Clinical trial NCT05590377
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2023-01-23; Completion date: 2024-05-22
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main aim of this study is to determine safety and tolerability of modakafusp alfa given together with daratumumab to find out the best treatment dose. Another aim of this study is to learn more about the characteristics of modakafusp alfa.

Detailed description:
The drug being tested in this study is called modakafusp alfa (TAK-573). Modakafusp alfa is being tested to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy in combination with daratumumab in participants with relapsed or refractory multiple myeloma (RRMM). The study will consist of 2 phases: Phase 1 Dose Escalation and a Phase 2a Dose Finding.

The study will enroll approximately 58 patients. Approximately 18 participants will be enrolled in the Phase 1 Dose Escalation/De-escalation and two dose levels of modakafusp alfa in combination with daratumumab SC will be selected to be further explored in the randomized Phase 2a Dose Finding part of the study wherein, approximately 40 participants will be randomly assigned by chance (like flipping a coin) to one of the two treatment groups:

* Phase 2a Dose Finding: Modakafusp Alfa (DL1) + Daratumumab
* Phase 2a Dose Finding: Modakafusp Alfa (DL2) + Daratumumab This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 60 months. Participants who discontinue study drug treatment for reasons other than progressive disease will continue progression-free survival (PFS) follow-up every 4 weeks from the end of treatment (EOT) visit until the occurrence of progressive disease, death, the start of subsequent systemic antineoplastic therapy, study termination, whichever occurs first.

Arms: arm 1: Modakafusp alfa 80 mg, infusion, intravenously (IV), once every 4 weeks (Q4W) with daratumumab 1800 mg, subcutaneously (SC), once weekly (QW) in Cycles 1 and 2, twice weekly (Q2W) in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression. arm 2: Modakafusp alfa 120 mg, infusion, IV, Q4W with daratumumab 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression. arm 3: Modakafusp alfa 240 mg, infusion, IV, Q4W with daratumumab 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression. arm 4: Modakafusp alfa at dose level 1 (DL1) \[selected from Phase 1 Dose Escalation\] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression. arm 5: Modakafusp alfa at dose level 2 (DL2) \[selected from Phase 1 Dose Escalation\] with daratumumab SC 1800 mg, SC, QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W thereafter in each 28-day treatment cycle until disease progression.
Interventions: intervention 1: Modakafusp Alfa intervention 2: Daratumumab
Intervention descriptions: intervention 1: Modakafusp alfa intravenous infusion intervention 2: Daratumumab SC injection

Protocol documents:
Prot_000.pdf: 


 
 
 
 
PROTOCOL 
 
A Phase 1/2a Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Efficacy of Modakafusp Alfa in Combination With 
Daratumumab Subcutaneous in Patients With Relapsed or Refractory Multiple Myeloma 
A Study of Modakafusp Alfa in Combination With Daratumumab Subcutaneous in 
Patients With Relapsed/Refractory Multiple Myeloma 
Sponsor: 
Takeda Development Center Americas, Inc 
500 Kendall Street 
Cambridge, MA 02142 USA 
Study Number: 
TAK-573-2001 
EudraCT Number: 
2022-002169-14 
 
 
Universal Trial 
Number: 
Not applicable 
 
 
Compound: 
Modakafusp alfa (TAK-573) 
Date: 
19 September 2024 
Amendment Number: 2 US v1 
 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
19 September 2024 
Amendment 2 US v1 
Substantial; Regional 
United States 
03 April 2024 
Amendment 1 v2 
Substantial 
Global 
28 February 2024 
Amendment 1 v1 (not 
implemented) 
Substantial 
Global 
15 September 2023 
Initial Protocol US v1 
Nonsubstantial; Regional 
United States 
23 June 2023 
Initial Protocol GB v1 
Nonsubstantial; Regional 
United Kingdom 
05 April 2023 
Initial Protocol DE v2 
Nonsubstantial; Regional 
Germany 
05 April 2023 
Initial Protocol DE v1 
Nonsubstantial; Regional 
Germany 
27 January 2023 
Initial Protocol CZ v1 
Nonsubstantial; Regional 
Czech Republic 
14 December 2022 
Initial Protocol FR v1 
Nonsubstantial; Regional 
France 
16 August 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 (e)consent from those persons to whom the drug may 
be administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 


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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Serious adverse event (SAE), pregnancy, and other applicable safety reporting information is 
presented in the study manual, as is information on reporting product complaints. 
Takeda Development Center–sponsored investigators per individual country requirements will 
be provided with emergency medical contact information cards to be carried by each patient. 
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 
provided to the site. 
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual. 


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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 also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (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 can be found on 
the signature page. 
Electronic signatures may be found on the last page of this document. 
 MD (or designee) 
 
 
Date 
 


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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 patients 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 C). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
 


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CONFIDENTIAL 
1.3 
Protocol Amendment 2 US v1 Summary of Changes 
Protocol Amendment 2 US v1 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 2 US 
v1. The primary reason for this amendment was to include the United States 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 G. 
Protocol Amendment 2 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.  7.2 Exclusion Criteria 
Added exclusion criterion #11: “Patient has a high 
risk of hemorrhage such as uncontrolled chronic 
bleeding disorder or is currently being treated 
with therapeutic anticoagulation.” 
Revised per FDA 
recommendation 
2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised per FDA 
recommendation 
FDA: Food and Drug Administration; TEAE: treatment-emergent adverse event. 


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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 2 US v1 Summary of Changes ...................................................5 
2.0 
STUDY SUMMARY.........................................................................................................12 
3.0 
STUDY REFERENCE INFORMATION .........................................................................19 
3.1 
Study-Related Responsibilities ....................................................................................19 
3.2 
Coordinating Investigator ............................................................................................19 
3.3 
List of Abbreviations ...................................................................................................20 
3.4 
Corporate Identification ...............................................................................................22 
4.0 
INTRODUCTION .............................................................................................................23 
4.1 
Background ..................................................................................................................23 
4.1.1 
Multiple Myeloma ...............................................................................................23 
4.1.2 
Modakafusp Alfa .................................................................................................24 
4.1.3 
Combination Agent .............................................................................................27 
4.2 
Rationale for the Proposed Study ................................................................................28 
4.2.1 
Modakafusp Alfa in Combination With Daratumumab SC ................................28 
4.2.2 
Study Population .................................................................................................29 
4.3 
Modakafusp Alfa Starting Dose Justification for the Phase 1 Dose Escalation in 
Combination With Daratumumab SC ..........................................................................29 
4.4 
Modakafusp Alfa Dose Selection for Phase 2a Dose Finding in Combination With 
Daratumumab SC .........................................................................................................30 
4.5 
Risks and Benefits........................................................................................................31 
4.5.1 
Modakafusp Alfa .................................................................................................31 
4.5.2 
Combination Agent .............................................................................................33 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................35 
5.1 
Objectives ....................................................................................................................35 
5.1.1 
Primary Objectives ..............................................................................................35 
5.1.2 
Secondary Objectives ..........................................................................................35 
5.1.3 
Exploratory Objectives ........................................................................................36 
5.2 
Endpoints .....................................................................................................................36 
5.2.1 
Primary Endpoints ...............................................................................................36 
5.2.2 
Secondary Endpoints ...........................................................................................36 
5.2.3 
Exploratory Endpoints .........................................................................................38 
6.0 
STUDY DESIGN...............................................................................................................39 


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6.1 
Overview of Study Design ...........................................................................................39 
6.2 
Number of Patients ......................................................................................................41 
6.2.1 
Phase 1 Dose Escalation ......................................................................................41 
6.2.2 
Phase 2a Dose Finding ........................................................................................41 
6.3 
Duration of Study .........................................................................................................41 
6.3.1 
Duration of an Individual Patient’s Study Participation ......................................41 
6.3.2 
End of Study/Study Completion Definition and Planned Reporting...................41 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures .......42 
6.3.4 
Total Study Duration ...........................................................................................44 
6.4 
Randomization in Phase 2a Dose Finding ...................................................................44 
6.5 
Posttrial Access ............................................................................................................44 
6.5.1 
Duration of PTA ..................................................................................................44 
6.5.2 
Combination Agent .............................................................................................44 
7.0 
STUDY POPULATION ....................................................................................................45 
7.1 
Inclusion Criteria .........................................................................................................45 
7.2 
Exclusion Criteria ........................................................................................................47 
7.3 
Excluded Prior Medications .........................................................................................49 
7.4 
Excluded Prior Procedures and Treatments .................................................................49 
8.0 
STUDY DRUG ..................................................................................................................50 
8.1 
Study Drug Administration ..........................................................................................50 
8.1.1 
Modakafusp Alfa .................................................................................................50 
8.1.2 
Combination Agent Daratumumab SC ................................................................51 
8.2 
List of EU Auxiliary Medicinal Products ....................................................................52 
8.3 
DLT (Phase 1 Dose Escalation) ...................................................................................53 
8.3.1 
Definitions of DLT ..............................................................................................53 
8.3.2 
Definition of DLT-Evaluable Patients .................................................................54 
8.4 
Dose Escalation Rules (Phase 1 Dose Escalation) .......................................................54 
8.5 
 ................................................................................57 
8.6 
Dose Modification Guidelines .....................................................................................57 
8.6.1 
Modakafusp Alfa .................................................................................................57 
8.6.2 
Combination Drug ...............................................................................................60 
8.7 
Prohibited Concomitant Medications and Procedures .................................................60 
8.8 
Permitted Concomitant Medications and Procedures ..................................................61 
8.9 
Precautions and Restrictions ........................................................................................62 
8.9.1 
Contraception and Pregnancy Avoidance Procedures .........................................62 


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8.9.2 
Pregnancy ............................................................................................................63 
8.10 
Management of Clinical Events ...................................................................................63 
8.10.1 
Modakafusp Alfa .................................................................................................64 
8.10.2 
Combination Agent .............................................................................................66 
8.11 
Blinding and Unblinding..............................................................................................66 
8.12 
Description of Investigational Agents .........................................................................66 
8.13 
Preparation, Reconstitution, and Dispensation ............................................................66 
8.14 
Packaging and Labeling ...............................................................................................66 
8.15 
Storage, Handling, and Accountability ........................................................................67 
8.15.1 
Modakafusp Alfa .................................................................................................67 
8.15.2 
Combination Agent .............................................................................................67 
9.0 
STUDY CONDUCT ..........................................................................................................68 
9.1 
Study Personnel and Organizations .............................................................................68 
9.2 
Arrangements for Recruitment of Patients ..................................................................68 
9.3 
Informed (e)Consent ....................................................................................................68 
9.4 
Treatment Group Assignments ....................................................................................68 
9.5 
Study Procedures .........................................................................................................68 
9.5.1 
Patient Demographics ..........................................................................................69 
9.5.2 
Medical History ...................................................................................................69 
9.5.3 
Physical Examination ..........................................................................................69 
9.5.4 
Patient Height and Weight ...................................................................................69 
9.5.5 
Vital Signs ...........................................................................................................69 
9.5.6 
Pregnancy Test ....................................................................................................70 
9.5.7 
Concomitant Medications and Procedures ..........................................................70 
9.5.8 
ECOG Performance Status ..................................................................................70 
9.5.9 
AEs ......................................................................................................................70 
9.5.10 
Enrollment ...........................................................................................................70 
9.5.11 
ECG .....................................................................................................................71 
9.5.12 
Clinical Laboratory Evaluations ..........................................................................71 
9.5.13 
Disease Assessment .............................................................................................72 
9.5.14 
Biomarker, PD, and PK Samples ........................................................................76 
9.5.15 
 .....................................................................78 
9.5.16 
Immunogenicity Sample Collection ....................................................................79 
9.6 
Completion of Study Treatment (for Individual Patients) ...........................................79 
9.7 
Completion of Study (for Individual Patients).............................................................79 


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9.8 
Discontinuation of Treatment With Study Drug and Patient Replacement .................79 
9.9 
Withdrawal of Patients From Study .............................................................................80 
9.10 
Study Compliance ........................................................................................................81 
9.11 
Posttreatment Follow-up Assessments (PFS and OS) .................................................81 
10.0 
ADVERSE EVENTS .........................................................................................................82 
10.1 
Definitions....................................................................................................................82 
10.1.1 
Pretreatment Event Definition .............................................................................82 
10.1.2 
AE Definition ......................................................................................................82 
10.1.3 
AESI ....................................................................................................................82 
10.1.4 
SAE Definition ....................................................................................................82 
10.2 
Procedures for Recording and Reporting AEs and SAEs ............................................83 
10.3 
Monitoring of AEs and Period of Observation ............................................................84 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........84 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .....................................................................................................................85 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities ...........85 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................86 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................86 
12.1 
eCRFs ...........................................................................................................................86 
12.2 
Record Retention .........................................................................................................86 
13.0 
STATISTICAL METHODS ..............................................................................................88 
13.1 
Statistical and Analytical Plans ....................................................................................88 
13.1.1 
Analysis Sets .......................................................................................................88 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ..........................89 
13.1.3 
Efficacy Analysis .................................................................................................89 
13.1.4 
PK Analysis .........................................................................................................92 
13.1.5 
 ................................................................................92 
13.1.6 
PK/PD Analysis ...................................................................................................92 
13.1.7 
Immunogenicity Analyses ...................................................................................92 
13.1.8 
Safety Analysis ....................................................................................................93 
13.2 
Determination of Sample Size .....................................................................................94 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................95 
14.1 
Study-Site Monitoring Visits .......................................................................................95 
14.2 
Protocol Deviations ......................................................................................................95 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................95 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................96 


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15.1 
IRB and/or IEC Approval ............................................................................................96 
15.2 
Patient Information, Informed (e)Consent, and Patient Authorization ........................97 
15.3 
Patient Confidentiality .................................................................................................98 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................98 
15.4.1 
Publication ...........................................................................................................98 
15.4.2 
Clinical Trial Registration ...................................................................................99 
15.4.3 
Clinical Trial Results Disclosure .........................................................................99 
15.5 
Insurance and Compensation for Injury .....................................................................100 
16.0 
REFERENCES ................................................................................................................101 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...............................................43 
Table 8.a 
Dose Escalation and De-escalation Rules ..............................................................55 
Table 8.b 
Dose Modification Recommendations for Modakafusp Alfa 
Nonhematological Toxicities .................................................................................58 
Table 8.c 
Dose Modification Recommendations for Modakafusp Alfa Hematological 
Toxicities................................................................................................................59 
Table 8.d 
Dose Modification Recommendations for Modakafusp Alfa Bleeding TEAEs ....59 
Table 8.e 
Dose Reduction Levels for Modakafusp Alfa .......................................................60 
Table 8.f 
Highly Effective Methods of Contraception ..........................................................63 
Table 8.g 
Recommendations for Managing Grade 1 and Grade 2 IRRs ...............................65 
Table 8.h 
Recommendations for Managing Grade ≥3 IRRs ..................................................65 
Table 9.a 
Clinical Chemistry .................................................................................................71 
Table 9.b 
Hematology Tests ..................................................................................................72 
Table 9.c 
Urinalysis ...............................................................................................................72 
Table 9.d 
Other Laboratory Tests ..........................................................................................72 
Table 9.e 
Primary Specimen Collection ................................................................................77 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Activity of Modakafusp Alfa Combined With the Anti-CD38 Antibody 
Daratumumab in NCI-H929 MM Xenograft Tumor Model ..................................29 
Figure 6.a 
Schematic of TAK-573-2001 Study Design ..........................................................39 
 


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LIST OF APPENDICES 
Appendix A 
Schedules of Events .............................................................................................103 
Appendix B 
PK Sampling ........................................................................................................122 
Appendix C 
Responsibilities of the Investigator ......................................................................127 
Appendix D 
Investigator Consent to Use of Personal Information ..........................................129 
Appendix E 
IMWG Definition of MM and Response Criteria ................................................130 
Appendix F 
ECOG Scale for Performance Status ...................................................................133 
Appendix G 
Protocol History ...................................................................................................134 
 


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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s):  
Takeda Development Center Americas, Inc 
Compound:  
Modakafusp alfa (TAK-573) 
Title of Protocol: A Phase 1/2a Open-label Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Efficacy of Modakafusp Alfa in 
Combination With Daratumumab Subcutaneous in 
Patients With Relapsed or Refractory Multiple Myeloma 
EudraCT No.: 
2022-002169-14 
Study Number: TAK-573-2001 
Phase: 1/2a 
Study Design: 
This is a global multicenter, open-label, phase 1/2a study designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of modakafusp alfa in combination 
with daratumumab subcutaneous (SC) in patients with relapsed or refractory multiple myeloma (RRMM). The 
study will begin with a phase 1 dose escalation to evaluate the safety and tolerability of modakafusp alfa in 
combination with daratumumab SC. Two dose levels of modakafusp alfa in combination with daratumumab SC 
will be selected to be further explored in the randomized phase 2a dose finding part of the study. Patients will be 
randomized in a 1:1 ratio across 2 dose levels (DL1 or DL2) of modakafusp alfa in combination with 
daratumumab SC. The confirmed overall response rate (ORR) assessed by the investigator per International 
Myeloma Working Group (IMWG) criteria will be determined as the primary efficacy endpoint of the phase 2a 
dose finding. The optimized recommended phase 2 dose (RP2D) of modakafusp in combination with 
daratumumab SC will be selected on the basis of integrated safety, efficacy, PK, and PD data from the current 
study and other relevant stud(ies). A schematic of the study design is shown below. 


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DL1: Dose Level 1; DL2: Dose Level 2; Q4W: every 4 weeks; R: randomization; SC: subcutaneous. 
 
Phase 1 Dose Escalation 
The study will begin with a phase 1 dose escalation to evaluate the safety and tolerability of modakafusp alfa in 
combination with daratumumab SC during the Cycle 1 (28 days per cycle) dose-limiting toxicity (DLT) 
evaluation period and beyond. The proposed population in the phase 1 dose escalation will be patients with 
RRMM with at least 3 prior lines of therapy, including at least 1 proteasome inhibitor (PI), 1 immunomodulatory 
imide drug (IMiD), and 1 anti-CD38 monoclonal antibody (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) or therapy. 
The dose escalation will follow the rolling six design with data collected in the dose escalation/de-escalation 
phase. Safety will be evaluated by the frequency of adverse events (AEs), severity, types of AEs, and by changes 
from baseline in patients’ vital signs, weights, and clinical laboratory results. 
The starting dose to be evaluated for modakafusp alfa will be 80 mg every 4 weeks (Q4W). Modakafusp alfa 
doses of 60, 120, or 240 mg Q4W could be evaluated depending on dose escalation/de-escalation rules specified 
by the rolling six design. Decision on dose escalation and de-escalation in phase 1 will be made on the basis of 
the number of patients in the current dose level, the number of patients experiencing DLTs, and the number of 
patients still at risk of developing a DLT at the time of a new patient entry. Three to 6 patients may concurrently 
be enrolled at a dose level in the study. The enrollment of the first 3 patients at the starting dose of 80 mg Q4W 
will be staggered by 24 hours each. The remaining patients can be dosed concurrently if there are no unexpected 
and significant acute toxicities. Accrual to the study may be paused while waiting for data from these 6 patients. 
Decisions as to whether to resume enrolling on the next dose level will be made using data available at the time 
of new patient enrollment. De-escalation will occur when 2 or more DLTs are observed at the current dose level, 


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whereas escalation will occur when 3 of 3, 4 of 4, 5 of 5, 5 of 6, or 6 of 6 patients are enrolled at the current dose 
level with no DLT observed and the next higher dose level has no more than 1 DLT observed. It is estimated that 
approximately 18 DLT-evaluable patients will be enrolled. 
The daratumumab SC dose of 1800 mg (every week [QW] in Cycles 1 and 2, once every 2 weeks [Q2W] in 
Cycles 3 to 6, and Q4W thereafter) will be used in combination with modakafusp alfa throughout the study. 
Phase 2a Dose Finding 
Two dose levels of modakafusp alfa in combination with daratumumab SC doses will be selected from phase 1 
dose escalation to be explored further in phase 2a open-label dose finding. Approximately 40 patients will be 
randomized 1:1 across 2 different dose levels (DL1 or DL2; N = 20 at each dose level) of modakafusp alfa in 
combination with daratumumab SC. Eligible patients will include patients with RRMM who have received 1 to 
3 prior lines of therapy, refractory to lenalidomide, and sensitive (nonrefractory) or naive to anti-CD38 mAb. 
The randomization will be stratified by the number of prior lines of therapy (1 vs 2 or 3). The primary endpoint 
is the confirmed ORR assessed by the investigator per IMWG criteria.  
Primary Objectives: 
Phase 1 Dose Escalation 
• 
To determine the safety and tolerability of modakafusp alfa in combination with daratumumab SC.  
Phase 2a Dose Finding 
• 
To inform the RP2D of modakafusp alfa in combination with daratumumab SC.  
• 
To provide a preliminary evaluation of the clinical efficacy of modakafusp alfa in combination with 
daratumumab SC as measured by ORR. 
Secondary Objectives: 
Phase 1 Dose Escalation 
• 
To characterize the PK profile of modakafusp alfa and daratumumab in the combination setting. 
• 
To characterize antimyeloma activity as measured by ORR, duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS).  
• 
To characterize the immunogenicity of modakafusp alfa in combination with daratumumab SC. 
• 
To characterize measurable (minimal) residual disease (MRD) negativity and duration of MRD negativity.  
Phase 2a Dose Finding 
• 
To determine DOR, clinical benefit rate (CBR), duration of clinical benefit (DCB), disease control rate 
(DCR), duration of disease control, time to progression (TTP), time to response (TTR), time to next 
treatment (TTNT), PFS, and OS. 
• 
To further characterize safety and tolerability of modakafusp alfa in combination with daratumumab SC. 
• 
To collect PK data for modakafusp alfa to support population PK and exposure-response analysis.  
• 
To collect PK data for daratumumab SC to assess any potential impact of immunogenicity on daratumumab 
PK.  
• 
To further characterize the immunogenicity of modakafusp alfa in combination with daratumumab SC. 
• 
To characterize MRD negativity and duration of MRD negativity.  
Patient Population: Patients aged 18 years or older with RRMM. 
Number of Patients: 
Phase 1 dose escalation: approximately 18 patients. 
Phase 2a dose finding: approximately 40 patients. 
A total of approximately 58 patients will be enrolled in 
this study. 
Number of Sites:  
Approximately 30 investigational centers globally. 


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Dose Level(s): 
Modakafusp alfa:  
Phase 1 dose escalation: 60, 80 (starting dose), 120, 
or 240 mg Q4W in 28-day cycles. 
Phase 2a dose finding: 2 dose levels (DL1 and DL2) 
selected after the phase 1 dose escalation. 
Daratumumab SC:  
1800 mg QW for Cycles 1 and 2, Q2W for Cycles 3 
to 6, and Q4W thereafter in 28-day cycles. 
Route of Administration: 
Modakafusp alfa: Intravenous  
Daratumumab: SC  
 
Duration of Treatment:  
Patients may receive study drug treatment until they 
experience progressive disease, unacceptable toxicity, or 
other discontinuation criteria are met. 
Period of Evaluation:  
The study is expected to enroll patients for 
approximately 12 to 18 months (phase 1 and 
phase 2a) and continue follow-up for a total study 
duration of approximately 60 months. 
Main Criteria for Inclusion: 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Patients aged 18 years or older. 
2. Documented MM diagnosis per IMWG criteria. 
3. Measurable disease, defined as at least 1 of the following: 
a. 
Serum M protein ≥0.5 g/dL (≥5 g/L) on serum protein electrophoresis.  
b. Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).  
c. 
Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum 
FLC ratio is abnormal. 
4. For patients in the phase 1 dose escalation only:  
Must have received at least 3 prior lines of 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) or therapy. 
5. For patients in phase 2a dose finding only: 
a. 
Received 1 to 3 prior line(s) of antimyeloma therapy. 
b. Must be refractory to prior lenalidomide treatment. 
c. 
Patients must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment. 
d. Documented progressive disease on or after the last regimen.  
e. 
Patients must have partial response (PR) or better to at least 1 line of prior therapy.  
Note:  
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a combination of 
several drugs, or a planned sequential therapy of various regimens (eg, 3 to 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 on 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 progressive disease while on therapy. 


