30.9
41.0
47.8
0.1
% pts treated
11.2
41.0
47.8
Scenario 3
True DLT 
rate
0.33
0.51
0.6
Selection %
53.7
28.3
11.0
14.2
53.7
39.3
28.7
71.3
7.0
% pts treated
28.7
36.4
34.9
DLT: dose-limiting toxicity; MTD: maximum tolerated dose; pts: patients.
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Signature Page for TAK-573-1502 SAP 09May2022_Approved_add signature
Title: 
Document Number: TDN-000243594 v1.0
Approval
Statistics
26-Feb-2024 14:37:06 GMT+0000
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