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Main Criteria for Exclusion: 
1. Prior exposure to modakafusp alfa. 
2. Patient has POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin 
changes) syndrome, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia, plasma cell 
leukemia, or lymphoplasmacytic lymphoma. 
3. Patient has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, 
immunotherapy, radiation therapy) to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 5 Grade ≤1 or baseline, except for alopecia. 
4. Previous allogeneic stem cell transplant at any time or autologous stem cell transplant within 12 weeks of 
planned start of dosing. 
5. 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 to have minimal risk 
of recurrence within 3 years. 
Endpoints: 
Primary Endpoints: 
Phase 1 Dose Escalation: 
• 
DLT incidences.  
• 
Frequency and severity of treatment-emergent adverse events (TEAEs) according to the NCI CTCAE, 
Version 5.0. 
Phase 2a Dose Finding: 
• 
ORR, defined as the proportion of patients who achieved a confirmed response of PR or better during the 
study as assessed by the investigator. 
Secondary Endpoints: 
Phase 1 Dose Escalation: 
• 
Summary statistics by dose level and cycle day for the following PK parameters for modakafusp alfa for 
Cycles 1 and 2: 
– 
Single-dose maximum observed serum concentration (Cmax). 
– 
Time of first occurrence of Cmax (tmax). 
– 
Area under the serum concentration-time curve from time 0 to infinity (AUC∞). 
– 
Area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast). 
– 
Apparent serum modakafusp alfa terminal disposition rate constant. 
– 
Apparent serum modakafusp alfa terminal disposition phase half-life. 
– 
Clearance. 
– 
Volume of distribution at steady state after intravenous administration. 
• 
Summary statistics by dose level and cycle day for the following PK parameters for daratumumab for 
Cycles 1 and 2: 
– 
Single-dose Cmax. 
– 
tmax. 
– 
Single-dose and multiple-dose observed concentration at the end of a dosing interval (Ctrough). 
– 
AUC∞. 


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– 
AUClast. 
• 
ORR by the investigator.  
• 
DOR by the investigator.  
• 
PFS by the investigator.  
• 
OS.  
• 
Antidrug antibody (ADA) incidence and characteristics (eg, titer and specificity) and neutralizing antibody 
(NAb). 
• 
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 negativity, at a threshold of 10-5. 
Phase 2a Dose Finding: 
• 
DOR by investigator. 
• 
CBR response of stringent complete response (sCR), CR, very good partial response (VGPR), PR, or 
minimal responses by investigator.  
• 
DCB by investigator. 
• 
DCR (CBR + stable disease) by investigator. 
• 
Duration of disease control by investigator. 
• 
TTP by investigator. 
• 
TTR by investigator. 
• 
TTNT. 
• 
PFS by investigator.  
• 
OS.  
• 
Frequency and severity of TEAEs according to the NCI CTCAE, Version 5.0. 
• 
ADA incidence and characteristics (eg, titer and specificity) and NAb. 
• 
Rate of MRD[-] CR, at threshold of 10-5, with CR assessed by the investigator. 
• 
Rate of MRD[-], at a threshold of 10-5.  
• 
Duration of MRD negativity, at a threshold of 10-5. 
Statistical Considerations: 
Phase 1 Dose Escalation 
The dose escalation/de-escalation will be guided by the rolling six design. 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 population. 
Phase 2a Dose Finding 
The primary endpoint of phase 2a is ORR, which is defined as the percentage of patients with a confirmed PR or 
better (ie, PR, VGPR, CR, and sCR) according to the IMWG Response Criteria assessed by the investigator 
during the study. The observed ORR as well as associated 95% exact CI will be presented for each treatment 
arm. No formal statistical test will be performed to compare the 2 treatment arms. 
Mean proportions and 2-sided 95% exact CIs will be presented for binary secondary endpoints, including CBR, 
DCR, rate of MRD[-] CR, and rate of MRD[-]. 


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For secondary endpoints of DOR, DCB, duration of disease control, TTP, TTNT, PFS, OS, and duration of MRD 
negativity, Kaplan-Meier (K-M) survival curves and K-M medians (if estimable), together with 95% CIs, will be 
calculated for each arm. 
For secondary endpoint of TTR, only responders are included in the analysis and it will be summarized as a 
continuous variable using mean TTR and 95% CI for each arm. 
All disease responses or progression are assessed by the investigator per IMWG criteria.  
Sample Size Justification:  
A total of approximately 58 patients will be enrolled in the study, including approximately 18 DLT-evaluable 
patients for the phase 1 dose escalation and approximately 40 patients (approximately 20 patients per dose level) 
for the phase 2a dose finding.  
The phase 1 dose escalation will accrue approximately 18 DLT-evaluable patients based on the algorithm of the 
rolling six design. 
For phase 2a, approximately 20 patients per arm with a total of 40 patients will be enrolled. Patients who are 
randomized but do not receive any study treatment will be replaced. Patients enrolled for replacement purpose 
will be randomized. Patients who received at least 1 dose of any study treatment will be included in the analysis 
and will not be replaced if they drop out after receiving study treatment.  


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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor. 
3.2 
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 and the study medication, expertise in the therapeutic area and the conduct of clinical 
research, and 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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3.3 
List of Abbreviations 
Term 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCT 
autologous stem cell transplant  
AST 
aspartate aminotransferase 
AUC∞ 
area under the serum concentration-time curve from time 0 to infinity 
AUClast 
area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration 
BMA 
bone marrow aspirate 
CBR 
clinical benefit rate  
CFR 
Code of Federal Regulations 
Cmax 
maximum observed serum concentration 
COVID-19 
coronavirus disease 2019  
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
DCB 
duration of clinical benefit 
DCR 
disease control rate 
DL1 
Dose Level 1 
DL2 
Dose Level 2 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eConsent 
electronic consent 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment  
E-R 
exposure-response 
EU 
European Union 
FDA 
[United States] Food and Drug Administration 
FLC 
free light chain  
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
IB 
investigator’s brochure 
ICF 
informed consent form (including electronic consent where applicable) 


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Term 
Definition 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
independent ethics committee 
IFN 
interferon 
IFN-α  
interferon alpha  
IFN-α2b 
interferon alpha 2b 
IMiD 
immunomodulatory imide drug 
IMWG 
International Myeloma Working Group 
IRB 
institutional review board 
IRR 
infusion-related reaction   
ITT 
intent-to-treat 
IV 
intravenous(ly) 
K-M 
Kaplan-Meier  
mAb 
monoclonal antibody 
MM 
multiple myeloma 
MOA 
mechanism of action 
MRD 
measurable (minimal) residual disease 
MRD[-]  
MRD negative 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NAb 
neutralizing antibody 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NDMM 
newly diagnosed multiple myeloma 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PET-CT 
positron emission tomography-computed tomography  
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PK 
pharmacokinetic  
PO 
orally 
PR 
partial response 
PTA 
posttrial access 
QW 
every week 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
RBC 
red blood cells 
RP2D 
recommended phase 2 dose 


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Term 
Definition 
RRMM 
relapsed or refractory multiple myeloma 
SAE 
serious adverse event 
SC 
subcutaneous 
sCR 
stringent CR 
SD 
stable disease 
SOE 
Schedules of Event 
SPEP 
serum protein electrophoresis 
SUSAR 
suspected unexpected serious adverse reaction 
 
 
TEAE 
treatment-emergent adverse event 
tmax 
time of first occurrence of maximum observed concentration 
TTNT 
time to next treatment 
TTP 
time to progression  
TTR 
time to response 
UPEP 
urine protein electrophoresis 
US 
United States 
VGPR 
very good partial response 
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 
Background 
4.1.1 
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 2016, the global incidence of 
MM increased by 126% (Cowan et al. 2018). The median age at diagnosis is 69 years with only 
3.1% of patients younger than 45 years at diagnosis. It occurs slightly more frequently in men 
(8.8 per 100,000 men vs 5.9 per 100,000 women). MM incidence rate and mortality rate are 
approximately twice as common in the black and African American population compared with 
the white population (age-adjusted incidence rate and mortality rate of 13.8 per 100,000 persons 
and 6 per 100,000 persons, respectively, in the black and African American population compared 
with 6.5 per 100,000 persons and 3 per 100,000 persons, respectively, among the white 
population) (seer.cancer.gov/statfacts/html/mulmy.html, SEER Cancer Stat Facts: Myeloma, 
SEER 12. National Cancer Institute, Bethesda, MD, Accessed 02 June 2022). In the 
non-Hispanic black population, the incidence of MM was 17 per 100,000 men and 12.9 per 
100,000 women; in the non-Hispanic white population, the incidence of MM was 8.1 per 
100,000 men and 5.0 per 100,000 women. This racial disparity is related to the higher prevalence 
of monoclonal gammopathy of undetermined significance in black and African American 
populations (Rajkumar and Kumar 2016).  
From 2010 to 2016, the 5-year survival rate of patients with MM was approximately 
53.9% (themmrf.org/multiple-myeloma/prognosis/understanding-survival-statistics, Relative 
Survival for Multiple Myeloma, Accessed 19 May 2022). 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 has improved in the last decade with 
the discovery, development, and approval of proteasome inhibitors (PIs) (eg, bortezomib) and 
immunomodulatory imide 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 
small molecular or biologic agents with newer mechanisms of action (MOAs), such as 
anti-CD38 monoclonal antibody (mAb) drugs including daratumumab and isatuximab (Darzalex 
Faspro (daratumumab and hyaluronidase-fihj) 2022; Sarclisa (Isatuximab) 2020), selinexor 
(selective inhibitor of nuclear export) (Xpovio (selinexor) tablets for oral use 2021), belantamab 
mafodotin (BCMA [B-cell maturation antigen]–targeting antibody drug conjugate) (Blenrep 
(belantamab mafodotin-blmf) 2020), idecabtagene vicleucel and ciltacabtagene autoleucel 
(chimeric antigen receptor T-cell therapies) (Abecma (idecabtagene vicleucel) suspension for 
intravenous infusion 2021; Carvykti (ciltacabtagene autoleucel) Suspension for Intravenous 
Infusion 2022). Despite these recent advances, these are not curative therapies and there is still a 


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need for the development of novel targeted therapies that are safe and efficacious against MM 
cells. 
While these new therapies are promising, improved treatment options for patients refractory to 
lenalidomide are needed. Efficacy results from phase 3 studies of novel combinations in patients 
refractory to lenalidomide are limited, as these patients are often under-represented in 
randomized trials. Furthermore, most of the treatment combinations that are currently approved 
to treat patients with relapsed or refractory multiple myeloma (RRMM) have lenalidomide in 
their regimen. Despite recently approved CD38 mAb combinations (ie, daratumumab 
subcutaneous [SC], bortezomib, and dexamethasone and daratumumab SC, pomalidomide, and 
dexamethasone), which do not include lenalidomide, the clinical outcomes for patients refractory 
to lenalidomide treated with novel combination therapies remain unsatisfactory, with lower 
responses and progression-free survival (PFS) compared with patients sensitive to lenalidomide 
(Richard et al. 2021). There is still a need for the development of novel targeted therapies that 
are efficacious and well-tolerated that may overcome certain limitations of current therapies. 
4.1.2 
Modakafusp Alfa 
Modakafusp alfa, previously known as TAK-573, is a novel, first-in-class immune targeting 
attenuated cytokine that delivers interferon alpha 2b (IFN-α2b) to immune cells. Modakafusp 
alfa consists of 2 IFN-α2b molecules that are genetically fused to the Fc portion of a humanized 
IgG4 anti-CD38 mAb. Modakafusp alfa binds noncompetitively to a different epitope on CD38 
than other commercially available anti-CD38 antibodies. The IFN-α2b molecules of modakafusp 
alfa are attenuated, leading to reduced interferon (IFN) receptor binding affinity, thereby driving 
targeted delivery of interferon alpha (IFN-α) to CD38 expressing cells. Because CD38 is 
expressed on a variety of immune cells, modakafusp alfa can promote broad innate and adaptive 
immune stimulation through activation of the IFN-α receptor pathway. Additionally, modakafusp 
alfa demonstrated direct antiproliferative effects on CD38 expressing MM plasma cells in 
nonclinical studies. 
4.1.2.1 
Nonclinical Studies 
Pharmacokinetic (PK) and toxicokinetic data were generated in nonclinical pharmacology and 
toxicology studies, and safety pharmacology endpoints were included in the 29-day repeat dose 
Good Laboratory Practice compliant toxicology study in cynomolgus monkeys. Detailed 
nonclinical information is provided in the IB. Nonclinical pharmacology data were also 
generated in support of Study TAK-573-2001. An in vivo nonclinical study was conducted with 
modakafusp alfa in combination with daratumumab (modakafusp alfa + daratumumab) in a 
nonclinical NCI H929 xenograft model, demonstrating a significant reduction of the median 
tumor volume when compared with either single agent alone. Combination toxicity studies were 
not performed in accordance with ICH S9. 
4.1.2.2 
Clinical Studies 
Clinical studies are ongoing with modakafusp alfa as a single agent in adult patients with RRMM 
(Study TAK-573-1501), with modakafusp alfa as part of combination therapy in adult patients 


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with newly diagnosed multiple myeloma (NDMM) in maintenance after autologous stem cell 
transplant (ASCT) or RRMM (Study TAK-573-1502), 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-573-1501 
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”, as of the data cutoff 
date of 23 January 2022 has enrolled 95 subjects. 
This study is being conducted in 3 parts: Part 1 is modakafusp alfa single agent dose escalation, 
Part 2 is single agent dose expansion, and Part 3 is designed as an extension study to assess 
safety and efficacy in patients with RRMM after modakafusp alfa single agent treatment with 
120 mg or 240 mg once every 4 weeks (Q4W) dosing. The phase 1 single agent portion of the 
study followed a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) or 
an optimal biologic dose. 
Part 1 of Study TAK-573-1501 was to evaluate the safety and tolerability of modakafusp alfa 
single agent in patients with RRMM. It involved extensive dose escalation with 10 dose levels of 
modakafusp alfa (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 Q4W on the basis of the recovery time of hematological toxicities. The MTD at this 
schedule was established as 3 mg/kg Q4W, because 6 mg/kg Q4W exceeded the MTD with 
2 dose-limiting toxicities (DLTs) (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 Q4W. 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 conducted with 1 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 
(PD) endpoints; up to 25 patients are planned to be enrolled in this cohort. 
As of 23 January 2022, 39 patients have been enrolled in the Part 2 dose expansion phase, with 
25 of these patients receiving 1.5 mg/kg Q4W. Of the additional patients in Part 2 expansion 
cohorts, 8 received 0.4 mg/kg once every 3 weeks (Q3W), 3 received 0.4 mg/kg 
Q3W + dexamethasone, and 3 received 1.5 mg/kg Q4W + dexamethasone. In the expansion 
cohort receiving 1.5 mg/kg Q4W (N = 25), the overall response rate (ORR) was 48% and the 
median duration of response (DOR) has not yet been reached. Since the data cutoff of 23 January 


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2022, an additional 5 patients have been enrolled to the expansion cohort of 1.5 mg/kg 
Q4W + dexamethasone.  
In the 1.5 mg/kg Q4W treatment group (N = 30) with pooled data from the Part 1 dose escalation 
and Part 2 dose expansion, toxicities were primarily hematologic, with thrombocytopenia and 
neutropenia observed at rates of 73.3% (16.7% Grade 4) and 70.0% (30.0% Grade 4), 
respectively. IRRs have been observed at a rate of 33.3%, with only 1 event (3.3%) being 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 the available data by May 2022, 13% of the immunogenicity-evaluable patients 
(ie, patients with antidrug antibodies [ADAs]) evaluated at baseline and at least 1 posttreatment 
visit, N = 90) reported positive ADA at baseline. Fifty-four percent of the 
immunogenicity-evaluable patients reported positive ADA posttreatment.  
No dose response on the ADA incidence and titer have been observed. The first incidence of 
posttreatment ADA formation was reported as early as Cycle 1 Day 15 (earliest posttreatment 
sampling), and most ADA appeared to be persistent. The potential impact of ADAs on PK, PD 
efficacy, and safety will be further evaluated in the study. 
Lastly, integrated dose-response and exposure-response (E-R) relationships based on efficacy 
and safety data indicate that 1.5 and 3 mg/kg Q4W dosing are within the optimal biological dose 
range. 
Based on holistic evaluations of the data (efficacy, safety, exposure, immunogenicity, E-R, etc), 
and to further assess the optimal dose, a randomized noncomparative Part 3 of the study is being 
conducted to evaluate modakafusp alfa 120 mg or 240 mg Q4W (the fixed dosing equivalents of 
1.5 and 3 mg/kg, respectively). Part 3 aims to compare the efficacy and safety between 120 and 
240 mg Q4W to establish the dose with an optimal benefit-risk profile. 
TAK-573-1502 
Study TAK-573-1502, “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”, is a planned study in patients with NDMM in maintenance posttransplant or RRMM 
assessing the safety of the combination of modakafusp alfa with different standard of care agents 
for MM. Clinical safety or efficacy data is not yet available from this study. 
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 Q3W. 


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The study consists of 2 phases. The phase 1b dose escalation portion of the study, which enrolled 
patients with advanced/metastatic solid tumors, was designed to determine the single-agent 
recommended phase 2 dose (RP2D) and schedule of modakafusp alfa. The phase 2 expansion 
portion will assess the efficacy of modakafusp alfa in combination with pembrolizumab in 
patients with unresectable/metastatic melanoma. The phase 2 expansion will begin with a safety 
lead-in to evaluate safety and tolerability of the combination. 
As of the data cutoff of 23 November 2021, a total of 2 DLTs were identified across all dose 
levels being tested in the phase 1b single-agent dose escalation; both DLTs were at 1.5 mg/kg 
Q3W, 1 of Grade 4 thrombocytopenia, and the other a Grade 3 confusion. The single-agent 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 pharmacologically active dose range was determined to be 0.1 to 1.5 mg/kg Q3W. 
Based on the available data of September 2021, 12% of patients at baseline and 100% of patients 
posttreatment who were immunogenicity-evaluable (N = 17) with solid tumors reported positive 
ADA. No dose response on the ADA incidence and titer has been observed. The first incidence 
of posttreatment ADA formation was reported as early as Cycle 2 Day 1 (earliest posttreatment 
sampling), and both transient and persistent ADAs were observed. The potential impact of ADAs 
on PK, PD efficacy, and safety will be further evaluated in the study. 
4.1.3 
Combination Agent  
4.1.3.1 
Daratumumab SC 
Study TAK-573-2001 will investigate modakafusp alfa in combination with daratumumab SC. 
Daratumumab is an immunoglobulin G1 kappa human mAb that binds to CD38 antigens and 
inhibits the growth of CD38-expressing tumor cells by inducing apoptosis directly through 
Fc-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 and hyaluronidase for 
SC administration. It is approved as monotherapy and in combination with standard antimyeloma 
therapies for adult patients with MM (Darzalex Faspro (daratumumab and hyaluronidase-fihj) 
2022).  
In patients with NDMM, daratumumab SC is approved in the United States (US) and the 
European Union (EU) in combination with bortezomib/melphalan/prednisone; in combination 
with lenalidomide/dexamethasone; or in combination with 
bortezomib/thalidomide/dexamethasone. In patients with RRMM, in US and EU daratumumab 
SC is approved in combination with bortezomib/dexamethasone or 
pomalidomide/dexamethasone in patients who have received at least 1 prior therapy. In patients 
with RRMM, daratumumab SC is also approved in the US and EU in combination with 
lenalidomide and dexamethasone in patients who have received at least 1 prior therapy. 
Daratumumab SC is also indicated as monotherapy in the US and EU in patients who have 


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received a PI and an immunomodulatory agent or who are double-refractory to a PI and an 
immunomodulatory agent. 
4.2 
Rationale for the Proposed Study 
4.2.1 
Modakafusp Alfa in Combination With Daratumumab SC 
Modakafusp alfa has both an epitope binding site on CD38 and an MOA, that are distinct from 
the commercially available anti-CD38 mAbs, daratumumab and isatuximab. Anti-CD38 mAbs 
mechanisms are driven through IgG1 Fc effector functionality, while modakafusp alfa’s 
mechanism is driven through induced IFN signaling within the CD38 expressing cells. Given the 
broad expression of CD38 on many immune cells, IFN signaling has been shown to induce both 
innate and adaptive immune cell activation as well as elicit antiproliferative and/or apoptotic 
effects within the myeloma tumor cells. Given the different, potentially complementary MOA, 
modakafusp alfa, at the sensitive dose, and daratumumab were combined in a nonclinical 
NCI-H929 xenograft model, which demonstrated a significant reduction of the median tumor 
volume when compared with either single agent alone (Figure 4.a). Because CD38 is an 
IFN-responsive gene, expression was evaluated both nonclinically and clinically after 
modakafusp alfa treatment, which showed an increase of CD38 expression of 2- to 3-fold on the 
surface of immune cells (Collins et al. 2020). In the context of the combination of modakafusp 
alfa and daratumumab, this increase in CD38 expression induced by modakafusp alfa could 
counteract the downregulation of CD38 typically seen with anti-CD38 mAbs (Vogl et al. 2021). 
In Study TAK-573-1501 (NCT03215030), a clinical study evaluating single-agent activity of 
modakafusp alfa in an RRMM patient population, modakafusp alfa has shown promising 
antimyeloma activity in heavily pretreated patients, including patients refractory to anti-CD38 
mAbs and those who have received an anti-CD38 mAb in their most recent line of treatment 
(N = 3). 




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every 2 weeks (Q2W) for Cycles 3 to 6, and Q4W thereafter in 28-day cycles (see Section 8.1.2 
for additional dosing information). 
At the modakafusp alfa 80 mg Q4W dose, the median single-dose AUC is expected to be 
approximately 3- and 6-fold below the potential single agent dose of 120 mg or 240 mg Q4W, 
respectively.  
On the basis of the single-agent safety profile of modakafusp alfa from Study TAK-573-1501 
described in Section 4.1.2.2, the major potential overlapping toxicities anticipated with 
modakafusp alfa in combination with daratumumab SC are thrombocytopenia and neutropenia, 
with the possible clinical manifestation of bleeding and infection. As such, these clinical events 
were analyzed in patients treated with modakafusp alfa (Study TAK-573-1501) at the body 
weight-based Q3W and Q4W dosing schedule equivalent to flat dose of 70 to 90 mg. Only 1 of 
10 patients in this group reported a treatment-emergent adverse event (TEAE) within the System 
Organ Class of infections and infestations, which was an event of oral herpes. This event was 
assessed as Grade 2 and unrelated to modakafusp alfa. There was 1 TEAE of Grade 1 epistaxis 
which was assessed as unrelated to modakafusp alfa.  
In addition, in the same 10 patients treated with equivalent flat dose of 70 to 90 mg, ORR 
responses were observed in 3 of 10 patients (30%). Clinical efficacy at doses <70 mg was very 
limited, with 1 of 19 patients (5%) with a reported response.  
On the basis of the anticipated 3- to 6-fold reduction in median single-dose AUC at 80 mg Q4W 
of modakafusp alfa versus 120 mg or 240 mg Q4W, and safety and clinical efficacy profiles 
observed at 70 to 90 mg Q3W and Q4W from a modakafusp alfa single-agent study, 80 mg Q4W 
would be an appropriate starting dose in combination with daratumumab SC for the phase 1 dose 
escalation. In addition, intensive safety monitoring including rigorous chemistry and hematologic 
assessments will be included in the initial cycles of the current study. This will enable close 
monitoring of TEAEs for prompt medical interventions if needed. 
4.4 
Modakafusp Alfa Dose Selection for Phase 2a Dose Finding in Combination With 
Daratumumab SC 
After the phase 1 dose escalation of modakafusp alfa in combination with daratumumab SC is 
completed, 2 modakafusp alfa dose levels will be selected for the 1:1 randomized phase 2a dose 
finding in combination with daratumumab SC.  
The selection of 2 dose levels of modakafusp alfa in combination with daratumumab SC for the 
phase 2a dose finding will be made on the basis of the overall assessment of the results from the 
following: 
1. The rolling six recommended tolerable doses in the phase 1 dose escalation based on DLT 
data in Cycle 1. 
2. Additional safety, tolerability, PK, and PD data as available from Cycle 1 and beyond in the 
phase 1 dose escalation. 


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3. The benefit-risk assessment for 120 mg Q4W and 240 mg Q4W based on emerging efficacy 
and safety data from the phase 2, Part 3 extension of the separate ongoing modakafusp alfa 
monotherapy study (Study TAK-573-1501).  
Therefore, integrated PK, PD, efficacy, and safety data analyses will be conducted using the 
phase 1 dose escalation data in combination with daratumumab SC and single-agent data from 
Study TAK-573-1501, Part 3 extension to select the 2 dose levels of modakafusp alfa in 
combination with daratumumab SC in the phase 2 dose finding.  
4.5 
Risks and Benefits 
4.5.1 
Modakafusp Alfa 
Modakafusp alfa has been administered to over 100 patients with MM and solid tumors in 
ongoing studies (see Study TAK-573-1501 and Study TAK-573-1001 in Section 4.1.2.2). 
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 central nervous system, 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 
As of 23 January 2022 in the single-agent study in patients with RRMM, Study TAK-573-1501 
(N = 95), the most common nonhematologic TEAEs were hyperglycaemia (33.7%), fatigue 
(32.6%), hypocalcaemia (23.2%), and hyponatraemia (22.1%). The most common TEAEs Grade 
≥3 were hematologic: neutropenia (52.6%), thrombocytopenia (49.5%), leukopenia (37.9%), and 
anemia (29.5%). Infections were uncommon, with pneumonia occurring in 8 patients (8.4%) and 
upper respiratory tract infection in 6 patients (6.3%). Two patients (2.1%) had TEAEs of febrile 
neutropenia. 
Hematologic Toxicities 
The most common TEAEs reported have been hematologic. Overall, these hematologic TEAEs 
were thrombocytopenia (including platelet count decreased) (77.9%), followed by neutropenia 
(including neutrophil count decreased) (58.9%), anaemia (56.8%), leukopenia (52.6%), and 


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lymphocyte count decreased (38.9%). The majority of patients (85.3%) had a TEAE related to 
study drug; the most frequently reported TEAEs related to study drug were hematologic, 
including thrombocytopenia (64.2%), neutropenia (49.5%), and leukopenia (44.2%). Two 
patients (2.1%) had Grade ≥3 TEAEs of febrile neutropenia. Grade ≥3 hematologic TEAEs 
included neutropenia (52.6%), thrombocytopenia (49.5%), leukopenia (37.9%), anaemia 
(29.5%), and lymphocyte count decreased (27.4%).  
Hematologic TEAEs leading to any dose modification were thrombocytopenia 15 (15.8%), 
leukopenia 2 (2.1%), anemia 2 (2.1%). The hematologic TEAEs leading to discontinuation of 
study drug were thrombocytopenia 2 (2.1%), disseminated intravascular coagulation 1 (1.1%) 
and neutropenia 1 (1.1%). 
With 1.5 mg/kg Q4W, mean platelet counts and absolute neutrophil count (ANC) were lowest at 
Day 8 or 15 of the first 2 cycles and recovered sufficiently to continue dosing in the next cycle 
without dosing delay in most cases. 
IRRs 
Patients receiving modakafusp alfa have experienced IRRs. In Study TAK-573-1501 (patients 
with RRMM), 18 patients (18.9%) experienced an IRR, 2 (2.1%) of which were Grade ≥3 and 
3 (3.2%) of which were SAEs. Four patients (4.2%) required a dose modification due to an IRR. 
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 mandatory that all patients receive premedication before modakafusp alfa dosing unless 
contraindicated (see Section 8.1.1.3).  
It is important to monitor for signs and symptoms of IRRs and treat accordingly. Resuscitation 
medications and equipment should be available before, during, and after the infusion. 
Premedications and treatment should be provided as described in Section 8.1.1.3. 
Other 
Neuropsychiatric events have been reported in modakafusp alfa clinical studies. In Study 
TAK-573-1501, overall (N = 95) there were 9 TEAEs (9.5%) of insomnia, 5 TEAEs (5.3%) of 
confusional state, 4 TEAEs (4.2%) each of agitation and depression, 2 TEAEs (2.1%) each of 
encephalopathy and mental status changes, and 1 TEAE (1.1%) each of anxiety and restlessness. 
Grade 3 and higher neuropsychiatric events were encephalopathy 2 (2.1%), spinal cord 
compression 2 (2.1%), syncope 1 (1.1%), mental status changes 1 (1.1%), and confusional state 
1 (1.1%). Of these, the events assessed as serious were encephalopathy 2 (2.1%), spinal cord 
compression 2 (2.1%), confusional state 1 (1.1%), and mental status changes 1 (1.1%). 
Some patients receiving modakafusp alfa have experienced elevation in liver enzymes. In 
Study TAK-573-1501, TEAEs of aspartate aminotransferase (AST) increased and alanine 


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aminotransferase (ALT) increased were observed in 18.9% and 14.7% of patients, respectively. 
One TEAE each of AST and ALT increased were Grade ≥3; however, none were SAEs. 
Modakafusp alfa elicited a low level of cytokine release (tumor necrosis factor alpha, IL-6, IL-8, 
interferon gamma, and IL-2) from human peripheral blood mononuclear cells 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. One TEAE 
of CRS Grade 2 was reported in Study TAK-573-1001 in solid tumors; this TEAE was 
considered to be related to the study drug. 
For more detailed information on the adverse events (AEs) associated with modakafusp alfa, as 
well as the identified and potential risks, please refer to the most recent IB. 
Clinical safety will be monitored per the assessments described in the Schedules of Events 
(SOEs) located in Appendix A. Dose modification should be applied per the guidelines in 
Section 8.6. 
Further details for modakafusp alfa administration, safety events, and management can be found 
in Section 8.0 and the Guidance for Investigator section of the IB. 
4.5.2 
Combination Agent 
4.5.2.1 
Combination Agent Daratumumab SC  
The most frequently reported adverse reactions associated with daratumumab SC monotherapy 
(incidence ≥20%) is upper respiratory infection. The most common (≥40%) hematology 
laboratory abnormalities with daratumumab SC are decreased leukocytes, decreased 
lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. Refer to 
daratumumab and hyaluronidase-fihj Prescribing Information for more details (Darzalex Faspro 
(daratumumab and hyaluronidase-fihj) 2022). 
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). 
Interference with serological testing has been described with the anti-CD38 antibody 
daratumumab, which binds to CD38 on red blood cells (RBCs) and results in a positive indirect 
antiglobulin test (indirect Coombs test). A daratumumab-mediated positive indirect antiglobulin 
test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to 
RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination 
of a patient’s ABO and Rhesus factor blood type are not impacted (Darzalex Faspro 
(daratumumab and hyaluronidase-fihj) 2022). Therefore, blood transfusion centers should be 
notified of this interference with serological testing, and patients should be typed and screened 
before starting daratumumab SC if not performed previously. 


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The main overlapping toxicities expected with modakafusp alfa and daratumumab SC, on the 
basis of the single-agent profile of both drugs are neutropenia, and thrombocytopenia (Mateos et 
al. 2020; Vogl et al. 2021). Hematologic AEs (eg, neutropenia and thrombocytopenia) will be 
managed with dose delays, growth factors, and platelet transfusion, if needed. Both modakafusp 
alfa and daratumumab SC were reported with IRRs but with only 2.1% and 1% at Grade 3 for 
each agent, respectively. IRRs will be proactively managed with premedication and careful 
patient monitoring after infusion.  


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objectives 
The primary objectives are: 
Phase 1 Dose Escalation 
• To determine the safety and tolerability of modakafusp alfa in combination with 
daratumumab SC.  
Phase 2a Dose Finding 
• To inform the RP2D of modakafusp alfa in combination with daratumumab SC.  
• To provide a preliminary evaluation of the clinical efficacy of modakafusp alfa in 
combination with daratumumab SC as measured by ORR. 
5.1.2 
Secondary Objectives 
Phase 1 Dose Escalation 
• To characterize the PK profile of modakafusp alfa and daratumumab in the combination 
setting. 
• To characterize antimyeloma activity as measured by ORR, DOR, PFS, and overall survival 
(OS).  
• To characterize the immunogenicity of modakafusp alfa in combination with daratumumab 
SC. 
• To characterize measurable (minimal) residual disease (MRD) negativity and duration of 
MRD negativity.  
Phase 2a Dose Finding 
• To determine DOR, clinical benefit rate (CBR), duration of clinical benefit (DCB), disease 
control rate (DCR), duration of disease control, time to progression (TTP), time to response 
(TTR), time to next treatment (TTNT), PFS, and OS. 
• To further characterize safety and tolerability of modakafusp alfa in combination with 
daratumumab SC. 
• To collect PK data for modakafusp alfa to support population PK and E-R analysis.  
• To collect PK data for daratumumab SC to assess any potential impact of immunogenicity on 
daratumumab PK.  
• To further characterize the immunogenicity of modakafusp alfa in combination with 
daratumumab SC. 


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• To characterize MRD negativity and duration of MRD negativity.  
5.1.3 
Exploratory Objectives 
  
 
 
 
5.2 
Endpoints 
Patients’ responses to the treatment will be determined per International Myeloma Working 
Group (IMWG) criteria in the current study. 
5.2.1 
Primary Endpoints 
The primary endpoints are: 
Phase 1 Dose Escalation 
• DLT incidences (see Section 8.3.1).  
• Frequency and severity of TEAEs according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. 
Phase 2a Dose Finding 
• ORR, defined as the proportion of patients who achieved a confirmed response of PR or 
better during the study as assessed by the investigator. 
5.2.2 
Secondary Endpoints 
The secondary endpoints are: 
Phase 1 Dose Escalation 
• Summary statistics by dose level and cycle day for the following PK parameters for 
modakafusp alfa for Cycles 1 and 2: 
– Single-dose maximum observed serum concentration (Cmax). 
– Time of first occurrence of Cmax (tmax). 
– Area under the serum concentration-time curve from time 0 to infinity (AUC∞). 
– Area under the serum concentration-time curve from time 0 to time of the last 
quantifiable concentration (AUClast). 
– Apparent serum modakafusp alfa terminal disposition rate constant. 
– Apparent serum modakafusp alfa terminal disposition phase half-life. 
– Clearance. 
– Volume of distribution at steady state after intravenous (IV) administration. 


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• Summary statistics by dose level and cycle day for the following PK parameters for 
daratumumab for Cycles 1 and 2: 
– Single-dose Cmax. 
– tmax. 
– Single-dose and multiple-dose observed concentration at the end of a dosing interval 
(Ctrough). 
– AUC∞. 
– AUClast. 
• ORR by the investigator.  
• DOR by the investigator.  
• PFS by the investigator.  
• OS.  
• ADA incidence and characteristics (eg, titer and specificity) and neutralizing antibody 
(NAb). 
• 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 negativity, at a threshold of 10-5. 
Phase 2a Dose Finding 
• DOR by investigator. 
• CBR response of sCR, CR, very good partial response (VGPR), PR, or minimal responses by 
investigator.  
• DCB by investigator. 
• DCR (CBR + stable disease [SD]) by investigator. 
• Duration of disease control by investigator. 
• TTP by investigator. 
• TTR by investigator. 
• TTNT. 
• PFS by investigator.  
• OS.  
• Frequency and severity of TEAEs according to the NCI CTCAE, Version 5.0. 


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• ADA incidence and characteristics (eg, titer and specificity) and NAb. 
• Rate of MRD[-] CR, at threshold of 10-5, with CR assessed by the investigator. 
• Rate of MRD[-], at a threshold of 10-5. 
• Duration of MRD negativity, at a threshold of 10-5. 
5.2.3 
Exploratory Endpoints 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 


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6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a global multicenter, open-label, phase 1/2a study designed to evaluate the safety, 
tolerability, PK, PD, and preliminary efficacy of modakafusp alfa in combination with 
daratumumab SC in patients with RRMM. The study will begin with a phase 1 dose escalation to 
evaluate the safety and tolerability of modakafusp alfa in combination with daratumumab SC. 
Two dose levels of modakafusp alfa in combination with daratumumab SC will be selected to be 
further explored in the randomized phase 2a dose finding part of the study (see Section 4.4). 
Patients will be randomized in a 1:1 ratio across 2 dose levels (DL1 or DL2) of modakafusp alfa 
in combination with daratumumab SC. The confirmed ORR assessed by the investigator per 
IMWG criteria will be determined as the primary efficacy endpoint of the phase 2a dose finding. 
The optimized RP2D of modakafusp in combination with daratumumab SC will be selected on 
the basis of integrated safety, efficacy, PK, and PD data from the current study and other relevant 
stud(ies) (eg, Study TAK-573-1501). 
A schematic of the study design is included as Figure 6.a. SOEs are provided in Appendix A. 
Figure 6.a 
Schematic of TAK-573-2001 Study Design 
 
DL1: Dose Level 1; DL2: Dose Level 2; Q4W: every 4 weeks; R: randomization; SC: subcutaneous.  


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Phase 1 Dose Escalation 
The study will begin with a phase 1 dose escalation to evaluate the safety and tolerability of 
modakafusp alfa in combination with daratumumab SC during the Cycle 1 (28 days per cycle) 
DLT evaluation period and beyond. The proposed population in the phase 1 dose escalation will 
be patients with RRMM with at least 3 prior lines of 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) or therapy. 
The dose escalation will follow the rolling six design (Skolnik et al. 2008) with data collected in 
the dose escalation/de-escalation phase. Safety will be evaluated by the frequency of AEs, 
severity, types of AEs, and by changes from baseline in patients’ vital signs, weights, and 
clinical laboratory results. 
The starting dose to be evaluated for modakafusp alfa will be 80 mg Q4W (Section 4.3). 
Modakafusp alfa doses of 60, 120, or 240 mg Q4W could be evaluated depending on dose 
escalation/de-escalation rules specified by the rolling six design. Decision on dose escalation and 
de-escalation in phase 1 will be made on the basis of the number of patients in the current dose 
level, the number of patients experiencing DLTs, and the number of patients still at risk of 
developing a DLT at the time of a new patient entry. Three to 6 patients may concurrently be 
enrolled at a dose level in the study. The enrollment of the first 3 patients at the starting dose of 
80 mg Q4W will be staggered by 24 hours each. The remaining patients can be dosed 
concurrently if there are no unexpected and significant acute toxicities. Accrual to the study may 
be paused while waiting for data from these 6 patients. Decisions as to whether to resume 
enrolling on the next dose level will be made using data available at the time of new patient 
enrollment (see Section 8.4 and Table 8.a for more details). De-escalation will occur when 2 or 
more DLTs are observed at the current dose level, whereas escalation will occur when 3 of 3, 
4 of 4, 5 of 5, 5 of 6, or 6 of 6 patients are enrolled at the current dose level with no DLT 
observed and the next higher dose level has no more than 1 DLT observed. It is estimated that 
approximately 18 DLT-evaluable patients will be enrolled.  
The daratumumab SC dose of 1800 mg (QW in Cycles 1 and 2, Q2W in Cycles 3 to 6, and Q4W 
thereafter) will be used in combination with modakafusp alfa throughout the study. 
Phase 2a Dose Finding 
Two dose levels of modakafusp alfa in combination with daratumumab SC doses will be selected 
from phase 1 dose escalation to be explored further in phase 2a open-label dose finding. 
Approximately 40 patients will be randomized 1:1 across 2 different dose levels (DL1 or DL2; 
N = 20 at each dose level) of modakafusp alfa in combination with daratumumab SC. Eligible 
patients will include patients with RRMM who have received 1 to 3 prior lines of therapy, 
refractory to lenalidomide, and sensitive (nonrefractory) or naive to anti-CD38 mAb. The 
randomization will be stratified by the number of prior lines of therapy (1 vs 2 or 3). The primary 
endpoint is the confirmed ORR assessed by the investigator per IMWG criteria.  


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6.2 
Number of Patients 
A total of approximately 58 patients will be enrolled in this study at approximately 30 study 
centers globally.  
6.2.1 
Phase 1 Dose Escalation  
Approximately 18 patients will be enrolled in the phase 1 dose escalation/de-escalation. During 
phase 1, patients who are determined as DLT non-evaluable will be replaced. The definition of 
DLT-evaluable patients is provided in Section 13.1.1. 
6.2.2 
Phase 2a Dose Finding 
Approximately 40 patients (approximately 20 patients per arm) will be enrolled in the phase 2a 
dosing-finding study. 
Patients who are randomized but do not receive any study treatment will be replaced. Patients 
enrolled for replacement purpose will be randomized. Patients who received at least 1 dose of 
any study treatment will be included in the analysis and will not be replaced if they drop out after 
receiving study treatment.  
The definition of evaluable patients and determination of sample size are provided in 
Section 13.0. 
6.3 
Duration of Study 
6.3.1 
Duration of an Individual Patient’s Study Participation 
Patients may receive study drug treatment until they experience progressive disease, 
unacceptable toxicity, or other discontinuation criteria are met. 
Patients who discontinue study drug treatment for reasons other than progressive disease will 
continue PFS follow-up every 4 weeks from the end of treatment (EOT) visit until the 
occurrence of progressive disease, death, the start of subsequent systemic antineoplastic therapy, 
study termination, whichever occurs first. OS follow-up continues every 12 weeks until death, 
study termination, or patient withdrawal. 
6.3.2 
End of Study/Study Completion Definition and Planned Reporting 
The final analysis for the clinical study report will be conducted after all patients enrolled in the 
study have completed 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:  


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• 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.  
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the password 
or access materials once their participation in the study has concluded. Any devices provided to 
access the EDC application will be returned to Takeda once the site’s participation in the study 
has concluded.  
Takeda must notify the competent authorities and IECs of any member state where the study is 
being conducted within 15 days of premature study closure and provide the reasons for study 
closure.  
Within 90 days of ending the study, the sponsor will notify the competent authorities and the 
IECs in all member states where the study was 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. 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures 
Refer to Table 6.a for disclosures information for all primary and secondary endpoints. 


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Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
Phase 1 Dose Escalation 
Primary: DLT incidences 
Section 8.3.1 
Up to 60 months 
Primary: Frequency and severity of TEAEs 
Section 13.1.8 
Up to 60 months 
Secondary: Summary PK statistics for modakafusp alfa in 
Cycles 1 and 2 
Sections 5.2.2 and 
13.1.4 
Up to 60 months 
Secondary: Summary PK statistics for daratumumab in 
Cycles 1 and 2 
Sections 5.2.2 and 
13.1.4 
Up to 60 months 
Secondary: ORR by investigator 
Section 13.1.3.1 
Up to 60 months 
Secondary: DOR by investigator 
Section 13.1.3.2.1 
Up to 60 months 
Secondary: PFS by investigator 
Section 13.1.3.2.1 
Up to 60 months 
Secondary: OS 
Section 13.1.3.2.1 
Up to 60 months 
Secondary: ADA incidence and characteristics and NAb 
Section 13.1.7 
Up to 60 months 
Secondary: Rate of MRD[-] CR by investigator 
Section 13.1.3.2.1 
Up to 60 months 
Secondary: Rate of MRD[-] 
Section 13.1.3.2.1 
Up to 60 months 
Secondary: Duration of MRD negativity 
Section 13.1.3.2.1 
Up to 60 months 
Phase 2a Dose Finding  
 
 
Primary: ORR 
Section 13.1.3.1 
Up to 60 months 
Secondary: DOR by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: CBR by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: DCB by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: DCR (CBR + SD) by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: Duration of disease control by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: TTP by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: TTR by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: TTNT 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: PFS by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: OS  
Section 13.1.3.2.2 
Up to 60 months 
Secondary: Frequency and severity of TEAEs 
Section 13.1.8 
Up to 60 months 
Secondary: ADA incidence and characteristics and NAb 
Section 13.1.7 
Up to 60 months 
Secondary: Rate of MRD[-] CR by investigator 
Section 13.1.3.2.2 
Up to 60 months 
Secondary: Rate of MRD[-]  
Section 13.1.3.2.2 
Up to 60 months 
Secondary: Duration of MRD negativity 
Section 13.1.3.2.2 
Up to 60 months 
ADA: antidrug antibody; AE: adverse event; CBR: clinical benefit rate; CR: complete response; DCB: duration 
of clinical benefit; DCR: disease control rate; DLT: dose-limiting toxicity; DOR: duration of response; MRD: 
measurable (minimal) residual disease; MRD[-]: MRD negative; NAb: neutralizing antibody; ORR: overall 
response rate; OS: overall survival; PFS: progression-free survival; PK: pharmacokinetic; SAE: serious adverse 
event; SD: stable disease; TEAE: treatment-emergent adverse event; TTNT: time to next treatment; TTP: time to 
progression; TTR: time to response. 
 


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6.3.4 
Total Study Duration 
The study is expected to enroll patients for approximately 12 to 18 months (phase 1 and 
phase 2a) and continue follow-up for a total study duration of approximately 60 months. 
6.4 
Randomization in Phase 2a Dose Finding 
Patients will be randomized in a 1:1 ratio across 2 dose levels (DL1 or DL2) of modakafusp alfa 
in combination with daratumumab SC. Randomization will be stratified by the number of prior 
lines of therapy (1 vs 2 or 3).  
Randomization procedures should be performed after complete eligibility assessments and before 
the initiation of assigned treatment. This study is unblinded. 
6.5 
Posttrial Access 
At the end or termination of the study (Section 6.3.2), ongoing patients who continue benefiting 
from modakafusp alfa in combination with daratumumab SC, 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).  
6.5.1 
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, that patient’s disease has progressed, or 
treatment is no longer tolerable). 
• Either 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 posttrial protocol and informed consent. 
6.5.2 
Combination Agent 
Only modakafusp alfa 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. 


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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Patients aged 18 years or older. 
2. Documented MM diagnosis per IMWG criteria. 
3. Measurable disease, defined as at least 1 of the following: 
a. Serum M protein ≥0.5 g/dL (≥5 g/L) on serum protein electrophoresis (SPEP).  
b. Urine M protein ≥200 mg/24 hours on urine protein electrophoresis (UPEP).  
c. Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) 
provided serum FLC ratio is abnormal. 
4. For patients in the phase 1 dose escalation only:  
Must have received at least 3 prior lines of 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) or therapy. 
5. For patients in phase 2a dose finding only: 
a. Received 1 to 3 prior line(s) of antimyeloma therapy. 
b. Must be refractory to prior lenalidomide treatment. 
c. Patients must be sensitive (nonrefractory) or naïve to prior anti-CD38 mAb treatment. 
d. Documented progressive disease on or after the last regimen.  
e. Patients must have PR or better to at least 1 line of prior therapy.  
Note:  
A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a 
combination of several drugs, or a planned sequential therapy of various regimens (eg, 3 to 
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 on 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 progressive disease while on 
therapy. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening. 
(ECOG performance status scoring is provided in Appendix F.) 


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7. Adequate organ function at screening as determined by the following laboratory values: 
Laboratory Test 
Value 
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) 
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 range. 
a Without ongoing growth factor or transfusion support for at least 1 week before Day 1. 
 
8. The minimal interval between the last dose of any of the following treatments/procedures and 
the first dose of study drug must be at least: 
Treatment/Procedure 
Minimum Interval 
Chemotherapy (including PIs), and IMiDs 
14 days 
Any investigational anticancer product 
28 days or 5 half-lives 
whichever is longer 
Antibody-based anticancer therapy 
28 days or 5 half-lives 
whichever is longer 
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  
28 days 
PI: proteosome inhibitor; IMiD: immunomodulatory drug.  
 
9. Reproductively female patients who: 
• Are postmenopausal for at least 2 years before the screening visit, OR 
• Are surgically sterile, OR 
• If they are of childbearing potential: 
– Agree to practice 1 highly effective method of contraception and 1 additional 
effective (barrier) method (see Table 8.f) at the same time, from the time of signing 
the informed (e)consent form (ICF) through 3 months after the last dose of 
daratumumab SC, or 7 days after the last dose of modakafusp alfa, whichever is 
longer, OR 


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– Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient during the entire study treatment period and through 3 months 
after the last dose of daratumumab SC, or 7 days after the last dose of modakafusp 
alfa, 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 an egg or eggs (ova) during the study and for 3 months after the 
last dose of daratumumab SC, or 7 days after the last dose of modakafusp alfa, 
whichever is longer. 
– Must also adhere to any applicable local (country-specified) treatment-specific 
pregnancy prevention guidelines. 
10. Reproductively male patients, unless surgically sterilized (ie, status postvasectomy), who: 
• Agree to practice effective barrier contraception (see Table 8.f) during the entire study 
treatment period and through 7 days after the last dose of modakafusp alfa, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient during the entire study treatment period and through 7 days after 
the last dose of modakafusp alfa. (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 for 7 days after the last dose of modakafusp alfa. 
• Must also adhere to any applicable local (country-specified) treatment-specific pregnancy 
prevention guidelines. 
11. Voluntary written or electronic consent (eConsent) must be given before performance of any 
study-related procedure not part of standard medical care, with the understanding that 
consent may be withdrawn by the patient at any time without prejudice to future medical 
care. 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Prior exposure to modakafusp alfa. 
2. Patient has POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
gammopathy, and skin changes) syndrome, solitary plasmacytoma, amyloidosis, 
Waldenström macroglobulinemia, plasma cell leukemia, or lymphoplasmacytic lymphoma. 
3. Patient has not recovered from adverse reactions to prior myeloma treatment or procedures 
(chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE, Version 5 Grade ≤1 or 
baseline, except for alopecia. 


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4. Previous allogeneic stem cell transplant at any time or ASCT within 12 weeks of planned 
start of dosing. 
5. 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 to have minimal risk of recurrence within 
3 years. 
6. Evidence of central nervous system involvement and/or meningeal involvement due to MM 
exhibited during screening. 
7. 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/premedications, their analogues, or excipients in the various formulations of any 
agent per the prescribing information. 
8. Patient is unable to take label-recommended/required prophylaxis needed for combination 
agents, ie, antiviral prophylaxis for daratumumab SC.  
9. Seropositive for hepatitis B, or known history of seropositivity for hepatitis C or of 
seropositivity for HIV. 
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen 
[HBsAg]). Patients with resolved infection (that is, patients who are HBsAg negative but 
positive for antibodies to hepatitis B core antigen and/or antibodies to HBsAg) 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: 
Participants with serologic findings suggestive of HBV vaccination (hepatitis B surface 
antibody 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. 
• Seropositive for hepatitis C (anti-hepatitis C virus antibody positive or anti-hepatitis C 
virus–RNA quantitation positive), except in the setting of a sustained virologic response 
with undetectable hepatitis RNA level at least 12 weeks (negative viremia) after 
completion of antiviral therapy. 
10. Patient has congestive heart failure (New York Heart Association Grade ≥II), cardiac 
myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina 
pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or 
clinically significant uncontrolled hypertension. 
11. Patient has a high risk of hemorrhage such as uncontrolled chronic bleeding disorder or is 
currently being treated with therapeutic anticoagulation. 
12. Patient has a history of acute myocardial infarction within 5 months from enrollment or has 
electrocardiogram (ECG) abnormalities during screening that are deemed medically relevant 
by the investigator. 


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13. Patient has QT interval corrected by the Fridericia method >480 msec (Grade ≥2).  
14. Patient has a concurrent illness that would preclude study conduct and assessment including 
but not limited to, uncontrolled medical conditions, uncontrolled and active infection 
(considered opportunistic, life threatening, or clinically significant), uncontrolled risk of 
bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive 
pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), 
alcoholic liver disease, or primary biliary cirrhosis. 
15. Patient has a chronic condition that will require the chronic use of systemic corticosteroids 
>10 mg/d of prednisone or equivalent on top of any required corticosteroids for MM. 
16. Female patients who are lactating and breastfeeding or have a positive urine or serum 
pregnancy test during the screening period or a positive urine or serum pregnancy test before 
first dose of study drug if applicable. 
17. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol. 
7.3 
Excluded Prior Medications 
Patients must not have received the final dose of any medications within the specified minimum 
intervals before first the dose of study drug as outlined in Section 7.1, Criterion 8. 
Patients must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
7.4 
Excluded Prior Procedures and Treatments 
Patients must not have received the final dose of any of the procedures or treatments within the 
specified minimum intervals before the first dose of study drug as outlined in Section 7.1, 
Criterion 8. 


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8.0 
STUDY DRUG 
Investigational medicinal product: Modakafusp alfa. 
Combination medicinal product: Daratumumab SC. 
8.1 
Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). 
8.1.1 
Modakafusp Alfa 
8.1.1.1 
Dosage 
Phase 1 dose escalation: 60, 80 (starting dose), 120, or 240 mg Q4W in 28-day cycles. 
Phase 2a dose finding: 2 dose levels (DL1 and DL2) selected after the phase 1 dose escalation. 
8.1.1.2 
Administration 
Modakafusp alfa will be administered by infusion over 1 hour (±10 minutes). Any decrease in 
infusion duration must be discussed with and agreed on by the sponsor. 
Daratumumab SC 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 daratumumab SC and the initiation of the infusion of modakafusp alfa. 
If a patient presents with an IRR at any dose level, the duration of the infusion may be extended 
per the investigator’s discretion. Infusion and pharmacy staff are advised to be prepared 
accordingly for either a planned, extended infusion time or for potential infusion interruptions. 
See the pharmacy manual for additional guidance. 
8.1.1.3 
Premedication 
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 
on by the sponsor. 
The clinical site is responsible for sourcing all treatments administered before or after 
modakafusp alfa administration. In the event that a protocol-required medication for prophylactic 
coadministration is not able to be obtained by a clinical site due to regional drug availability, the 
medication may be supplied by the sponsor. 
Before each infusion of modakafusp alfa, patients must receive the following premedications 
unless contraindicated per investigator discretion: 
• Corticosteroid IV or orally (PO) (methylprednisolone 100 mg, dexamethasone 20 mg, or 
equivalent) 60 minutes to 2 hours before treatment. If a patient experiences no significant 


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IRR, the dose of methylprednisolone may be 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 mg to 1000 mg PO 60 minutes to 2 hours before treatment. 
• Diphenhydramine or equivalent 25 mg to 50 mg PO approximately 12 hours before and again 
approximately 1 hour before Cycle 1 treatment; for all subsequent infusions, approximately 
1 hour before. 
Montelukast 10 mg PO may be given to patients who are intolerant to diphenhydramine or for 
whom diphenhydramine is ineffective. 
On days on which the combination agent daratumumab and hyaluronidase-fihj is given on the 
same visit day as modakafusp alfa, administer the modakafusp alfa-specific premedication only 
(see Section 8.10.2). 
8.1.1.4 
Postinfusion Medication and Monitoring 
Patients may receive 20 to 25 mg prednisone or 4 mg of dexamethasone PO or equivalent on the 
first and second days after all full-dose infusions. Other concomitant medications can be 
administered per institutional protocols. 
During the infusion and for 2 hours after the end of infusion, the patient should be continually 
monitored by medically qualified staff with access to emergency medical equipment and 
medications to manage infusion reactions. 
On days on which the combination agent daratumumab and hyaluronidase-fihj is given on the 
same visit day as modakafusp alfa, administer the modakafusp alfa-specific postinfusion 
medications only. 
8.1.1.5 
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. 
8.1.2 
Combination Agent Daratumumab SC 
8.1.2.1 
Dosage 
Daratumumab SC: 1800 mg QW for Cycles 1 and 2, Q2W for Cycles 3 to 6, and Q4W thereafter 
in 28-day cycles. 
8.1.2.2 
Administration 
Daratumumab SC will be administered SC 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 and the initiation of the infusion of modakafusp alfa. 


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8.1.2.3 
Premedication 
Before each injection, patients will receive the following premedication approximately 1 to 
3 hours before the daratumumab and hyaluronidase-fihj on each dosing day (Darzalex Faspro 
(daratumumab and hyaluronidase-fihj) 2022). 
• 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. 
• Antihistamine: 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 premedication only. 
8.1.2.4 
Postinjection Medication 
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 from the day after the 
administration of daratumumab and hyaluronidase-fihj (Darzalex Faspro (daratumumab and 
hyaluronidase-fihj) 2022). 
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 in the event when 
corticosteroid is required as a premedication 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. After 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) 2022). 
8.1.2.5 
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 after EOT.  
8.2 
List of EU Auxiliary Medicinal Products  
• 
Corticosteroids. 
• Analgesics and antipyretics. 
• Antihistamines. 


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• Leukotriene receptor antagonists. 
• Antivirals. 
8.3 
DLT (Phase 1 Dose Escalation) 
8.3.1 
Definitions of DLT 
Toxicity will be evaluated according to the NCI CTCAE, Version 5.0. 
Patients will be monitored through all cycles of therapy for toxicities. Primarily, only toxicities 
that occur during Cycle 1 will be used for the purposes of defining DLT. 
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: 
• Any Grade 5 AE. 
• Hematologic toxicity, clearly unrelated to the underlying disease are defined as follows: 
– Nonfebrile Grade 4 neutropenia (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 single episode of body 
temperature >38.3°C (101°F) or sustained temperature 38.0°C (100.4°F) for more than 
1 hour. 
– Grade 4 thrombocytopenia (platelets <25,000/mm3) lasting more than 14 consecutive 
days. 
– Grade ≥3 thrombocytopenia (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 
improve within 72 hours (reversion of Grade 4 events to Grade ≤2, reversion of Grade 3 
events to Grade ≤1 or baseline). 
– Grade 3 nausea and/or emesis that can be controlled to Grade ≤2 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. 


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– 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 within 
7 days. 
– Grade 3 diarrhea that can be controlled to Grade ≤2 in ≤72 hours with appropriate 
treatment. 
– Grade 3 rash and pruritis that respond to standard treatment and resolve or improve to 
Grade ≤2 in ≤72 hours. 
• Delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of 
treatment-related hematological or nonhematologic toxicities. 
8.3.2 
Definition of DLT-Evaluable Patients 
The DLT-evaluable population will include patients in the dose escalation/de-escalation phase 
who either experienced a DLT in Cycle 1 in the treatment phase of the study, or who have 
completed the Cycle 1 dose of modakafusp alfa and received at least 75% of the planned dose of 
daratumumab SC. 
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. 
8.4 
Dose Escalation Rules (Phase 1 Dose Escalation) 
The rolling six design (Skolnik et al. 2008) will be implemented to guide the dose 
escalation/de-escalation to evaluate the safety and tolerability of modakafusp alfa in combination 
with daratumumab SC. 
Rolling Six Design 
In the rolling six design, up to 6 patients may be concurrently enrolled into a given dose level. 
Dose levels will be assigned, as outlined below, on the basis of the number of patients currently 
enrolled in the cohort, the number of DLTs observed, and the number of patients whose 
evaluation is pending at the time of new patient entry. 
• Three to 6 patients may concurrently be enrolled in the study.  
• Accrual to the study may be suspended if there are already 6 patients enrolled at the current 
dose level but not sufficient information to make the decision for the next action.  
• Decisions as to whether to resume enrolling on the next dose level will be made using data 
available at the time of new patient enrollment. 


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– De-escalation will occur when 2 or more DLTs are observed at the current dose level 
regardless the number of patients enrolled. The current dose level will be considered 
toxic.  
– If no more than 1 DLT is observed at the next higher dose level, escalation will occur 
when 3 of 3, 4 of 4, 5 of 5, 5 of 6, or 6 of 6 patients are enrolled at the current dose level 
with no DLT observed. If at least 2 DLTs have been observed at the next higher dose 
level, no escalation is allowed.  
– In all other situations, patients will be enrolled and dosed at the current dose level up to a 
total of 6. 
The initial dose level to be evaluated for modakafusp alfa will be 80 mg Q4W (Section 4.3). If 
2 or more DLTs are observed at the starting dose level during the 28-day cycle, the dose for 
modakafusp alfa will be de-escalated to 60 mg Q4W. The modakafusp alfa 120 or 240 mg Q4W 
doses could be evaluated depending on the observed number of DLTs (observed in Cycle 1 of a 
28-day cycle) as well as pending data as illustrated in Table 8.a. Daratumumab SC dosing will be 
administered according to the daratumumab SC (4-week cycle) prescribing information 
(Darzalex Faspro (daratumumab and hyaluronidase-fihj) 2022). It is estimated that 
approximately 18 DLT-evaluable patients will be enrolled in the phase 1 dose escalation and at 
least 6 DLT-evaluable patients will be enrolled at the modakafusp alfa MTD in combination with 
daratumumab SC.  
The dose escalation/de-escalation will stop when (1) the decision for the next patient is to be 
dosed at the next higher dose level and the next higher dose level is considered toxic (ie, 
≥2 DLTs observed), or (2) the decision for the next patient is to be dosed at the next higher dose 
level and the current dose level is the highest dose level planned and 6 patients have already been 
evaluated, or (3) the decision for the next patient is to be dosed at the next lower dose level and 
6 patients have already been evaluated with the next lower dose level, or (4) the decision for the 
next patient is to be dosed at the next lower dose level and the current dose level is the lowest 
dose level planned.  
The MTD will be claimed as the highest dose level that has 6 evaluated patients with fewer than 
2 DLTs. 
Table 8.a 
Dose Escalation and De-escalation Rules 
No. Patients 
Enrolled at 
Current Dose 
No. DLTs 
No. 
Without 
DLT 
No. With 
Data 
Pending 
If MTD Not Exceeded a 
If MTD Exceeded b 
2 
0,1 
Any 
Any 
Stay 
Stay 
2 
2 
0 
0 
De-escalate 
De-escalate 
3 
0 
0, 1, 2 
3, 2, 1 
Stay 
Stay 
3 
0 
3 
0 
Escalate 
Stay 
3 
1 
0, 1 
2, 1 
Stay 
Stay 
3 
1 
2 
0 
Stay 
Stay 


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Table 8.a 
Dose Escalation and De-escalation Rules 
No. Patients 
Enrolled at 
Current Dose 
No. DLTs 
No. 
Without 
DLT 
No. With 
Data 
Pending 
If MTD Not Exceeded a 
If MTD Exceeded b 
3 
≥2 
Any 
Any 
De-escalate 
De-escalate 
4 
0 
0, 1, 2 
4, 3, 2 
Stay 
Stay 
4 
0 
3 
1 
Stay 
Stay 
4 
0 
4 
0 
Escalate 
Stay 
4 
1 
0, 1 
3, 2 
Stay 
Stay 
4 
1 
2 
1 
Stay 
Stay 
4 
1 
3 
1 
Stay 
Stay 
4 
≥2 
Any 
Any 
De-escalate 
De-escalate 
5 
0 
0, 1, 2 
5, 4, 3 
Stay 
Stay 
5 
0 
3, 4 
2, 1 
Stay 
Stay 
5 
0 
5 
0 
Escalate 
Stay 
5 
1 
0, 1 
4, 3 
Stay 
Stay 
5 
1 
2 
2 
Stay 
Stay 
5 
1 
3, 4 
1, 0 
Stay 
Stay 
5 
≥2 
Any 
Any 
De-escalate 
De-escalate 
6 
0 
0, 1, 2 
6, 5, 4 
Suspend c 
Suspend 
6 
0 
3, 4 
3, 2 
Suspend 
Suspend 
6 
0 
5, 6 
1, 0 
Escalate 
MTD 
6 
1 
0, 1 
5, 4 
Suspend 
Suspend 
6 
1 
2 
3 
Suspend 
Suspend 
6 
1 
3, 4 
2, 1 
Suspend 
Suspend 
6 
1 
5 
0 
Escalate 
MTD 
6 
≥2 
Any 
Any 
De-escalate 
De-escalate 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose. 
a MTD not exceeded: no more than 1 DLT is observed at any dose level.  
b MTD exceeded: 2 or more DLTs are observed at any dose level.  
c “Suspend” means that enrollment will halt until sufficient DLT data is available to determine the action for the 
next new patient. 
 
Additional patients are permissible to be enrolled if the stopping rule for dose 
escalation/de-escalation is not triggered after the last patient has been evaluated.  
More conservative dose escalation, evaluation of intermediate doses or different dosing intervals, 
and expansion of an existing dose level are all permissible after discussions between the sponsor 
and the investigators if such measures are needed for patient safety or for a better understanding 
of the dose-related toxicity, exposure, or PD of modakafusp alfa in combination with 
daratumumab SC. 


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8.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
8.6 
Dose Modification Guidelines 
8.6.1 
Modakafusp Alfa 
8.6.1.1 
Intrapatient Dose Escalation 
No intrapatient dose escalation is planned for this study. 
8.6.1.2 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
Treatment with modakafusp alfa will use a cycle length of 28 days. For a new cycle of treatment 
to begin, the patient must meet the following criteria: 
• ANC ≥1000/mm3. Granulocyte-colony stimulating factor can be used to reach this level. 
• Platelet count must be ≥50,000/mm3. Platelet transfusion can be applied any time clinically 
indicated but should not be applied only for the purpose of meeting the treatment criterion of 
platelet count.  
For therapy to resume, toxicity considered to be related to treatment with modakafusp alfa must 
have resolved to Grade ≤1 or baseline (Grade 2 for neutrophil and platelets), or to a level 
considered acceptable by the physician. If the above-cited criteria for retreatment are not met for 
a patient, 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. 


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8.6.1.3 
Criteria for Dose Interruption 
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients experiencing AEs attributed to modakafusp 
alfa may continue study treatment with the same dose, may have modakafusp alfa treatment held, 
may have their dose reduced, or may be permanently discontinued from the study. Patients who 
have study drug held because of treatment-related or possibly related AEs may resume study 
drug treatment after resolution of the AE at the same dose level or at a reduced dose, depending 
on the nature and severity of the AE and whether it is the first occurrence or is recurrent. 
Table 8.b and Table 8.c provide general dose modification recommendations for nonhematologic 
and hematologic toxicities, respectively. Table 8.d 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 on discussion with the sponsor. 
Table 8.b 
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.d for the management of bleeding TEAEs and Table 8.g and Table 8.h for the 
management of IRRs. 
Criteria 
Action 
Grade 1 and 2 AEs 
No dose reductions or interruptions. Treat according to local practice. 
Grade 3 AEs and asymptomatic 
Grade 4 laboratory AEs 
Hold modakafusp alfa next infusion until resolution to Grade ≤1 or 
baseline, and then resume treatment. 
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 (see 
Table 8.e). 
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.d or for 
the management of IRRs, which is found in Table 8.g, Table 8.h, and Section 8.10.1.1. 
 


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Table 8.c 
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.d for the management of bleeding TEAEs and Table 8.g and Table 8.h for the 
management of IRRs. 
Criteria 
Action 
Grade 1 and 2 AEs 
No dose reductions or interruptions. 
Grade 3 and 4 AEs 
Hold modakafusp alfa next infusion until resolution to Grade ≤2 then 
resume treatment. 
Consider growth factors and/or transfusion according to local practice 
when clinically indicated. Please refer to Section 8.6.1.2 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.d or for 
the management of IRRs, which is found in Table 8.g, Table 8.h, and Section 8.10.1.1. 
 
Table 8.d 
Dose Modification Recommendations for Modakafusp Alfa Bleeding 
TEAEs 
This table does not include guidance for management of IRRs. Refer to Table 8.g and Table 8.h 
for the management of IRRs. 
Criteria 
Action 
Grade 1 and 2 
No dose reductions or interruptions. Treat according to local practice. 
Grade 3 without associated Grade 4 
thrombocytopenia 
Hold next infusion of modakafusp alfa until resolution to Grade ≤1 or 
baseline, and then resume treatment. 
Subsequent occurrence: Discontinue modakafusp alfa. 
Grade 3 with associated Grade 4 
thrombocytopenia 
Discontinue modakafusp alfa. 
Grade 4 
Discontinue modakafusp alfa. 
IRR: infusion-related reaction; TEAE: treatment-emergent adverse event. 
This table does not include guidance for the management of IRRs, which is found in Table 8.g, Table 8.h, and 
Section 8.10.1.1 
 
8.6.1.4 
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.e). 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. 


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Table 8.e 
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 
NA 
60 mg 
NA: not applicable. 
8.6.1.5 
Criteria for Discontinuation 
In the dose escalation, 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. If treatment discontinuation is determined, 
the EOT visit should be completed within 30 days (+10 days) after the last administration of 
modakafusp alfa. 
Patients who discontinue modakafusp alfa because of TEAEs assessed by the investigator as 
related only to modakafusp alfa may continue daratumumab SC treatment at the discretion of the 
investigator and with agreement by the sponsor. 
8.6.2 
Combination Drug 
Dose modification, if any (dose change, interruption, discontinuation, etc.) of the combination 
drug (daratumumab SC) should be done in accordance with the 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 
Prohibited Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
• Radiation therapy for disease under study. Local radiotherapy for bone pain is permitted after 
agreement with the sponsor and once progressive disease 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. 
• 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 


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management, suspected or confirmed immune-mediated thrombocytopenia, or if tumor flare 
is suspected. 
• Live vaccines are not recommended. 
8.8 
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, granulocyte 
macrophage-colony stimulating factor) and erythropoietin are permitted. Their use should 
follow the product label, published guidelines, and institutional practice. Granulocyte colony 
stimulating factor is allowed to accelerate the recovery of neutropenia to enable the start of a 
new cycle (Section 8.6.1.2). 
• 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 monoclonal antibodies like denosumab will 
be encouraged for all patients with evidence of lytic destruction of bone or with osteopenia, 
according to the American Society of Clinical Oncology Clinical Practice Guidelines or 
institutional practice in accordance with the product label, unless specifically contraindicated. 
If bisphosphonate therapy was not started before the study start, it should be initiated as soon 
as clinically indicated. 
• Topical or inhaled steroids (eg, for the treatment of asthma) are permitted. 
• Systemic steroids for acute management of pain, suspected or confirmed immune-mediated 
thrombocytopenia or other disease or treatment-related complications are permitted. 
• Plasmapheresis. 
• IV immunoglobulins 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. 


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8.9 
Precautions and Restrictions 
8.9.1 
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 and should not donate sperm or ova. Patients of reproductive 
potential should use effective methods of contraception through defined periods during and after 
study treatment as specified below. 
Reproductively female patients 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.f) at the same time, from 
the time of signing of the ICF through 3 months after the last dose of daratumumab SC, or 
7 days after the last dose of modakafusp alfa, whichever is longer, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient during the entire study treatment period and through 3 months after the last dose 
of daratumumab SC, or 7 days after the last dose of modakafusp alfa, 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 an egg or eggs (ova) or breastfeed a baby during the study through 
3 months after the last dose of daratumumab SC or 7 days after the last dose of modakafusp 
alfa, whichever is longer. 
• Must also adhere to any applicable local (country-specified) treatment-specific pregnancy 
prevention guidelines. 
Reproductively male patients, unless surgically sterilized (ie, status postvasectomy), must agree 
to 1 of the following: 
• Agree to practice effective barrier contraception (see Table 8.f) during the entire study 
treatment period and through 7 days after the last dose of modakafusp alfa, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient during the entire study treatment period and through 7 days after the last dose of 
modakafusp alfa. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
• Agree not to donate sperm during the study and for 7 days after the last dose of modakafusp 
alfa 


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• Must also adhere to any applicable local (country-specified) treatment-specific pregnancy 
prevention guidelines. 
Table 8.f 
Highly Effective Methods of Contraception 
Highly Effective Methods 
Additional Effective (Barrier) Methods 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Male or female condom with or without spermicide 
(female and male condoms should not be used 
together) 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• 
Oral 
• 
Injectable 
• 
Implantable 
Intrauterine device 
Cap, diaphragm, or sponge with spermicide 
Intrauterine hormone-releasing system 
Bilateral tubal occlusion 
Vasectomized partner 
Sexual abstinence 
8.9.2 
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, after authorization from the study 
participant’s partner.  
If a participant or a study participant’s partner 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 up 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. 
8.10 
Management of Clinical Events 
If dose alterations are necessary as a result of the events detailed below, 
 
 


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8.10.1 
Modakafusp Alfa 
8.10.1.1 
IRRs 
An IRR is a reaction that develops during or shortly after administration of a drug, and with 
modakafusp, an IRR can occur during any cycle. 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 8.1.1.3). Recommendations for premedications for the 
combination agent daratumumab SC are detailed in Section 8.1.2.3. On days on which the 
combination agent is administered 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. 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) 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. 
If the patient continues on treatment, premedication and postinfusion medication should be 
considered for future modakafusp alfa administrations per Section 8.1.1. 
All IRRs, including the signs and symptoms, will be reported in the eCRF per completion 
guidelines.  
Serious AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner 
within 24 hours. 
Grade 1 and 2 IRRs 
The recommendations for managing Grade 1 and Grade 2 IRRs are presented in Table 8.g. 


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Table 8.g 
Recommendations for Managing Grade 1 and Grade 2 IRRs 
IRR 
Action 
Grade 1 or 2 
The infusion should be paused. When the patient’s condition is stable, 
infusion may be restarted at the investigator’s discretion. 
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 event of laryngeal edema, or 
Grade 2 event of bronchospasm that 
does not respond to systemic therapy.  
Patient must be withdrawn from treatment if the event does not resolve 
within 6 hours from onset. 
IRR: infusion-related reaction. 
Grade 3 or Higher IRRs 
The recommendations for managing Grade ≥3 IRRs are presented in Table 8.h. 
Table 8.h 
Recommendations for Managing Grade ≥3 IRRs 
IRR 
Action 
Any Grade 4 event: 
Patient must be withdrawn from treatment. 
Grade 3 bronchospasm or laryngeal edema: 
Patient must be withdrawn from treatment. 
Grade 3 event other than bronchospasm or laryngeal 
edema: 
Infusion must be stopped, and the patient must be 
observed carefully until resolution of the IRR. 
If the intensity of the IRR remains at Grade 3 after 
2 hours: 
Patient must be withdrawn from treatment. 
If the intensity of the IRR decreases to Grades 1 or 2: 
Infusion may be restarted at the investigator’s 
discretion. Within 2 hours of restart, the infusion rate 
should be half of that employed before the interruption. 
Subsequently, the infusion rate may be increased at the 
investigator’s discretion. 
If the intensity of the IRR returns to Grade 3: 
The procedure described above may be repeated after 
restart of the infusion at the investigator’s discretion. 
If the intensity of the IRR increases to Grade 3 for a 
third time: 
Patient must be withdrawn from treatment. 
IRR: infusion-related reaction.  
8.10.1.2 
Low Platelet Count 
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.d. The investigator can consider the usage of 


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corticosteroids, IV immunoglobulins 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. 
8.10.1.3 
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. Please also see Sections 8.1.1.5 and 8.1.2.5. 
8.10.2 
Combination Agent 
Please refer to the product labels for daratumumab SC (Darzalex Faspro (daratumumab and 
hyaluronidase-fihj) 2022) 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.  
8.11 
Blinding and Unblinding 
This is an open-label study.  
8.12 
Description of Investigational Agents 
Modakafusp alfa and the combination agent daratumumab SC are described in Sections 4.1.2 and 
4.1.3.1. Further details on modakafusp alfa may be found in the IB. 
8.13 
Preparation, Reconstitution, and Dispensation 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration whenever solution and container permit. 
Modakafusp alfa is an anticancer agent, and as with other potentially toxic compounds, caution 
should be exercised when handling modakafusp alfa. 
Please refer to the pharmacy manual for the preparation of each dose of modakafusp alfa. 
Please refer to the respective package insert for the preparation of daratumumab SC. 
8.14 
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. 
Modakafusp alfa is supplied as sterile, lyophilized powder in a single-use, 20R stoppered glass 
vial with an aluminum flip-off seal, on reconstitution providing 10 mg/mL (50 mg) of 
modakafusp alfa. 


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Details for daratumumab SC and other comparator agents are provided in the respective package 
insert for each agent. 
8.15 
Storage, Handling, and Accountability 
8.15.1 
Modakafusp Alfa 
Modakafusp alfa must be stored according to the manufacturer’s stipulation in a dry place and at 
temperature as stated on the product labeling. 
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 
before the use of modakafusp alfa. 
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 the 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) location 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. 
If there is a discrepancy in product storage or handling between the protocol and other protocol 
related documentation, the product label shall supersede. 
Further guidance and information are provided in the pharmacy manual. 
8.15.2 
Combination Agent  
The combination agent (daratumumab SC) should be stored at temperatures in accordance with 
the instructions provided in the manufacturer’s product label and information in the pharmacy 
manual. Additional details are provided in the respective package insert for each agent.  
If there is a discrepancy in product storage or handling between the protocol and other protocol 
related documentation, the product label or commercial package (as applicable) shall supersede. 


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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 may be found in the study manual. 
A full list of investigators is available in Takeda’s investigator database. 
For 24-hour contact information, please refer to the study manual or equivalent. 
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 institutional review board (IRB)/ 
independent ethics committee (IEC). 
9.3 
Informed (e)Consent 
Each patient must provide written or electronic informed consent before any protocol-directed 
procedures are conducted, unless those procedures are performed as part of the patient’s standard 
care. 
Patients consenting electronically (eConsent), where 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. 
The requirements of informed consent are described in Section 15.2. 
9.4 
Treatment Group Assignments 
During the phase 1 dose escalation, patients will be enrolled according to a rolling six design 
(see Section 8.4). During the phase 2a dose finding, patients will be randomized in a 1:1 ratio to 
treatment across 2 dose levels of modakafusp alfa in combination with daratumumab SC. 
Randomization will be stratified (see Section 6.1).  
In phase 2a, the window allowed between randomization to Cycle 1 Day 1 dosing is 3 days.  
9.5 
Study Procedures 
Refer to the SOEs (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow. 


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9.5.1 
Patient Demographics 
The date of birth or age, race, ethnicity, and sex of the patient are to be recorded during 
screening as permitted by local regulations. 
9.5.2 
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 the Revised International 
Staging System. Known cytogenetic alterations should be also collected. 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. 
9.5.3 
Physical Examination 
A physical examination will be completed per standard of care at the times specified in the SOEs 
(Appendix A). 
If an investigator considers it safe and appropriate for a subject to miss a protocol-specified 
physical examination for coronavirus disease 2019 (COVID-19)-related reasons, the study site 
physician or other qualified site staff will speak directly with the subject by telephone or other 
medium (eg, a computer-based video communication) to assess subject safety and overall 
clinical status with a plan for in-person evaluation if signs and symptoms warrant. Such instances 
will be documented in the study records and eCRF if applicable, and the sponsor will be 
informed. 
9.5.4 
Patient Height and Weight 
Height will be measured during the screening visit only. Weight will be measured at the times 
specified in in the SOEs (Appendix A). 
9.5.5 
Vital Signs 
Vital signs include temperature, pulse, respiratory rate, oxygen saturation, and blood pressure. 
They include also supine or seated measurements of diastolic and systolic blood pressure (after 
3 to 5 minutes in this position; all measurements should be performed in the same initial 
position). They will be measured at the times specified in in the SOEs (Appendix A). Vital signs 
will be measured at any time a patient complains of symptoms consistent with IRR or clinically 
indicated. If the patient experiences hypotension (with or without symptoms), intensive blood 
pressure monitoring according to local practice should be instituted. The patient cannot be 
released from the site until blood pressure has returned to Grade 1 or baseline for at least 1 hour. 
Patients must be observed for at least 2 hours after the end of the infusion of modakafusp alfa in 
each cycle when modakafusp is administered.  


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Any vital sign value that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the eCRF as an AE and monitored as described in 
Section 10.2. 
9.5.6 
Pregnancy Test 
Participants of childbearing potential must have 2 negative pregnancy tests before starting study 
drug. A urine or serum pregnancy test will be required during screening and at baseline (within 
72 hours before the start of study drug). A participant of childbearing potential is defined as a 
reproductive female who (1) has not undergone a hysterectomy or bilateral oophorectomy or 
(2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule 
out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in 
the preceding 24 consecutive months). 
During the study, participants of childbearing potential must have a negative urine or serum 
pregnancy test result within 72 hours before dosing on Day 1 of each cycle during treatment 
before dosing. Pregnancy tests may also be repeated during the study per request of the IRB or if 
required by local regulations.  
At EOT, a urine or serum pregnancy test is required in participants of childbearing potential. 
9.5.7 
Concomitant Medications and Procedures 
Any prior or concomitant medication a patient has had from signing of the ICF through 
30 (+10) days after the last dose of study drug treatment (modakafusp alfa and/or daratumumab 
SC) or the start of subsequent systemic anticancer therapy, whichever occurs first, will be 
recorded on the eCRF. Trade name and international nonproprietary name (if available), 
indication, and start and end dates of the administered medication will be recorded. Medications 
used by the patient and therapeutic procedures (including any transfusion) completed by the 
patient will be recorded in the eCRF. See Sections 8.7 and 8.8 regarding medications and 
therapies that are prohibited or allowed, respectively, during the study. 
9.5.8 
ECOG Performance Status 
ECOG performance status (Appendix F) will be evaluated and recorded as specified in the SOEs 
(Appendix A). 
9.5.9 
AEs 
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in the SOEs (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of AEs and SAEs. 
9.5.10 
Enrollment 
Procedures for completing enrollment information are described in the study manual. 


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Rescreening is permitted if deemed appropriate by the investigator upon consultation with the 
sponsor when a patient might meet all the eligibility criteria with the cause(s) of previous 
screening failure being resolved.  
9.5.11 
ECG 
A 12-lead ECG will be obtained 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. 
9.5.12 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally. 
In extenuating circumstances, such as during the COVID-19 public health emergency, 
laboratories closer to a patient’s home may be used for local clinical laboratory assessments 
provided that pertinent laboratory information, including normal reference ranges, are provided 
to the sponsor or designee. 
9.5.12.1 
Clinical Chemistry, Hematology, Urinalysis and Indirect Antiglobulin Test (Coombs 
Test) 
Blood samples will be obtained for analysis of clinical chemistry, hematology, and urinalysis as 
shown in Table 9.a, Table 9.b, and Table 9.c, respectively. Samples will be obtained at time 
points as specified in the SOEs (Appendix A).  
Table 9.a 
Clinical Chemistry 
Albumin 
Standard C-reactive protein 
Alkaline phosphatase 
Chloride 
Alanine aminotransferase 
Glucose (nonfasting) 
Aspartate aminotransferase 
Lactate dehydrogenase 
Bilirubin (total) 
Magnesium 
Blood urea nitrogen 
Phosphate 
Calcium 
Potassium 
Bicarbonate (HCO3-) or carbon dioxide (CO2) 
Sodium 
Creatinine 
Urate 
 
If creatinine clearance is to be estimated, the Cockcroft-Gault formula will be used as follows: 


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Estimated creatinine clearance 
= [(140-Age) * weight(kg)] / [72 * serum creatinine(mg/dL)] 
For female patients, the result of the formula above should be multiplied by 0.85. 
Table 9.b 
Hematology Tests 
Hematocrit 
Leukocytes with differential a 
Hemoglobin 
Neutrophils (ANC) 
Platelet count 
 
ANC: absolute neutrophil count. 
a Differential to include basophils, eosinophils, lymphocytes, monocytes, and neutrophils. 
Table 9.c 
Urinalysis 
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 clinical laboratory tests are outlined in Table 9.d. 
Table 9.d 
Other Laboratory Tests 
Serum β2 microglobulin 
Blood type, Rh factor and indirect antiglobulin 
test (indirect Coombs test) 
Thyroid function test (TSH, T4, T3) 
Hepatitis B serology 
HBV DNA test 
 
HBV: hepatitis B virus; Rh: Rhesus; T3: triiodothyronine; T4: thyroxine; TSH: thyroid stimulating 
hormone/thyrotropin. 
9.5.13 
Disease Assessment 
Unless otherwise specified as detailed in the SOEs (Appendix A), response assessment for 
phase 1 dose escalation and phase 2a dose finding will be made locally. Disease assessment will 
be conducted per the SOEs (Appendix A) and evaluated according to IMWG criteria 
(Appendix E).  
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. 
Serum and urine response assessments will be performed as indicated in the SOE (Appendix A).  


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Imaging tests for qualifying patients are to be performed every 12 weeks beginning with Cycle 3 
only for patients with extramedullary disease at screening or when there is a clinical suspicion of 
extramedullary progression. Investigators will assess disease response/status. Response and 
relapse categories are described in Appendix E.  
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 (locally) is required to document a CR; no second bone marrow 
confirmation is needed. At the time of collecting BMA samples to confirm CR locally, a BMA 
sample will be also collected for central analysis of MRD as the first pull. 
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.  
The disease assessments outlined in the following sections will be performed as shown in the 
SOEs (Appendix A). 
9.5.13.1 
Extramedullary Disease Imaging 
Imaging will be evaluated locally for all patients. For patients with previously documented 
extramedullary disease or with suspicion of extramedullary progression, a positron emission 
tomography-computed tomography (PET-CT) scan, computed tomography (CT) scan, or 
magnetic resonance imaging (MRI) scan will be performed at screening (if the patient has 
adequate image test performed within 5 weeks of the planned first dose of study drug, they can 
be used as baseline and do not need to be repeated as part of screening) as needed for evaluation 
of disease. If extramedullary disease is documented at screening, 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 (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 progressive disease. 
All follow-up scans should use the same imaging modality as used at screening. 
9.5.13.2 
Bone Imaging 
Imaging will be evaluated locally for all patients. Whole body bone imaging will be performed at 
screening (if the patient has adequate image test performed within 5 weeks of the planned first 
dose of study drug, they can be used as baseline and do not need to be repeated as part of 
screening). Whole body bone imaging can be done using either low-dose total body CT scan or 
whole body MRI or PET-CT (Hillengass et al. 2019). A conventional skeletal survey should only 
be done if other imaging modalities are not available. If there are symptoms or signs that suggest 
increased or new bone lesions, either whole body bone imaging or localized imaging of 
symptomatic sites may be repeated any time during the study and at the EOT visit. The same 
modality for assessment should be used throughout the study. 


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Patients with no bone disease, or only bone disease at baseline, do not need to repeat imaging 
periodically unless clinically indicated. 
Radiographs will be analyzed locally and reports maintained with the patient record for retrieval 
during monitoring visits. 
9.5.13.3 
Quantification of Immunoglobulins 
A blood sample for quantification of immunoglobulins (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 immunoglobulins (in addition to quantitative IgM, IgG, and 
IgA). Analysis of immunoglobulins will be performed locally. 
9.5.13.4 
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).  
M-protein in serum and urine will be quantified by SPEP and UPEP, respectively. These samples 
will be tested locally. 
9.5.13.5 
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. 
9.5.13.6 
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 testing will be performed locally. 
9.5.13.7 
Interference Assay 
IgG mAbs given recently as prior therapy can interfere with assays used to monitor endogenous 
M-protein. The SPEP and serum immunofixation can be positive due to mAb. This interference 
can impact the determination of CR and of disease progression in some patients with IgG 
myeloma protein. Therefore, in patients with persistent VGPR by IMWG criteria where mAb 
interference is suspected or whenever the SPEP values reach ≤0.2 g/dL for 2 consecutive disease 
evaluations during a period of time when the mAb could be circulating at detectable levels, a CR 
should be suspected triggering the need for interference testing on the M-protein sample at the 
central laboratory. Currently, if the interference test results are positive, the assay is considered 
positive for endogenous protein, and thus there is still disease present. If the interference test 
result is negative, the assay is considered negative for endogenous protein, and thus the 
remaining protein is likely the mAb. This is communicated back to the sites, and the sites can 
proceed to perform a confirmatory BMA evaluation for possible CR if not already performed 
earlier. 


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9.5.13.8 
Bone Marrow Aspirate 
Bone marrow samples will be collected as specified in Appendix A.  
9.5.13.9 
Local Laboratory Evaluations 
9.5.13.9.1 
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 progressive disease 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 E).  
9.5.13.9.2 
Cytogenetics 
The most recent cytogenetic results from samples taken between diagnosis and before study 
enrollment will be requested as part of medical history of the patients. The historical cytogenetic 
evaluation should have been analyzed locally, according to local standards, if the site has the 
capability to perform analysis using methodologies such as fluorescence in situ hybridization 
and/or conventional cytogenetics (karyotype).  
All patients should also have a sample from screening sent for central analysis (BMA for 
cytogenetics). 
9.5.13.10 Central Laboratory Evaluations 
BMA for MRD 
For all patients, a BMA for MRD sample to determine rate and duration of MRD negativity 
should be collected at screening at the same time as the BMA and biopsy procedure is performed 
for local disease assessment purposes. Additionally, when a CR is suspected based on laboratory 
values, per routine clinical practice (Appendix E), a BMA should be drawn for local disease 
assessment and central analysis of MRD. Additionally for patients with a confirmed CR, BMAs 
for MRD should be collected at 6, 12, and 24 months following CR confirmation. 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. These 
evaluations will be performed at a central laboratory. 
BMA for Cytogenetics 
During the screening period, an additional 3 mL pull of bone marrow (fresh BMA) will be 
collected, on completion of the BMA for MRD sample collection, to centrally analyze a broad 
spectrum of cytogenetic abnormalities and 
, perform immunoprofiling, 
 
, and plasma biomarker evaluation. Where country guidelines and/or 
regulations prohibit genomic analysis, a fluorescent in-situ hybridization will be used to evaluate 


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cytogenetic abnormalities and remaining biomarker assessments limited to immunoprofiling and 
plasma analysis. 
  
 
 
 
 
 
  
 
 
9.5.14 
Biomarker, PD, and PK Samples 
9.5.14.1 
Primary Specimen Collection 
Table 9.e summarizes primary specimen collection for the study. 
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 
(Appendix B) and biomarker assessments. Bone marrow biopsy and aspirate collections are 
specified in the SOE (Appendix A). 
Details on sample handling, storage, shipment, and analysis are provided in the laboratory 
manual. 


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Table 9.e 
Primary Specimen Collection 
Specimen Name 
Primary 
Specimen 
Primary Specimen 
Derivative 
Description of 
Intended Use 
Sample 
Collection 
Serum sample for 
modakafusp alfa PK 
Blood 
Serum 
Modakafusp alfa 
concentrations 
Mandatory a 
Serum sample for 
daratumumab PK 
Blood 
Serum 
Daratumumab 
concentrations 
Mandatory a 
BMA for MRD 
BMA 
DNA 
Biomarker 
measurements 
Mandatory a 
BMA for cytogenetics 
BMA 
DNA, RNA, plasma 
and immune cells 
Biomarker 
measurements 
Mandatory a 
Serum sample for 
immunogenicity 
Blood 
Serum 
Immunogenicity 
measurement (ADA 
and NAb)  
Mandatory  
Blood sample for flow 
cytometry 
Blood 
N/A 
Biomarker 
measurements 
Mandatory  
Serum sample for 
circulating biomarkers 
Blood 
Serum 
Biomarker 
measurements 
Mandatory  
Blood sample for RNA 
Blood 
RNA 
Biomarker 
measurements 
Mandatory a 
ADA: antidrug antibody; BMA: bone marrow aspirate; MRD: measurable (minimal) residual disease; NAb: 
neutralizing antibody; PK: pharmacokinetics. 
a Mandatory unless local regulations prohibit. 
9.5.14.2 
PK Sampling 
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 B. 
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 and/or daratumumab. 
9.5.14.3 
 
9.5.14.3.1 
 
 
 


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9.5.14.3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.15 
  
 
 
 
 


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9.5.16 
Immunogenicity Sample Collection 
Serum samples prepared from blood for assessment of immunogenicity will be collected at time 
points specified in the SOE (Appendix A) and as outlined in the laboratory manual. Samples 
must be collected before either 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 8.10.1.1). Samples confirmed ADA positive against modakafusp 
alfa will be assayed for the ADA titer and domain specificity characterization as well as their 
neutralizing ability. If serum PK samples from the modakafusp alfa in combination with 
daratumumab SC indicate a loss of detectible daratumumab PK, ADA against daratumumab may 
be evaluated as sample volume supports. 
 
. These samples will be 
analyzed at a central laboratory (Appendix A). 
9.6 
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 9.8. 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. 
9.7 
Completion of Study (for Individual Patients) 
Patients will be considered to have completed the study if they withdrew from the study for any 
reason outlined in Section 9.9. 
9.8 
Discontinuation of Treatment With Study Drug and Patient Replacement 
Study drug must be permanently discontinued for patients meeting any of the following criteria: 
• Patient experiences an AE or other medical condition that indicates to the investigator that 
continued participation is not in the best interest of the patient. 


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Treatment with study drug may also be discontinued for any of the following reasons: 
• AE. 
• Protocol deviation. 
• Progressive disease. 
• Symptomatic deterioration. 
• Confirmed pregnancy. 
• Study terminated by sponsor. 
• Withdrawal by patient. 
• Lost to follow-up. 
• Other. 
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF. 
In the case of study termination by the sponsor, eligible patients may have continued access to 
modakafusp alfa as described in Section 6.5. 
Only patients who are withdrawn from treatment during Cycle 1 during the safety lead-in for 
reasons other than DLT will be replaced. 
Note that some patients may discontinue study drug for reasons other than progressive disease 
before completing the full treatment course; these patients will remain in the study for 
posttreatment assessments as outlined in the SOE (Appendix A) until progressive disease occurs. 
9.9 
Withdrawal of Patients From Study 
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. 
• Transfer of patient to a long-term safety study, single-patient investigational new drug 
application, or similar program. 
• Death. 
• Other. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 


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9.10 
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. 
9.11 
Posttreatment Follow-up Assessments (PFS and OS) 
Patients who stop treatment for any reason other than progressive disease will continue to have 
PFS visits. The PFS visits should occur every 4 weeks from the EOT until the occurrence of 
progression, death, the start of subsequent systemic antineoplastic therapy, study termination, 
whichever occurs first. OS follow-up continues every 12 weeks until death, study termination, or 
patient withdrawal. Imaging tests for patients with extramedullary disease should be performed 
every 12 weeks or if new symptoms suggest progressive disease.  
See the SOE (Appendix A) for appropriate assessments during follow-up. 
NOTE: Treatment-related SAEs must be reported to the Global Pharmacovigilance department 
or designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.  


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient who has provided 
informed (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 
AESI 
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 Takeda are provided in Section 10.2. 
10.1.4 
SAE Definition 
SAE means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 


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• 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 
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 laboratory 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_Referen
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 Recording and Reporting 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 (see Section 10.3 for the period of observation) 
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 electronic data 
capture (EDC) SAE report. If transmission of an EDC SAE report is not feasible, then 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 Study Manual. 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 


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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. 
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 study manual. 
Relationship of the event to study drug administration (ie, its causality) will be determined by 
the investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug? 
10.3 
Monitoring of AEs and Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
• AEs will be reported from the signing of informed (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).  
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. 


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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 study manual. 
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 study manual. 
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, including the European 
Medicines Agency, investigators, and IRBs and IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as expedited reports within 7 days for fatal and life-threatening events 
and within 15 days for other serious events, unless otherwise required by national regulations. 
The sponsor will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal product’s administration 
or in the overall conduct of the study. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
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 
Medical Dictionary for Regulatory Activities. Drugs will be coded using the World Health 
Organization Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each patient who signs an informed (e)consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, contract 
research organization partners, 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 designee) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for the change.  
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or 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 those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated informed (e)consent forms, patient authorization forms 
regarding the use of personal health information (if separate from the ICFs), electronic copies of 


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eCRFs including the audit trail, and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities and the sponsor (or designees), and telemedicine records. Any 
source documentation printed on degradable thermal-sensitive paper should be photocopied by 
the site and filed with the original in the patient’s chart to ensure long-term legibility. 
Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain essential documents 
specified in ICH E6 (Section 8) until at least 2 years after the last approval of a marketing 
application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained 
until an amount of time specified by applicable regulatory requirements or for a time specified in 
the clinical study site agreement between the investigator and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
The investigator and the head of the institution are required to retain essential relevant 
documents until the later of:  
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after 
the date of notification that investigation was discontinued.) 
2. The day 3 years after the date of early termination or completion of the study. 
Should the sponsor request a longer retention period, the head of the institution should discuss 
how long and how to retain those documents with the sponsor. In addition, the investigator and 
the head of the institution should retain the essential relevant documents until the receipt of a 
sponsor-issued notification to state the retention is no longer required.  
When proceeding to a local post-marketing study, the investigator and the head of the institution 
are required to retain essential relevant documents until the later of the end of the re-examination 
or re-evaluation. However, if the sponsor requests a longer time period for retention, the head of 
the institution should discuss how long and how to retain those documents with the sponsor. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
In general, summary tabulations will be presented by dose level for the phase 1 dose escalation 
and phase 2a dose finding, and will display the number of observations, mean, standard 
deviation, median, minimum, and maximum for continuous data, and the number and percentage 
per category for categorical data. The Kaplan-Meier (K-M) survival curves and 25th, 50th 
(median), and 75th percentiles (if estimable) will be provided along with their 95% CIs for 
time-to-event data. 
Deviations from the statistical analyses outlined in this protocol will be indicated in the statistical 
analysis plan; any further modifications will be noted in the final clinical study report. 
13.1.1 
Analysis Sets 
The populations used for analyses will include the following: 
• DLT-evaluable population: The DLT-evaluable population will include patients from the 
phase 1 dose escalation who experienced a DLT in Cycle 1 in the treatment phase of the 
study or have completed the Cycle 1 dose of modakafusp alfa and at least 75% of the planned 
dose of daratumumab SC. The DLT-evaluable population will be used to inform the 2 dose 
levels for modakafusp alfa to be selected in the phase 2a dose finding in combination with 
daratumumab SC. 
• Safety population: The safety population is defined as all patients (phase 1 dose escalation 
and phase 2a dose finding) who receive at least 1 dose, even an incomplete dose, of any 
study drug. Patients will be analyzed according to the actual treatment they received for the 
safety population.  
• Intent-to-treat (ITT) population: The ITT population is defined as all patients in the phase 
2a dose finding who are randomized. Patients in this population will be analyzed according 
to the treatment they were randomized to receive, regardless of any dosing errors. 
• Per protocol population: The per protocol population is a subset of the safety population 
that includes subjects who do not have major protocol deviations that are considered to have 
an effect on efficacy outcomes. The list of major protocol deviations is maintained by the 
sponsor on an ongoing basis and will be finalized before the primary analysis of the study. 
• Response-evaluable population: The response-evaluable population is defined as patients 
who receive at least 1 dose, even an incomplete dose, of any study drug, have a disease 
assessment at screening (baseline evaluation), and at least 1 postbaseline disease assessment. 
• PK-evaluable population: The PK-evaluable population includes patients from the safety 
population with sufficient PK data to reliably report 1 or more PK parameters. 
• Immunogenicity-evaluable population: The immunogenicity-evaluable population includes 
patients who received at least 1 dose of modakafusp alfa in combination with daratumumab 


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SC (partial or complete) with a baseline assessment and at least 1 postbaseline 
immunogenicity assessment. 
13.1.2 
Analysis of Demographics 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, 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. No inferential statistics will be carried out. 
13.1.3 
Efficacy Analysis 
All available efficacy data will be included in data tabulations. Data that are potentially spurious 
or erroneous will be examined according to standard data management operating procedures. In 
general, missing data will be treated as missing, and no data imputation will be applied, unless 
otherwise specified. 
Disease responses are assessed by the investigator per IMWG criteria, unless otherwise stated.  
13.1.3.1 
Analysis of Primary Efficacy Endpoint 
ORR 
ORR is defined as the proportion of patients who achieved a confirmed PR or better during the 
study. The analysis will be based on the safety population for the phase 2a dose finding with 
responses assessed by the investigator per IMWG criteria. ORR proportions and associated 
2-sided 95% exact binomial CIs will be presented for each treatment arm. No formal statistical 
test will be performed to compare the 2 treatment arms.  
Sensitivity analyses for ORR include, but not limited to: 
1. ORR assessed by investigator will be analyzed using the ITT population. 
2. ORR assessed by investigator will be analyzed using the per protocol population.  
13.1.3.2 
Analysis of Secondary Efficacy Endpoints 
13.1.3.2.1 
Phase 1 Dose Escalation 
For the phase 1 dose escalation, secondary efficacy endpoints include ORR, DOR, PFS, OS, 
MRD[-] CR rate, MRD[-] rate, and duration of MRD negativity. 
All disease responses are assessed by the investigator per IMWG criteria.  
ORR, MRD[-] CR Rate and MRD[-] Rate 
ORR is defined in Section 13.1.3.1. The analysis will be based on the response-evaluable 
population.  


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MRD[-] CR rate is defined as the proportion of patients who have achieved confirmed CR 
assessed by the investigator and MRD[-] status using a threshold of 10-5. The analysis will be 
based on the response-evaluable population. 
MRD[-] rate is defined as the proportion of patients who have achieved MRD[-] status using a 
threshold of 10-5. The analysis will be based on the response-evaluable population. 
All these endpoints will be summarized by mean proportions and 2-sided 95% exact binomial 
CIs for each dose level.  
DOR, PFS, OS, and Duration of MRD Negativity 
DOR is defined as the time from the date of first documentation of a confirmed PR or better to 
the date of first documentation of confirmed progressive disease or death due to any cause, 
whichever occurs first. DOR will be calculated for confirmed responders only (PR or better). 
Responders without documentation of confirmed progressive disease or death will be censored at 
the date of last adequate disease assessment.  
PFS is defined as the time from the date of the first dose administration of any study drug to the 
first documentation of confirmed progressive disease or death due to any cause, whichever 
occurs first. Patients without documentation of confirmed progressive disease or death will be 
censored at the date of last adequate disease assessment. The analysis will be based on the safety 
population. 
OS is defined as the time from the date of the first dose administration of any study drug to the 
documentation 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. The analysis will be based on the 
safety population. 
Duration of MRD negativity for patients achieving MRD negativity is defined as the time from 
the date of first documentation of MRD negativity to the first documentation of MRD positivity 
or confirmed progressive disease, whichever occurs first. It will be calculated for patients 
achieving MRD negativity only. Patients without documentation of MRD positivity or confirmed 
progressive disease will be censored at the date last known to be MRD negativity. 
For these endpoints, K-M survival curves and K-M medians (if estimable), together with 95% 
CIs, may be calculated if appropriate.  
13.1.3.2.2 
Phase 2a Dose Finding 
Secondary efficacy endpoints include DOR, CBR, DCB, DCR, duration of disease control, TTP, 
TTR, TTNT, PFS, OS, MRD[-] CR rate, MRD[-] rate, and duration of MRD negativity for 
patients achieving MRD negativity.  
All disease responses are assessed by the investigator per IMWG criteria.  
CBR, DCR, MRD[-] CR Rate, and MRD[-] Rate 
CBR is defined as the proportion of patients who had a confirmed response of sCR, CR, VGPR, 
PR, or minimal response based on investigators’ disease assessment per IMWG criteria.  


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DCR is defined as the proportion of patients with a confirmed response of sCR, CR, VGPR, PR, 
minimal response, or SD based on investigators’ disease assessment per IMWG criteria.  
MRD[-] CR rate is defined in Section 13.1.3.2.1.  
MRD[-] rate is defined in Section 13.1.3.2.1. 
CBR, DCR, MRD[-] CR rate, and MRD[-] rate as well as associated 95% exact binomial CIs 
will be presented for each treatment arm. These analyses will be based on the safety population. 
DOR, DCB, Duration of Disease Control, TTP, TTNT, PFS, OS, and Duration of MRD 
Negativity for Patients Achieving MRD Negativity 
DOR and duration of MRD negativity are defined in Section 13.1.3.2.1.  
DCB is defined as the time from the date of first documentation of a minimal response or better 
to the date of first documentation of confirmed progressive disease or death due to any cause, 
whichever occurs first. DCB will be calculated for only patients who achieved a minimal 
response or better. Patients without documentation of confirmed progressive disease or death 
will be censored at the date of last adequate disease assessment. 
Duration of disease control is defined as the time from date of first documentation of SD or 
better to the date of first documentation of confirmed progressive disease or death due to any 
cause. Duration of disease control will be calculated for only patients who achieved SD or better. 
Patients without documentation of confirmed progressive disease or death will be censored at the 
date of last adequate disease assessment.  
TTP is defined as the time from the date of randomization to the first documentation of 
confirmed progressive disease as defined by IMWG criteria. Patients without documentation of 
confirmed progression will be censored at the date of last adequate disease assessment. The 
analysis will be based on the ITT population. 
TTNT is defined as the time from the date of first dose administration of any study drug to the 
date of the first dose initiation of the next line of anticancer therapy for any reason or death from 
any cause, whichever comes first. Patients who have not started the next-line therapy will be 
censored at the date last known to be alive before subsequent anticancer therapy. The analysis 
will be based on the safety population. 
PFS is defined as the time from the date of randomization to the first documentation of 
confirmed progressive disease or death due to any cause, whichever occurs first. Patients without 
documentation of confirmed progressive disease or death will be censored at the date of last 
adequate disease assessment. The analysis will be based on the ITT population. 
OS is defined as the time from the date of randomization to the documentation 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. The analysis will be based on the ITT population.  
Disease responses are assessed by the investigator per IMWG criteria. K-M survival curves and 
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TTR 
TTR is defined as time from the date of first dose administration of any study drug to the date of 
the first documentation of a confirmed PR or better. TTR will be calculated for responders only 
and summarized as a continuous variable. Mean TTR as well as associated 95% CI for each arm 
will be presented.  
13.1.4 
PK Analysis 
The PK data collected in this study are intended to contribute to future population PK analyses of 
modakafusp alfa and daratumumab SC. These population PK analyses may include data 
collected in other modakafusp alfa clinical single or combination studies. The analysis plan for 
the population PK analysis will be separately defined, and the results of these analyses will be 
reported separately. 
13.1.5 
 
 
 
 
 
 
 
 
 
13.1.6 
PK/PD Analysis 
The PK and PD data collected in this study may contribute in future population PK/PD analyses 
conducted to characterize the E-R relationships between modakafusp alfa and daratumumab 
serum exposure and response (eg, serum M-protein, platelet count). These population PK/PD 
analyses may include data collected in other modakafusp alfa clinical single or combination 
studies. The analysis plan for the PK/PD analysis will be separately defined, and the results of 
these analyses, if conducted, will be reported separately. 
13.1.7 
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. 
 
 
 
 
 
 


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13.1.8 
Safety Analysis 
AEs will be summarized using the safety population. 
Safety will be evaluated by the frequency of AEs, severity, and types of AEs, and by changes 
from baseline in patients’ vital signs, weights, ECOG performance status, ECG results, and 
clinical laboratory results using the safety analysis set. 
Exposure to study drug over time will be summarized with time on treatment, total amount of 
administered treatment, dose intensity, and relative dose intensity. Reasons for treatment 
discontinuation and modification 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 or start of subsequent anticancer therapy, whichever occurs first will 
be tabulated. All AEs will be coded using the Medical Dictionary for Regulatory Activities. Data 
will be summarized using Preferred Term and/or primary System Organ Class and will include 
the following categories: 
• TEAEs. 
• Drug-related TEAEs. 
• Grade 3 or higher TEAEs. 
• Grade 3 or higher drug-related TEAEs. 
• Grade 5 TEAEs. 
• Grade 5 drug-related TEAEs. 
• The most commonly reported TEAEs (ie, those reported by ≥10% of all patients). 
• SAEs (related and regardless of relationship). 
• SAEs Grade 3 or higher. 
• Drug-related SAEs Grade 3 or higher. 
• AESIs Grade 3 or higher. 
• TEAE leading to study drug modification and discontinuation. 
The incidence of DLTs will be tabulated using the DLT-evaluable population. 
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. 


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Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs, 
weight and ECOG performance status scores will be tabulated by scheduled time points.  
Physical examination findings will be presented in the data listings. 
13.2 
Determination of Sample Size 
A total of approximately 58 patients will be enrolled in the study, including approximately 
18 DLT-evaluable patients for the phase 1 dose escalation and approximately 40 patients 
(approximately 20 patients per arm) for the phase 2a dose finding.  
The phase 1 dose escalation will accrue approximately 18 DLT-evaluable patients based on the 
algorithm of the rolling six design. 
With approximately 20 patients per arm in the phase 2a dose finding, the probability of 
observing at least 1 AE given a different true AE rate is as follows: 
True AE rate 
5% 
10% 
15% 
20% 
Probability of observing at least 1 AE 
64% 
88% 
96% 
99% 
 
With approximately 20 patients per arm in the phase 2a dose finding, the 95% exact binomial 
CIs associated with different observed ORR are as follows: 
Observed ORR 
60% 
70% 
80% 
95% CI 
(0.361, 0.809) 
(0.457, 0.881) 
(0.563, 0.943) 
Width of the 95% CI 
0.448 
0.424 
0.379 


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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. Where permitted by local and country regulations, 
alternative approaches such as remote source data review via phone or video may be used to 
ensure data quality and integrity and patient safety. Additional details are in the monitoring plan. 
Source documents will be reviewed for verification of data recorded on the eCRFs. Source 
documents are defined as original documents, data, and records. The investigator and institution 
guarantee access to source documents by the sponsor or its designee (contract research 
organization) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s binder, study medication, patient 
medical records, informed consent documentation, documentation of patient authorization to use 
personal health information (if separate from the ICFs), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of the primary 
study assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a 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 US Food and Drug Administration [FDA], the 


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United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (herein 
“patients”) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the responsibilities of the 
investigator that are listed in Appendix C. 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, federal, and 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 because of privacy and conflict of interest concerns should instead 
provide a Federalwide Assurance number or comparable number assigned by the US 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, patient recruitment materials and 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 patient 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 its exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by 
country or regional regulations or procedures, approval from the competent regulatory authority 
will be obtained before commencement of the study or implementation of a substantial 
amendment. 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 
the 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 


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materials intended for viewing by patients, 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 
designee). 
Patient incentives should not exert undue influence for participation. Payments to patients must 
be approved by the IRB or IEC and sponsor. 
15.2 
Patient Information, Informed (e)Consent, and Patient Authorization 
Written and eConsent 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, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study, including the use of electronic devices and associated technologies (if applicable). The 
ICF and the patient information sheet (if applicable) further explain the nature of the study, its 
objectives, and potential risks and benefits, and 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 patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use. 
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the patient is not capable of rendering adequate written or 
electronic informed consent, then the patient’s legally acceptable representative may provide 
such consent for the patient in accordance with applicable laws and regulations. 
The patient, or the patient’s legally acceptable representative, must be given ample opportunity 
to (1) inquire about details of the study and (2) decide whether to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines that he or she will 
participate in the study, then the ICF and patient authorization form (if applicable) must be 
(e)signed and dated by the patient, or the patient’s legally acceptable representative, at the time 
of (e)consent and before the patient enters into the study. The patient or the patient’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink in the case of written informed consent. The 
investigator must also (e)sign and date the ICF and patient authorization (if applicable) at the 


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time of (e)consent and before the patient enters into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law. 
Once (e)signed, the original ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) will be stored in the investigator’s site file. The investigator 
must document the date the patient signs the informed consent in the patient’s medical record. 
Copies of the signed ICF, the signed patient authorization form (if applicable), and patient 
information sheet (if applicable) shall be provided to the patient. 
All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s 
legally acceptable representative in the same manner as the original informed (e)consent. The 
date the revised (e)consent was obtained should be recorded in the patient’s medical record, and 
the patient should receive a copy of the revised ICF. 
15.3 
Patient Confidentiality 
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or 
date of birth, and patient initials may be used to verify the patient and accuracy of the patient’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, US FDA, United Kingdom Medicines and Healthcare 
products Regulatory Agency, Pharmaceuticals and Medical Devices Agency of Japan), the 
sponsor’s designated auditors, and the appropriate IRBs and IECs to review the patient’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 patient’s study participation, and autopsy reports. Access to a patient’s original medical 
records requires the specific authorization of the patient as part of the informed (e)consent 
process (see Section 15.2). 
Copies of any patient source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, patient name, address, and other identifier fields 
not collected on the patient’s eCRF. 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication  
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 


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disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the clinical study site agreement. In the event of any 
discrepancy between the protocol and the clinical study site agreement, the clinical study site 
agreement will prevail. 
15.4.2 
Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined by Takeda policy/standards. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing.  
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once patients 
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 patient screening process. If the caller asks additional questions beyond the topic of 
trial enrollment, they should be referred to the sponsor.  
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site.  
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and clinicaltrialsregister.eu, 
and other publicly accessible websites (including the Takeda corporate site) and registries, as 
required by Takeda policy/standards, applicable laws, and/or regulations. 
Data Sharing 
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 


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15.5 
Insurance and Compensation for Injury 
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the clinical study site agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
Abecma (idecabtagene vicleucel) suspension for intravenous infusion 2021. Prescribing 
Information. Summit, NJ: Celgene Corporation. 
Blenrep (belantamab mafodotin-blmf) 2020. Prescribing Information. Brentford, UK: 
GlaxoSmithKline. 
Carvykti (ciltacabtagene autoleucel) Suspension for Intravenous Infusion 2022. Full Prescribing 
Information. Horsham, PA: Janssen Biotech, Inc. 
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. 
Collins, S., Joshi, A., Shen, L., Das, S., Suryanarayan, K., Bottino, D., et al. 2020. TAK-573, an 
anti-CD38–attenuated interferon alpha (IFNα) fusion protein (Attenukine™), has 
demonstrated IFNα receptor (IFNAR) pathway modulation in patients with 
relapsed/refractory multiple myeloma. Abstract No. 357. J Immunother Cancer, 8(Suppl 
3), A218. 
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 Faspro (daratumumab and hyaluronidase-fihj) 2022. Full Prescribing Information. 
Horsham, PA: Janssen Biotech, Inc. 
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. 
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. 
Mateos, M. V., Nahi, H., Legiec, W., Grosicki, S., Vorobyev, V., Spicka, I., et al. 2020. 
Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory 
multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, 
phase 3 trial. Lancet Haematol, 7(5), e370-e80. 
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. 
American Journal of Clinical Oncology, 5(6), 649-55. 
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. 


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Rajkumar, S. V. and Kumar, S. 2016. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin 
Proc, 91(1), 101-19. 
Richard, S., Jagannath, S., Cho, H. J., Parekh, S., Madduri, D., Richter, J., et al. 2021. A 
comprehensive overview of daratumumab and carfilzomib and the recently approved 
daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple 
myeloma. Expert Rev Hematol, 14(1), 31-45. 
Sarclisa (Isatuximab) 2020. Package Insert. Bridgewater, NJ: Sanofi-Aventis. 
Skolnik, J. M., Barrett, J. S., Jayaraman, B., Patel, D. and Adamson, P. C. 2008. Shortening the 
timeline of pediatric phase I trials: the rolling six design. Journal of Clinical Oncology, 
26(2), 190-5. 
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. 
 


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Appendix A Schedules of Events 
 














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Footnotes for Appendix A Tables 1 and 2 
a 
Written informed consent must be obtained before performing any protocol-specific procedure. Test results from routine clinical management are acceptable for screening if 
obtained within the specified time window. 
b 
Height will be measured only at the screening visit. 
c 
All patients will have 1 standard local ECG collected and read locally at screening and at the end of dosing (+30 minutes) of all planned medications in the clinic on the days 
indicated. 
d 
Vital signs will be measured at predose of each drug administration (eg, predose of daratumumab SC and predose of modakafusp alfa for modakafusp alfa in combination 
with daratumumab SC treatment), and after completing the administration of the last treatment medication (eg, after the completion of modakafusp alfa administration when 
daratumumab SC and modakafusp alfa are administered sequentially) on the days indicated. Vital signs include temperature, pulse, respiratory rate, oxygen saturation, and 
blood pressure. Vital signs will be measured at any time a patient complains of symptoms consistent with IRR or clinically indicated.  
e 
Clinical imaging assessments to summarize status of known lesions should be based on available imaging at each respective time point. 
f 
In case of an IRR, collect serum sample for circulating biomarkers, blood sample for flow cytometry, blood sample for RNA, and serum sample for immunogenicity (ADA), 
if clinical management of patient allows. Any decrease in infusion duration of modakafusp alfa must be discussed with and agreed on by the sponsor. If a patient presents with 
an IRR at any dose level, the duration of the infusion for 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 modakafusp alfa Pharmacy Manual for additional guidance. 
g 
Imaging to assess bone disease is required for all patients at screening. Imaging performed within 5 weeks of the planned first dose of study drug can be used as baseline 
evaluations and does not need to be repeated as part of screening. Low-dose whole-body CT is recommended over conventional skeletal survey for the evaluation of multiple 
myeloma bone disease. Conventional skeletal survey can be used for the diagnosis of multiple myeloma when whole-body CT or other novel imaging methods are not 
available. Additional assessments for bone disease can be done at the discretion of the investigator (ie, for suspected increased or new bone lesions or progressive disease). 
The same modality for assessment should be used throughout the study.  
h 
Imaging to assess extramedullary disease is required for all patients at screening by PET-CT, MRI, or CT. Imaging performed within 5 weeks of the planned first dose of 
study drug can be used as baseline evaluations and does not need to be repeated as part of screening. If extramedullary disease is documented at screening, repeat imaging 
using the same modality every 12 weeks (±1 week) until a plateau or complete response is reached, or as clinically indicated, and then at suspected progression. Imaging tests 
for patients with extramedullary disease should be performed if new symptoms suggest progressive disease. 
i 
Chemistry will consist of albumin, ALT, alkaline phosphatase, AST, HCO3- or CO2, blood urea nitrogen, calcium, chloride, magnesium, potassium, sodium, phosphate, 
creatinine, total bilirubin, LDH, urate, blood glucose (nonfasting), and standard C-reactive protein and may be collected up to 3 days before dosing. It is not necessary to 
repeat these tests on C1D1 predose if the tests performed at screening are less than 3 days old.  
j 
Hematology will consist of hemoglobin, hematocrit, platelet count, leukocytes with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils), and absolute 
neutrophil count (ANC) and may be collected up to 3 days before dosing. It is not necessary to repeat these tests on C1D1 predose if the tests performed at screening are less 
than 3 days old. 
k 
Urinalysis (dipstick) includes bilirubin, glucose, ketones, leukocytes, nitrite, occult blood, pH, protein, specific gravity, turbidity and color, and urobilinogen. Microscopic 
analysis only if clinically indicated: bacteria, RBCs, WBCs, casts, and crystals. 


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l 
Pregnancy test (refer to Section 9.5.6).  
• 
Screening: Participants of childbearing potential must have 2 negative pregnancy tests before starting study drug. A negative urine or serum pregnancy test result will be 
required at screening and a negative urine or serum pregnancy test is required at within 72 hours of dosing at baseline.  
• 
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.  
• 
A urine or serum pregnancy test is required at EOT in participants of childbearing potential.  
m 
To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
n 
Sample to be collected at any time on Day 2 of the cycle. 
o 
Urine M-protein 24-hour urine sample required while on treatment and during follow-up. To be repeated at baseline (C1D1) if screening sample was taken more than 7 days 
before C1D1. 
p 
Serum FLC to be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
q 
Immunofixation in serum and urine is required for patients evaluated for CR; see Section 9.5.13.6. To be repeated at baseline (C1D1) if screening sample was taken more than 
7 days before C1D1. 
r 
A blood sample for quantification of immunoglobulins (IgM, IgG, and IgA) will be obtained. For the rare patient with known IgD or IgE MM, the quantitative test for that 
antibody will be followed at the same time points throughout the treatment period and PFS follow-up period as quantitative immunoglobulins (in addition to quantitative IgM, 
IgG, and IgA) (see Section 9.5.13.3). To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1. 
s 
For local analysis of disease assessment at screening, a standard BMA drawn before consent is acceptable provided this is collected within 5 weeks of the first dose.  
t 
Blood samples for PK will be collected at time points specified in Appendix B. 
u 
All patients should have a fresh BMA sample from screening sent for central cytogenetic analysis.  
v 
At predose (before the administration of the first agent when drug combinations are administered), unless otherwise specified.  
w 
Thyroid function tests (TSH, T3, T4) will be performed during screening, Cycle 3, and every 3 cycles (up to 3 days before dosing) thereafter until EOT and will be analyzed 
locally. 
x 
Blood samples for immunogenicity (ADA/NAb) testing will be collected at predose on indicated visits during the treatment period and, if possible, at the EOT and PFS FU 
visits. In case of an infusion reaction, blood draws should be performed for central evaluation of immunogenicity (see Section 9.5.16). On days when dosing is not required, 
samples may be collected at any point during the clinic visit. 
y 
Only repeat tests in parentheses for patients terminating treatment due to progressive disease if they were not performed before for progressive disease determination at the 
last visit, and for patients in CR if not performed before for CR confirmation. 
z 
End-of-treatment laboratory assessments are to be performed before the patient starting a new treatment or a maximum of 30 days (+10 days) after the last dose. 
aa 
Patients who discontinue study drug treatment for reasons other than progressive disease will continue PFS follow-up every 4 weeks from the EOT visit until the occurrence 
of progressive disease, death, the start of subsequent systemic antineoplastic therapy, study termination, whichever occurs first.  
bb OS follow-up continues every 12 weeks until death, study termination, or patient withdrawal. 
cc 
At predose (before the administration of the first agent when drug combinations are administered) and also at 4 hours (±60 minutes) after the end of infusion of modakafusp 
alfa. 
dd Immediately after the bone marrow aspirate/biopsy obtained for local disease assessment at screening and for confirmation of a suspected CR, an additional 1 mL of BMA 
will be collected for evaluation of MRD and sent to a central laboratory for analysis. If a BMA/biopsy drawn before consent, within 5 weeks of first dose, is used for local 


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disease assessment at screening, the first BMA pull at screening will be drawn for the MRD sample. Additionally, BMAs will be requested for MRD assessment at the time of 
suspected CR, and at 6, 12, and 24 months following CR confirmation. 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. 
ee 
Following the collection of BMA for MRD sample at screening, an additional 3 mL pull of BMA will be collected for cytogenetic analysis and central evaluation of both 
tumor and immune fractions of bone marrow. Where country guidelines and/or regulations prohibit genomic analysis, a fluorescent in-situ hybridization will be used to 
evaluate cytogenetic abnormalities. 
ff 
Sample collection allowance per country regulations.  
gg It is required that, in addition to blood type (ABO) and Rh typing, the indirect antiglobulin test (also known as Indirect Coombs Test) be performed and the subject carries an 
identification wallet card with these results at all times during the study.  
hh A portion of this sample may be used 
. 
ii 
See Section 9.5.13.7 for details regarding interference testing for patients who received an IgG mAb as recent prior therapy.  
 
 
 
 
kk Only for patients with test positive for HBV serologies (antibodies to hepatitis B core antigen and/or antibodies to hepatitis B surface antigen) or have a known history of 
HBV infection. Participants with serologic findings suggestive of HBV vaccination (hepatitis B surface antibody 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. 
 














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Footnotes for SOE Appendix Tables 3–4 
a 
Written informed consent must be obtained before performing any protocol-specific procedure. Test results from routine clinical management are acceptable for screening if 
obtained within the specified time window. 
b 
Height will be measured only at the screening visit. 
c 
All patients will have 1 standard local ECG collected and read locally at screening and at the end of dosing (+30 minutes) of all planned medications in the clinic on the days 
indicated.  
d 
Vital signs will be measured at predose of each drug administration (eg, predose of daratumumab SC and predose of modakafusp alfa for modakafusp alfa in combination 
with daratumumab SC treatment), and after completing the administration of the last treatment medication (eg, after the completion of modakafusp alfa administration when 
daratumumab SC and modakafusp alfa are administered sequentially) on the days indicated. Vital signs include temperature, pulse, respiratory rate, oxygen saturation, and 
blood pressure. Vital signs will be measured at any time a patient complains of symptoms consistent with IRR or clinically indicated.  
e 
Clinical imaging assessments to summarize status of known lesions should be based on available imaging at each respective time point. 
f 
In case of an IRR, collect serum sample for circulating biomarkers, blood sample for flow cytometry, blood sample for RNA, and serum sample for immunogenicity (ADA), 
if clinical management of patient allows. Any decrease in infusion duration of modakafusp alfa must be discussed with and agreed on by the sponsor. If a patient presents with 
an IRR at any dose level, the duration of the infusion for 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 modakafusp alfa Pharmacy Manual for additional guidance. 
g 
Imaging to assess bone disease is required for all patients at screening. Imaging performed within 5 weeks of the planned first dose of study drug can be used as baseline 
evaluations and does not need to be repeated as part of screening. Low-dose whole-body CT is recommended over conventional skeletal survey for the evaluation of multiple 
myeloma bone disease. Conventional skeletal survey can be used for the diagnosis of multiple myeloma when whole-body CT or other novel imaging methods are not 
available. Additional assessments for bone disease can be done at the discretion of the investigator (ie, for suspected increased or new bone lesions progressive disease). The 
same modality for assessment should be used throughout the study.  
h 
Imaging to assess extramedullary disease is required for all patients at screening by PET-CT, MRI, or CT. Imaging performed within 5 weeks of the planned first dose of 
study drug can be used as baseline evaluations and does not need to be repeated as part of screening. If extramedullary disease is documented at screening, repeat imaging 
using the same modality every 12 weeks (±1 week) until a plateau or complete response is reached, or as clinically indicated, and then at suspected progression. Imaging tests 
for patients with extramedullary disease should be performed if new symptoms suggest progressive disease. 
i 
Chemistry will consist of albumin, ALT, alkaline phosphatase, AST, HCO3- or CO2, blood urea nitrogen, calcium, chloride, magnesium, potassium, sodium, phosphate, 
creatinine, total bilirubin, LDH, urate, blood glucose (nonfasting), and standard C-reactive protein and may be collected up to 3 days before dosing. It is not necessary to 
repeat these tests on C1D1 predose if the tests performed at screening are less than 3 days old.  
j 
Hematology will consist of hemoglobin, hematocrit, platelet count, leukocytes with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils) and absolute 
neutrophil count (ANC) and may be collected up to 3 days before dosing. It is not necessary to repeat these tests on C1D1 predose if the tests performed at screening are less 
than 3 days old. 
k 
Urinalysis (dipstick) includes bilirubin, glucose, ketones, leukocytes, nitrite, occult blood, pH, protein, specific gravity, turbidity and color, and urobilinogen. Microscopic 
analysis only if clinically indicated: bacteria, RBCs, WBCs, casts, and crystals. 
l 
Pregnancy test (refer to Section 9.5.6).  


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• 
Screening: Participants of childbearing potential must have 2 negative pregnancy tests before starting study drug. A negative urine or serum pregnancy test result is 
required at screening, and a negative urine or serum pregnancy test result is required at baseline.  
• 
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. 
• 
A urine or serum pregnancy test is required at EOT in participants of childbearing potential.  
m 
To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
n 
Urine M-protein 24-hour urine sample required while on treatment and during follow-up. To be repeated at baseline (C1D1) if screening sample was taken more than 7 days 
before C1D1. 
o 
Serum FLC to be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1.  
p 
Immunofixation in serum and urine is required for patients evaluated for CR; see Section 9.5.13.6. To be repeated at baseline (C1D1) if screening sample was taken more than 
7 days before C1D1. 
q 
A blood sample for quantification of immunoglobulins (IgM, IgG, and IgA) will be obtained. For the rare patient with known IgD or IgE MM, the quantitative test for that 
antibody will be followed at the same time points throughout the treatment period and PFS follow-up period as quantitative immunoglobulins (in addition to quantitative IgM, 
IgG, and IgA) (see Section 9.5.13.3). To be repeated at baseline (C1D1) if screening sample was taken more than 7 days before C1D1. 
r 
For local analysis of disease assessment, a standard BMA drawn before consent is acceptable provided this is collected within 5 weeks of the first dose.  
s 
Blood samples for PK will be collected at time points specified in Appendix B. 
t 
All patients should have a fresh BMA sample from screening sent for central cytogenetic analysis.  
u 
At predose (before the administration of the first agent when drug combinations are administered), unless otherwise specified.  
v 
Thyroid function tests (TSH, T3, T4) will be performed during screening, Cycle 3, and every 3 cycles (up to 3 days before dosing) thereafter until EOT and will be analyzed 
locally. 
w 
Blood samples for immunogenicity (ADA/NAb) testing will be collected at predose on indicated visits during the treatment period and, if possible, at the EOT and PFS FU 
visits. In case of an infusion reaction, blood draws should be performed for central evaluation of immunogenicity (see Section 9.5.16). On days when dosing is not required, 
samples may be collected at any point during the clinic visit.  
x 
Only repeat tests in parentheses for patients terminating treatment due to progressive disease if they were not performed before for progressive disease determination at the 
last visit, and for patients in CR if not performed before for CR confirmation. 
y 
End-of-treatment laboratory assessments are to be performed before the patient starting a new treatment or a maximum of 30 days (+10 day) following the last dose. 
z 
Patients who discontinue study drug treatment for reasons other than progressive disease will continue PFS follow-up every 4 weeks from the EOT visit until the occurrence 
of progressive disease, death, the start of subsequent systemic antineoplastic therapy, study termination, whichever occurs first.  
aa 
OS follow-up continues every 12 weeks until death, study termination, or patient withdrawal. 
bb At predose (before the administration of the first agent when drug combinations are administered), and also at 4 hours (±60 minutes) after the end of infusion of modakafusp 
alfa. 
cc 
Immediately after the bone marrow aspirate/biopsy obtained for local disease assessment at screening and for confirmation of a suspected CR, an additional 1 mL of BMA 
will be collected for evaluation of MRD and sent to a central laboratory for analysis. If a BMA/biopsy drawn before consent, within 5 weeks of first dose, is used for local 
disease assessment at screening, the first BMA pull at screening will be drawn for the MRD sample. Additionally, BMAs will be requested for MRD assessment at the time of 
suspected CR, and at 6, 12, and 24 months following CR confirmation. If a patient has an MRD[-] result for any of the on-treatment assessments, this will trigger yearly 


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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. 
dd Following the collection of BMA for MRD sample at screening, an additional 3 mL pull of BMA will be collected for cytogenetic analysis and central evaluation of both 
tumor and immune fractions of bone marrow. Where country guidelines and/or regulations prohibit genomic analysis, a fluorescent in-situ hybridization will be used to 
evaluate cytogenetic abnormalities.  
ee 
Sample collection allowance per country regulations.  
ff 
It is required that, in addition to blood type (ABO) and Rh blood typing, the indirect antiglobulin test (also known as Indirect Coombs Test) be performed and that the subject 
carries an identification wallet card with these results at all times during the study.  
gg A portion of this sample may be used for 
. 
hh See Section 9.5.13.7 for details regarding interference testing for patients who received an IgG mAb as recent prior therapy.  
 
 
 
 
jj 
Only for patients with test positive for HBV serologies (antibodies to hepatitis B core antigen and/or antibodies to hepatitis B surface antigen) or have a known history of 
HBV infection. Participants with serologic findings suggestive of HBV vaccination (hepatitis B surface antibody 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. 


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Appendix B PK Sampling 










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Appendix C 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 who 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 patients 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 patients. 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 (e)consent, as outlined in 21 CFR Part 50, ICH and 
local regulations, are met. 
9. Obtain valid informed (e)consent from each patient who participates in the study, and 
document the date of (e)consent in the patient’s medical chart. Valid informed (e)consent is 
the most current version approved by the IRB/IEC. Each ICF should contain a patient 
authorization section that describes the uses and disclosures of a patient’s personal 
information (including personal health information) that will take place in connection with 
the study. If an ICF does not include such a patient authorization, then the investigator must 
obtain a separate patient authorization form from each patient or the patient’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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Appendix D Investigator Consent to Use of Personal Information  
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the 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. 
The 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 the 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. 
The 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 the 
investigator’s own country. 
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above. 


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Appendix E 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 (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‡. 
• 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). 
PET-CT: [18F]ﬂuorodeoxyglucose PET with CT. 
* Clonality should be established by showing κλ light-chain restriction on ﬂow cytometry, immunohistochemistry, 
or immunoﬂuorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. 
† Measured or estimated by validated equations. 
‡ If bone marrow has less than 10% clonal plasma cells, more than 1 bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement. 
§ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The 
involved FLC must be ≥100 mg/L. Each focal lesion must be 5 mm or more in size (Rajkumar 2014). 
 


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Appendix E Table 1 IMWG Criteria for Response  
Response Category  Response Criteria (Kumar et al. 2016; Rajkumar et al. 2011)  
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). 


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Appendix E Table 1 IMWG Criteria for Response  
Response Category  Response Criteria (Kumar et al. 2016; Rajkumar et al. 2011)  
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 
• 
Increase of 25% from lowest response value in one or more of the following: 
– 
Serum M-component (absolute increase must be ≥0.5 g/dL) 
– 
Urine M-component (absolute increase must be ≥200 mg per 24 hours) 
– 
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%) 
• 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% 
increase in the longest diameter of a previous lesion >1 cm in short axis 
• 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be 
attributed solely to the plasma cell proliferative disorder. 
BM: bone marrow; CR: complete response; FLC: free light chain; MR: minimal response; ORR: objective response rate; PD: 
progression of disease; sCR: stringent complete response; SD: stable disease; SPD: maximal perpendicular diameter; 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. 
 
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. A diagnosis of progression of disease must be 
confirmed by 2 consecutive assessments. 
Plasmacytomas: A definite increase in the size is defined as a ≥50% increase from nadir as 
measured serially by the sum of the products of the maximal perpendicular diameter of the 
measurable lesion or a ≥50% increase in the longest diameter of a previous lesion with ≥1 cm 
short axis. 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 non-measurable. The requirement for bi-directional measurements applies only to 
plasmacytomas. For defining nadir, in the case where a value is felt to be a spurious result per 
physician/IRC discretion (eg, a possible laboratory error), that value will not be considered when 
determining the lowest value. 


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Appendix F 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). 


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Appendix G Protocol History 
Date 
Amendment Number 
Amendment Type 
Region 
03 April 2024 
Amendment 1 v2 
Substantial 
Global 
28 February 2024 
Amendment 1 v1 (not implemented) 
Substantial 
Global 
15 September 2023 
Initial Protocol US v1 
Nonsubstantial; Regional 
United States 
23 June 2023 
Initial Protocol GB v1 
Nonsubstantial; Regional 
United Kingdom 
05 April 2023 
Initial Protocol DE v2 
Nonsubstantial; Regional 
Germany 
05 April 2023 
Initial Protocol DE v1 
Nonsubstantial; Regional 
Germany 
27 January 2023 
Initial Protocol CZ v1 
Nonsubstantial; Regional 
Czech Republic 
14 December 2022 
Initial Protocol FR v1 
Nonsubstantial; Regional 
France 
16 August 2022 
Initial protocol 
Not applicable 
Global 
 
Protocol Amendment 1 v2 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 1 v2. 
The primary reason for this amendment was to implement new dose modification guidelines in 
cases of bleeding treatment-emergent adverse events (TEAEs) as an urgent safety measure to 
mitigate the risk of fatal hemorrhagic events in response to the observation of a suspected 
unexpected serious adverse reaction (SUSAR) in 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 1 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.  8.6.1.3 Criteria for Dose 
Interruption 
Addition of Table 8.d with the dose modifications 
for modakafusp alfa bleeding TEAEs. 
Updated to 
mitigate the risk 
of fatal 
hemorrhagic 
events. 
2.  8.6.1.5 Criteria for 
Discontinuation 
Modification of phase name to indicate “dose 
escalation” rather than “safety lead-in”. 
Removal of criteria related to Grade 4 life 
threatening TEAEs. 
Updated to align 
with changes 
made in this 
protocol 
amendment. 
3.  8.8 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. 


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CONFIDENTIAL 
Protocol Amendment 1 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 
4.  8.10.1.2 Low Platelet Count 
Addition of mention to reference Table 8.d with 
the dose modifications for modakafusp alfa 
bleeding TEAEs 
Updated to 
mitigate the risk 
of fatal 
hemorrhagic 
events. 
 
Protocol Amendment 1 v1 Summary and Rationale (Not Implemented) 
As of 25 October 2023, Takeda decided to not proceed to the Phase 2a part after completing 
phase 1 dose escalation of Study TAK-573-2001. As of 20 November 2023, Takeda decided to 
discontinue the development of modakafusp alfa, including Study TAK-573-2001. These 
decisions were made due to strategic reasons and not due to any safety concerns with 
modakafusp alfa. 
The purpose of this amendment (Amendment 1 v1; not implemented) is to ease the burden of 
protocol-mandated assessments on remaining patients in phase 1, and to confirm the cancellation 
of phase 2a. 
Any country specific protocol was to be followed before the implementation of this global 
Protocol Amendment 1 v1 (not implemented).  
Phase 1 Dose Escalation:  
The primary reason for Amendment 1 v1 (not implemented) in this phase is to reduce the data 
collection activities and study assessments for remaining patients in this study. Upon 
implementation of this amendment, data collection activities will be limited to dosing of study 
drug and the following safety assessments: all serious adverse events (SAEs), 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. 
Phase 2a Dose Finding:  
The primary reason for Amendment 1 v1 (not implemented) in this phase is to confirm that the 
phase 2a dose finding part of the study was terminated on 25 October 2023.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 


Modakafusp alfa (TAK-573) 
 
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19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 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 
Changes for Phase 1 Dose Escalation: 
1.  • 
Section 2.0 STUDY 
SUMMARY 
• 
Section 6.1 Overview of 
Study Design 
• 
Section 6.3.1 Duration of 
an Individual Patient’s 
Study Participation 
• 
Section 9.0 STUDY 
CONDUCT 
• 
Section 9.5 Study 
Procedures 
• 
Section 9.5.6 Pregnancy 
Test 
• 
Section 9.5.8 ECOG 
Performance Status 
• 
Section 9.5.9 AEs 
• 
Section 9.5.11 ECG 
• 
Section 9.5.12 Clinical 
Laboratory Evaluations 
• 
Section 10.2 Procedures 
for Recording and 
Reporting AEs and SAEs 
• 
Section 10.3 Monitoring 
of AEs and Period of 
Observation 
• 
Section 10.4 Procedures 
for Reporting Drug 
Exposure During 
Pregnancy and Birth 
Events 
• 
Section 10.5 Procedures 
for Reporting Product 
Complaints or Medication 
Errors (Including 
Overdose) 
• 
Section 10.6 Safety 
Reporting to Investigators, 
IRBs or IECs, and 
Regulatory Authorities 
• 
Section 13.0 
STATISTICAL 
METHODS 
Revise protocol throughout to 
identify that the majority of study 
assessments will be discontinued to 
ease the burden of protocol-
mandated assessments on patients, 
including simplifying the SOE to 
apply to the remainder of the study 
(Appendix A Table 1) 
Define the ongoing safety 
assessments of Amendment 1 as 
follows: 
• 
All data collection activities 
will be limited to: 
      - Dosing (drug exposure) 
– 
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  
– 
Medication errors 
(including overdose). 
• 
All other study assessments are 
no longer required 
To clarify that no further formal 
efficacy or safety analyses are 
planned and select safety 
assessments are retained to 
ensure patient safety 


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CONFIDENTIAL 
Protocol Amendment 1 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 
• 
Section 13.1 Statistical 
and Analytical Plans 
• 
Section 13.1.1 Analysis 
Sets 
• 
Section 13.1.8 Safety 
Analysis 
• 
Appendix A Schedules of 
Events (Appendix A 
Table 1) 
2.  • 
Section 6.3.2 End of 
Study/Study Completion 
Definition and Planned 
Reporting 
• 
Section 9.5 Study 
Procedures 
• 
Section 9.11 Posttreatment 
Follow-up Assessments 
(PFS and OS) 
Discontinue the PFS and OS follow-
up periods 
To clarify that patients no longer 
need to be followed once they 
come off study treatment, as no 
further efficacy or formal safety 
analyses will be performed in the 
study.  
3.  • 
Section 9.5.13 Disease 
Assessment 
• 
Section 9.5.13.1 
Extramedullary Disease 
Imaging 
• 
Section 9.5.13.2 Bone 
Imaging 
• 
Section 9.5.13.3 
Quantification of 
Immunoglobulins 
• 
Section 9.5.13.4 
Quantification of M-
Protein in Serum and 
Urine 
• 
Section 9.5.13.5 Serum 
FLC Assay 
• 
Section 9.5.13.6 
Immunofixation of Serum 
and Urine 
• 
Section 9.5.13.7 
Interference Assay 
• 
Section 9.5.13.8 Bone 
Marrow Aspirate 
• 
Section 9.5.13.9.1 Disease 
Assessment 
• 
Section 9.5.13.9.2 
Cytogenetics 
Discontinue all disease and efficacy 
response assessments, including 
central laboratory assessments of 
efficacy and safety, for protocol 
purposes  
To clarify that no further efficacy 
or formal safety analyses will be 
performed for the study. 


Modakafusp alfa (TAK-573) 
 
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CONFIDENTIAL 
Protocol Amendment 1 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 
• 
Section 9.5.13.10 Central 
Laboratory Evaluations 
• 
Section 13.1.3 Efficacy 
Analysis 
• 
Section 13.1.3.1 Analysis 
of Primary Efficacy 
Endpoint 
• 
Section 13.1.3.2 Analysis 
of Secondary Efficacy 
Endpoints 
• 
Section 13.1.3.2.2 Phase 
2a Dose Finding 
4.  • 
Section 9.5.14 Biomarker, 
PD, and PK Samples 
• 
Section 9.5.14.1 Primary 
Specimen Collection 
• 
Section 9.5.14.2 PK 
Sampling 
• 
Section 9.5.14.3.1 
 
• 
Section 9.5.14.3.2 
 
 
• 
Section 9.5.15 
 
 
• 
Section 9.5.16 
Immunogenicity Sample 
Collection 
• 
Section 13.1.4 PK 
Analysis 
• 
Section 13.1.5 
 
 
• 
Section 13.1.6 PK/PD 
Analysis 
• 
Section 13.1.7 
Immunogenicity Analyses 
Discontinue biomarker, 
pharmacodynamic (PD), 
pharmacokinetic (PK), and 
immunogenicity sampling, and 
pharmacogenomic measurements for 
ongoing patients 
No further analyses will be 
performed 
5.  • 
Section 6.2 Number of 
Patients 
Confirm number of patients enrolled 
as of Amendment 1 and that no 
additional patients will be enrolled 
in the study 
To clarify that no additional 
patients will be enrolled in the 
study. 
6.  • 
Section 6.3.2 End of 
Study/Study Completion 
Definition and Planned 
Reporting 
Confirm prompt notification by 
sponsor to investigators, institutions, 
and regulatory authorities should a 
clinical study prematurely 
discontinue 
To clarify notification process by 
sponsor should a clinical study 
be prematurely terminated or 
suspended 


Modakafusp alfa (TAK-573) 
 
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Protocol Incorporating Amendment No. 2 US v1 
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CONFIDENTIAL 
Protocol Amendment 1 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 
7.  • 
Section 6.5 Posttrial 
Access 
Add text that after data cutoff, 
ongoing patients must transition to 
the posttrial (PTA) program once it 
becomes available in their country 
To clarify PTA program  
8.  • 
Section 6.5.1 Duration of 
PTA 
Revise conditions under which 
sponsor could terminate PTA of 
modakafusp alfa  
To make consistent with 
TAK 573-1501 Protocol 
Amendment 1 
9.  • 
Section 9.5.7 Concomitant 
Medications and 
Procedures 
Discontinue collection of 
concomitant medications and 
procedures 
To confirm that no further 
analyses will be performed 
10.  • 
Section 9.5.12 Clinical 
Laboratory Evaluations 
• 
Section 9.5.12.1 Clinical 
Chemistry, Hematology, 
Urinalysis and Indirect 
Antiglobulin Test 
(Coombs Test) 
Confirm that only local laboratory 
evaluations should be entered into 
the eCRF only if required to 
understand a TEAE 
To clarify what laboratory 
evaluations should continue to 
entered into the eCRF  
Changes for Phase 2a Dose Finding: 
1.  • 
Section 2.0 STUDY 
SUMMARY 
• 
Section 4.4 Modakafusp 
Alfa Dose Selection for 
Phase 2a Dose Finding in 
Combination With 
Daratumumab SC 
• 
Section 5.1.1 Primary 
Objectives 
• 
Section 5.1.2 Secondary 
Objectives 
• 
Section 5.1.3 Exploratory 
Objectives 
• 
Section 5.2.1 Primary 
Endpoints 
• 
Section 5.2.2 Secondary 
Endpoints 
• 
Section 5.2.3 Exploratory 
Endpoints 
• 
Section 6.1 Overview of 
Study Design 
• 
Figure 6.a 
Schematic of 
TAK-573-2001 Study 
Design 
• 
Section 6.2.2 Phase 2a 
Dose Finding 
Confirm that the Phase 2a Dose 
Finding part of the study was 
terminated on 25 October 2023; 
therefore, all planned study activities 
during this phase are now cancelled 
Sponsor decision to cancel this 
part of the study 


Modakafusp alfa (TAK-573) 
 
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19 September 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 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 
• 
Section 6.3.3 Timeframes 
for Primary and 
Secondary Endpoints to 
Support Disclosures 
• 
Section 6.3.4 Total Study 
Duration 
• 
Section 6.4 
Randomization in Phase 
2a Dose Finding 
• 
Section 9.4 Treatment 
Group Assignments 
• 
Section 9.5 Study 
Procedures 
• 
Section 13.2 
Determination of Sample 
Size 
• 
Appendix A Schedules of 
Events (Appendix A 
Table 1) 
INITIAL PROTOCOL US V1 SUMMARY OF CHANGES 
Initial Protocol US v1 Summary Rationale: 
This section describes the changes to the Initial Protocol Incorporating US v1. The primary 
reasons for this amendment are to: 
• Change the current eligibility criteria for phase 2a to not only require refractoriness to 
lenalidomide, but also prior exposure to a proteasome inhibitor (PI). 
• Modify the dose limiting toxicity (DLT) criteria for neutropenia, infusion-related 
reactions (IRRs), and rash. 
• Modify the DLT criteria for Grade 4 thrombocytopenia lasting more than 14 consecutive 
days to lasting more than 7 consecutive days. 
• Modify dose modification recommendations for modakafusp alfa nonhematological 
toxicities (Table 8.b) to indicate that modakafusp alfa should be resumed at a reduced 
dose after recovery to Grade ≤1 or baseline in the event of symptomatic Grade ≥3 non-
hematological toxicities; but for asymptomatic Grade 3 and Grade 4 nonhematological 
laboratory AEs, modakafusp alfa can be resumed either at the same dose or a reduced 
dose at the discretion of the investigator for the first occurrence and then reduce 
modakafusp alfa by 1 dose level for subsequent occurrence. 


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Study No. TAK-573-2001 
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19 September 2024 
 
CONFIDENTIAL 
• Clarify that patients who experience Grade 4 life-threatening TEAEs will be 
permanently withdrawn from the study. 
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. 
Initial Protocol US v1 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 2.0 STUDY  SUMMARY 
Section 4.2.2 Study Population 
Section 6.1 Overview of Study Design 
Section 7.1 Inclusion Criteria 
Inclusion Criterion #5a was updated 
to include prior treatment with 
proteasome inhibitor and 
lenalidomide. 
Response to United States health 
authority request. 
Section 8.3.1 Definitions of DLT 
Modify the DLT criteria for 
neutropenia, IRRs, and rash. 
Modify the DLT criteria for Grade 4 
thrombocytopenia lasting more than 
14 consecutive days to lasting more 
than 7 consecutive days. 
Response to United States health 
authority request. 
Section 8.6.1.3 Criteria for Dose 
Interruption 
Modify dose modification 
recommendations for modakafusp 
alfa nonhematological toxicities. 
Response to United States health 
authority request. 
Section 8.6.1.5 Criteria for 
Discontinuation 
Clarify that patients who experience 
Grade 4 life-threatening TEAEs will 
be permanently withdrawn from the 
study. 
Response to United States health 
authority request. 
 
INITIAL PROTOCOL GB V1 SUMMARY OF CHANGES 
Initial Protocol GB v1 Summary Rationale: 
This section describes the changes to the Initial Protocol Incorporating GB v1. The primary 
reasons for this amendment are to: 
• Clarify that patients with seropositive results for hepatitis B virus (HBV), hepatitis C 
virus (HCV), and HIV at screening be excluded, and added HCV and HIV serology tests 
besides HBV serology tests at screening. 
• Update inclusion criterion for phase 2a on prior treatment to include proteasome 
inhibitor and lenalidomide. 
• Clarify that investigators are part of the decision-making team for determining dose 
escalation stopping decisions, study stop or termination. 
• Add definition of sterile to contraception language. 


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Study No. TAK-573-2001 
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Protocol Incorporating Amendment No. 2 US v1 
19 September 2024 
 
CONFIDENTIAL 
• Add that daratumumab will be discontinued if a patient is pregnant. 
• Add that patients must not receive a live vaccine during treatment, 90 days after the last 
dose of daratumumab, and 1 week after the last dose of 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. 
Initial Protocol GB v1 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 7.2 Exclusion Criteria 
Section 9.5.12.1 Clinical Chemistry, 
Hematology, Urinalysis and Indirect 
Antiglobulin Test (Coombs Test) 
Appendix A Schedules of Events 
Exclusion Criterion #9 was clarified 
to exclude patients with seropositive 
results for hepatitis B virus, 
hepatitis C virus, and HIV testing at 
screening. 
Response to United Kingdom 
health authority request. 
Section 2.0 STUDY SUMMARY 
Section 6.1 Overview of Study Design 
Section 7.1 Inclusion Criteria 
Inclusion Criterion #5a was updated 
to include prior treatment with 
proteasome inhibitor and 
lenalidomide. 
Response to United Kingdom 
health authority request. 
 
 
 
 
 
 
Response to United Kingdom 
health authority request. 
Section 7.1 Inclusion Criteria 
Section 8.9.1 Contraception and 
Pregnancy Avoidance Procedures 
Added definition of sterile (via 
hysterectomy, salpingectomy or 
oophorectomy). 
Response to United Kingdom 
health authority request. 
Section 8.9.2 Pregnancy 
Added that daratumumab will be 
discontinued if a patient is pregnant. 
Response to United Kingdom 
health authority request. 
Section 8.7 Prohibited Concomitant 
Medications and Procedures 
Added that patients must not receive 
a live vaccine during treatment, 90 
days after the last dose of 
daratumumab, and 1 week after the 
last dose of modakafusp alfa. 
Response to United Kingdom 
health authority request. 
 
INITIAL PROTOCOL DE V2 SUMMARY OF CHANGES 
Initial Protocol DE v2 Summary and Rationale: 
This section describes the changes to the Initial Protocol incorporating DE v2. The primary 
reasons for this amendment are to: 
• Modify the inclusion criteria that patients in phase 1 must have received anti-BCMA 
(anti–B-cell maturation antigen) therapy and that patients in phase 2a must have been 
exposed to both a proteosome inhibitor (PI) and lenalidomide. 


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-2001 
Page 143 of 145 
Protocol Incorporating Amendment No. 2 US v1 
19 September 2024 
 
CONFIDENTIAL 
• Provide consistent antiviral prophylaxis guidance.  
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. 
Initial Protocol DE v2 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 2.0 STUDY SUMMARY 
Section 4.2.2 Study Population 
Section 6.1 Overview of Study Design 
Section 7.1 Inclusion Criteria 
Modified the inclusion criteria that 
patients in phase 1 must have 
received anti-BCMA (anti–B-cell 
maturation antigen) therapy and that 
patients in phase 2a must have been 
exposed to both a proteosome 
inhibitor (PI) and lenalidomide. 
To ensure patient access to the 
study per local guidance. 
Section 8.1.1.5 Prophylaxis Against 
Risk of Infection 
Section 8.1.1.5 Prophylaxis Against 
Risk of Infection 
Section 8.10.1.3 Prophylaxis  
Provided consistent antiviral 
prophylaxis guidance. 
To provide consistent guidance. 
 
INITIAL PROTOCOL DE V1 SUMMARY OF CHANGES 
Initial Protocol DE v1 Summary and Rationale: 
This section describes the changes to the Initial Protocol incorporating DE v1. The primary 
reason for this amendment is to ensure that the sponsor will keep the study sample data 
confidential and in a pseudonymized form. 
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. 
Initial Protocol DE v1 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 15.3 Patient Confidentiality 
 
Ensure that the sponsor will keep 
the study sample data confidential 
and in a pseudonymized form.  
Response to Germany Ethics 
Committee request. 
 


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Protocol Incorporating Amendment No. 2 US v1 
19 September 2024 
 
CONFIDENTIAL 
INITIAL PROTOCOL CZ V1 SUMMARY OF CHANGES 
Initial Protocol CZ v1 Summary Rationale: 
This section describes the changes to the Initial Protocol incorporating CZ v1. The primary 
reason for this amendment is to prohibit live vaccines for 90 days after modakafusp alfa 
treatment. 
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. 
Initial Protocol CZ v1 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 7.1 Inclusion Criteria 
Section 8.7 Prohibited Concomitant 
Medications and Procedures 
Inclusion Criterion #8 revised to 
exclude live vaccines within 30 
days before first administration of 
study treatment for patients. Live 
vaccines are excluded during study 
treatment and for 90 days after the 
last dose of modakafusp alfa. 
Response to Czech Republic 
health authority request. 
 
INITIAL PROTOCOL FR V1 SUMMARY OF CHANGES 
Initial Protocol FR v1 Summary and Rationale: 
This section describes the changes to the Initial Protocol incorporating FR v1. The primary 
reasons for this amendment are to: 
• Clarify in the inclusion criteria that patients in phase 2a must have been exposed to both a 
proteosome inhibitor and immunomodulatory drug. 
• Revise the inclusion criteria to increase the duration of the washout period to 14 days for 
patients who have received radiation therapy for localized bone lesions. 
• Add that hospitalization is required for the first infusion of modakafusp alfa in 
combination with daratumumab administered subcutaneously. 
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. 


Modakafusp alfa (TAK-573) 
 
Study No. TAK-573-2001 
Page 145 of 145 
Protocol Incorporating Amendment No. 2 US v1 
19 September 2024 
 
CONFIDENTIAL 
Initial Protocol FR v1 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description  
Rationale 
Section 2.0 STUDY SUMMARY 
Section 4.2.2 Study Population 
Section 6.1 Overview of Study Design 
Section 7.1 Inclusion Criteria 
Clarified in the inclusion criteria 
that patients in phase 2a must have 
been exposed to both a proteasome 
inhibitor and an immunomodulatory 
drug. 
To ensure patient access to the 
study per local guidance. 
Section 7.1 Inclusion Criteria 
Revised the inclusion criteria to 
increase the duration of the washout 
period to 14 days for patients who 
have received radiation therapy for 
localized bone lesions. 
To ensure patient safety. 
Section 8.1.1.2 Administration 
Section 8.1.1.4 Postinfusion 
Medication and Monitoring 
Appendix A Schedule of Events 
Added that hospitalization is 
required for the first infusion of 
modakafusp alfa in combination 
with daratumumab administered 
subcutaneously. 
To ensure patient safety. 
 
 
 


Signature Page for TAK-573-2001 Protocol Amend 02 US v1 2024-09-19
Title: Amend 02 US v1 to A Phase 1/2a Open-label Study to Evaluate the Safety, T
Document Number: TDN-000443418 v1.0
Approval
Clinical
25-Sep-2024 21:53:13 GMT+0000

SAP_001.pdf: 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Number: 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 Subcutaneous in Patients With Relapsed or Refractory Multiple Myeloma 
Phase 1/2a 
Version: 1.0 
Date: October 4, 2022 
 
 
 
Prepared by:  
, PhD 
Statistics and Quantitative Sciences 
 
Based on: 
Protocol Version: Initial Version 
Protocol Date: 16 August 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. 
 
 
 
 


TAK-573-2001 
Page 2 of 37
Statistical Analysis Plan Draft 
04-Oct-2022
 
CONFIDENTIAL 
REVISION HISTORY 
 
Version  
Approval Date 
Primary Rationale for Revision 
Original Version 
Not Applicable 
Not Applicable 
 
 
 


TAK-573-2001 
Page 3 of 37
Statistical Analysis Plan Draft 
04-Oct-2022
 
CONFIDENTIAL 
TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
REVISION HISTORY....................................................................................................... 2 
TABLE OF CONTENTS ......................................................................................................... 3 
LIST OF IN-TEXT TABLES ............................................................................................. 5 
ABBREVIATIONS ................................................................................................................. 6 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS........................................................ 8 
1.1 
Objectives .............................................................................................................. 8 
1.1.1 
Primary Objective ........................................................................................... 8 
1.1.2 
Secondary Objective(s) ................................................................................... 8 
1.1.3 
Additional Objective(s) ................................................................................... 9 
1.1.3.1 
Exploratory Objectives............................................................................ 9 
1.2 
Endpoints ............................................................................................................... 9 
1.2.1 
Primary Endpoint(s)........................................................................................ 9 
1.2.2 
Secondary Endpoint(s) .................................................................................... 9 
1.2.3 
Exploratory Endpoint(s) ................................................................................ 11 
1.3 
Estimand(s) .......................................................................................................... 11 
2.0 
STUDY DESIGN....................................................................................................... 12 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES ......................................... 12 
3.1 
Statistical Hypotheses ........................................................................................... 12 
3.2 
Statistical Decision Rules...................................................................................... 13 
3.3 
Multiplicity Adjustment ........................................................................................ 13 
4.0 
SAMPLE-SIZE DETERMINATION .......................................................................... 13 
5.0 
POPULATIONS ........................................................................................................ 13 
5.1 
DLT-evaluable Population .................................................................................... 13 
5.2 
Response-evaluable Population ............................................................................. 13 
5.3 
Safety Population ................................................................................................. 14 
5.4 
Per-Protocol Population ........................................................................................ 14 
5.5 
Intent-to-treat (ITT) Population ............................................................................. 14 
5.6 
Pharmacokinetic Population.................................................................................. 14 
5.7 
Immunogenicity-evaluable Population................................................................... 14 
6.0 
STATISTICAL ANALYSIS....................................................................................... 14 
6.1 
General Considerations ......................................................................................... 14 
6.1.1 
Study Definitions .......................................................................................... 15 
6.1.1.1 
Definition of Study Days ....................................................................... 15 


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CONFIDENTIAL 
6.1.1.2 
Definition of Study Cycle ...................................................................... 15 
6.1.1.3 
Definition of Study Visit Window ......................................................... 15 
6.1.2 
Analysis Approach for Continuous Variables................................................. 15 
6.1.3 
Analysis Approach for Binary Variables and Categorical Variables ................ 15 
6.1.4 
Analysis Approach for Time-to-Event Variables ............................................ 15 
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................................................. 19 
6.4.1 
Prior Therapy ............................................................................................... 20 
6.4.2 
Concomitant Medications.............................................................................. 20 
6.5 
Study Drug Exposure and Compliance .................................................................. 20 
6.6 
Efficacy Analysis ................................................................................................. 20 
6.6.1 
Primary Endpoint Analysis............................................................................ 20 
6.6.1.1 
Derivation of Endpoint(s) ...................................................................... 21 
6.6.1.2 
Main Analytical Approach .................................................................... 21 
6.6.1.3 
Sensitivity Analysis............................................................................... 22 
6.6.2 
Secondary Endpoints Analysis ...................................................................... 23 
6.6.2.1 
Phase 1 dose escalation ......................................................................... 23 
6.6.2.2 
Phase 2a dose finding ............................................................................ 26 
6.6.3 
Exploratory Endpoints Analysis .................................................................... 29 
6.6.4 
Subgroup Analyses ....................................................................................... 29 
6.7 
Safety Analysis .................................................................................................... 30 
6.7.1 
Adverse Events............................................................................................. 30 
6.7.2 
Adverse Events of Special Interest................................................................. 32 
6.7.3 
Clinical Laboratory Evaluations .................................................................... 32 
6.7.4 
Vital Signs.................................................................................................... 33 
6.7.5 
12-Lead ECGs .............................................................................................. 33 
6.7.6 
Other Observations Related to Safety ............................................................ 34 
6.8 
Pharmacokinetic,
, and Biomarker Analyses .............................. 34 
6.8.1 
Pharmacokinetic Analysis ............................................................................. 34 
6.8.1.1 
Serum Modakafusp alfa Concentrations ................................................. 34 
6.8.1.2 
Serum PK Parameters (Phase 1 Dose Escalation) ................................... 35 


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6.8.2 
 .......................................................................... 36 
6.8.3 
Immunogenicity Analysis.............................................................................. 36 
7.0 
REFERENCES .......................................................................................................... 37 
 
LIST OF IN-TEXT TABLES 
Table 1: PFS Event and Censoring Method............................................................................. 24 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Term 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
AUCτ 
area under the concentration-time curve during a dosing interval 
AUC∞ 
area under the serum concentration-time curve from time 0 to infinity 
AUClast 
area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration 
BLQ 
below the limit of quantitation 
CBR 
clinical benefit rate 
CI 
confidence interval 
CL 
total clearance after administration 
Cmax 
maximum observed serum concentration 
CR 
complete response 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR  
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
FLC 
free light chain 
ICF 
informed consent form 
ICU 
intensive care unit 
IDMC 
independent data monitoring committee 
Ig 
immunoglobulin 
IMWG 
International Myeloma Working Group 
IRC 
Independent review committee 
IRR 
Infusion-related reaction 
IV 
intravenous(ly) 
ĸD 
dissociation constant 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MRD 
measurable (minimal) residual disease 
MRD[-] 
MRD negative 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OBD 
optimal biological dose 
ORR 
objective response rate 


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Abbreviation 
Term 
PD 
progressive disease; disease progression 
PFS 
progression-free survival 
PoS 
probability of success 
PI 
Proteasome inhibitor 
PK 
pharmacokinetic(s) 
PO 
orally 
PPOS 
posterior probability of success 
PR 
partial response 
PT 
preferred term 
QD 
once daily 
QTcF 
QT interval with Fridericia correction method 
RBC 
red blood cells 
RP2D 
recommended phase 2 dose 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SD 
stable disease 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
t1/2 
terminal disposition phase half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time of first occurrence of maximum observed serum modakafusp alfa concentration 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
VGRP 
very good partial response 
Vss 
volume of distribution at steady state 
λz 
terminal disposition phase rate constant 
 
 
 


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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
The primary objectives are: 
Phase 1 Dose Escalation 
• To determine the safety and tolerability of modakafusp alfa in combination with 
daratumumab SC.  
Phase 2a Dose Finding 
• To inform the RP2D of modakafusp alfa in combination with daratumumab SC.  
• To provide a preliminary evaluation of the clinical efficacy of modakafusp alfa in 
combination with daratumumab SC as measured by ORR. 
 
1.1.2 
Secondary Objective(s) 
Phase 1 Dose Escalation 
• To characterize the PK profile of modakafusp alfa and daratumumab in the combination 
setting. 
• To characterize antimyeloma activity as measured by ORR, DOR, PFS, and overall survival 
(OS).  
• To characterize the immunogenicity of modakafusp alfa in combination with daratumumab 
SC. 
• To characterize measurable (minimal) residual disease (MRD) negativity rate and duration of 
MRD negativity.  
Phase 2a Dose Finding 
• To determine DOR, clinical benefit rate (CBR), duration of clinical benefit (DCB), disease 
control rate (DCR), duration of disease control, time to progression (TTP), time to response 
(TTR), time to next treatment (TTNT), PFS, and OS. 
• To further characterize safety and tolerability of modakafusp alfa in combination with 
daratumumab SC. 
• To collect PK data for modakafusp alfa to support population PK and E-R analysis.  
• To collect PK data for daratumumab SC to assess any potential impact of immunogenicity on 
daratumumab PK.  


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• To further characterize the immunogenicity of modakafusp alfa in combination with 
daratumumab SC. 
• To characterize MRD negativity rate and duration of MRD negativity.  
 
1.1.3 
Additional Objective(s) 
1.1.3.1 
Exploratory Objectives 
  
 
 
 
 
1.2 
Endpoints 
Patients’ responses to the treatment will be determined per International Myeloma Working 
Group (IMWG) criteria in the current study. 
1.2.1 
Primary Endpoint(s) 
The primary endpoints are: 
Phase 1 Dose Escalation 
• DLT incidences.  
• Frequency and severity of TEAEs according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. 
Phase 2a Dose Finding 
• ORR, defined as the proportion of patients who achieved a confirmed response of PR or 
better during the study as assessed by the investigator. 
 
1.2.2 
Secondary Endpoint(s)  
The secondary endpoints are: 
Phase 1 Dose Escalation 
• Summary statistics by dose level and cycle day for the following PK parameters for 
modakafusp alfa for Cycles 1 and 2: 
– Single-dose maximum observed serum concentration (Cmax). 
– Time of first occurrence of Cmax (tmax). 


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– Area under the serum concentration-time curve from time 0 to infinity (AUC∞). 
– Area under the serum concentration-time curve from time 0 to time of the last 
quantifiable concentration (AUClast). 
– Apparent serum modakafusp alfa terminal disposition rate constant. 
– Apparent serum modakafusp alfa terminal disposition phase half-life. 
– Clearance. 
– Volume of distribution at steady state after intravenous (IV) administration. 
• Summary statistics by dose level and cycle day for the following PK parameters for 
daratumumab for Cycles 1 and 2: 
– Single-dose Cmax. 
– tmax. 
– Single-dose and multiple-dose observed concentration at the end of a dosing interval 
(Ctrough). 
– AUC∞. 
– AUClast. 
• ORR by the investigator.  
• DOR by the investigator.  
• PFS by the investigator.  
• OS.  
• ADA incidence and characteristics (eg, titer and specificity) and neutralizing antibody 
(NAb). 
• Rate of MRD negative (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 negativity, at a threshold of 10-5. 
Phase 2a Dose Finding 
• DOR by investigator. 
• CBR response of sCR, CR, very good partial response (VGPR), PR, or minimal responses 
(MR) by investigator.  
• DCB by investigator. 
• DCR (CBR + stable disease [SD]) by investigator. 


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• Duration of disease control by investigator. 
• TTP by investigator. 
• TTR by investigator. 
• TTNT. 
• PFS by investigator.  
• OS.  
• Frequency and severity of TEAEs according to the NCI CTCAE, Version 5.0. 
• ADA incidence and characteristics (eg, titer and specificity) and NAb. 
• Rate of MRD[-] CR, at threshold of 10-5, with CR assessed by the investigator. 
• Rate of MRD[-], at a threshold of 10-5. 
• Duration of MRD negativity, at a threshold of 10-5. 
 
1.2.3 
Exploratory Endpoint(s) 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
1.3 
Estimand(s) 
Not applicable.  


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2.0 
STUDY DESIGN 
This is a global multicenter, open-label, phase 1/2a study designed to evaluate the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of 
modakafusp alfa in combination with daratumumab subcutaneous (SC) in patients with relapsed 
or refractory multiple myeloma (RRMM). The study will begin with a phase 1 dose escalation to 
evaluate the safety and tolerability of modakafusp alfa in combination with daratumumab SC. 
Two dose levels of modakafusp alfa in combination with daratumumab SC will be selected to be 
further explored in the randomized phase 2a dose finding part of the study. Patients will be 
randomized in a 1:1 ratio across 2 dose levels (DL1 or DL2) of modakafusp alfa in combination 
with daratumumab SC. The confirmed ORR assessed by the investigator per IMWG criteria will 
be determined as the primary efficacy endpoint of the phase 2a dose finding. The optimized 
recommended phase 2 dose (RP2D) of modakafusp in combination with daratumumab SC will 
be selected on the basis of integrated safety, efficacy, PK, and PD data from the current study 
and other relevant stud(ies).  
 
Phase 1 Dose Escalation 
The study will begin with a phase 1 dose escalation to evaluate the safety and tolerability of 
modakafusp alfa in combination with daratumumab SC during the Cycle 1 (28 days per cycle) 
dose-limiting toxicity (DLT) evaluation period and beyond. The proposed population in the 
phase 1 dose escalation will be patients with RRMM with at least 3 prior lines of therapy, 
including at least 1 proteasome inhibitor (PI), 1 immunomodulatory imide drug (IMiD), and 1 
anti-CD38 monoclonal antibody (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) or therapy. 
The dose escalation will follow the rolling six design with data collected in the dose 
escalation/de-escalation phase.  
 
Phase 2a Dose Finding 
Two dose levels of modakafusp alfa in combination with daratumumab SC doses will be selected 
from phase 1 dose escalation to be explored further in phase 2a open-label dose finding. 
Approximately 40 patients will be randomized 1:1 across 2 different dose levels (DL1 or DL2; N 
= ~20 at each dose level) of modakafusp alfa in combination with daratumumab SC. Eligible 
patients will include patients with RRMM who have received 1 to 3 prior lines of therapy, 
refractory to lenalidomide, and sensitive (nonrefractory) or naive to anti-CD38 mAb. The 
randomization will be stratified by the number of prior lines of therapy (1 vs 2 or 3). The primary 
endpoint is the confirmed ORR assessed by the investigator per IMWG criteria. 
 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
3.1 
Statistical Hypotheses 
Not Applicable 


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3.2 
Statistical Decision Rules 
Not Applicable 
3.3 
Multiplicity Adjustment 
Not Applicable 
 
4.0 
SAMPLE-SIZE DETERMINATION 
A total of approximately 58 patients will be enrolled in the study, including approximately 
18 DLT-evaluable patients for the phase 1 dose escalation and approximately 40 patients 
(approximately 20 patients per arm) for the phase 2a dose finding.  
The phase 1 dose escalation will accrue approximately 18 DLT-evaluable patients based on the 
algorithm of the rolling six design. 
With approximately 20 patients per arm in the phase 2a dose finding, the probability of 
observing at least 1 AE given a different true AE rate is as follows: 
True AE rate 
5% 
10% 
15% 
20% 
Probability of observing at least 1 AE 
64% 
88% 
96% 
99% 
With approximately 20 patients per arm in the phase 2a dose finding, the 95% exact binomial 
CIs associated with different observed ORR are as follows: 
Observed ORR 
60% 
70% 
80% 
95% CI 
(0.361, 0.809) 
(0.457, 0.881) 
(0.563, 0.943) 
Width of the 95% CI 
0.448 
0.424 
0.379 
 
5.0 
POPULATIONS 
5.1 
DLT-evaluable Population 
The DLT-evaluable population includes all patients from the phase 1 dose escalation portion 
who experienced a DLT in Cycle 1 in the treatment phase of the study or have completed the 
Cycle 1 dose of modakafusp alfa and at least 75% of the planned dose of daratumumab SC. The 
DLT-evaluable population will be used to inform the 2 dose levels for modakafusp alfa to be 
selected in the phase 2a dose finding portion in combination with daratumumab SC. 
5.2 
Response-evaluable Population 
The response-evaluable population includes all patients who receive at least 1 dose, even an 
incomplete dose, of any study drug, have a disease assessment at screening (baseline evaluation), 
and at least 1 postbaseline disease assessment. The response-evaluable population will be used 


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for the primary analysis for ORR in phase 1 dose escalation portion and sensitivity analysis in 
phase 2a dose finding portion.  
5.3 
Safety Population 
The safety population will include all patients who receive at least 1 dose, even an incomplete 
dose, of any study drug. Patients in this set will be analyzed according to the actual treatment 
they received. The safety population will be used for the baseline assessment and efficacy 
analysis except for the endpoints of PFS, OS and TTP in Phase 2a. It will be also used for the 
safety analysis.  
5.4 
Per-Protocol Population  
The per-protocol population is a subset of subjects in the safety population who do not have 
major protocol deviations that are considered to impact efficacy outcomes. The list of major 
protocol deviations is documented and maintained by the sponsor on an ongoing basis and will 
be finalized prior to database lock. The per-protocol population will be used in the sensitivity 
efficacy analysis for endpoint of ORR if patients excluded due to major protocol deviation are 
deemed to have significant impact on the analysis of primary endpoints.  
5.5 
Intent-to-treat (ITT) Population 
The ITT population will include all patients who are randomized. Patients in this set will be 
analyzed according to the treatment they are randomized to receive, regardless of any dosing 
errors. The ITT population will be used for the main efficacy analysis for endpoints of PFS, OS 
and TTP.  
5.6 
Pharmacokinetic Population  
The pharmacokinetic (PK) population includes patients from the safety population with 
sufficient PK data to reliably report 1 or more PK parameters.  
5.7 
Immunogenicity-evaluable Population 
The immunogenicity-evaluable population includes patients who received at least 1 dose of 
modakafusp alfa + daratumumab SC (partial or complete) with a baseline assessment and at least 
1 postbaseline immunogenicity assessment. Immunogenicity analysis will be primarily based on 
the immunogenicity-evaluable population.  
 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
All statistical analyses will be conducted using SAS® Version 9.4 or later. 
For categorical variables, the count and proportions of each possible category value will be 
tabulated. The denominator for the proportion will be based on the number of subjects in the 


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populations. For continuous variables, the mean, median, standard deviation, minimum, and 
maximum values will be presented for all patients in the relevant population.  
All 95% confidence intervals will be reported as 2-sided. No formal statistical comparisons will 
be performed between dose levels. 
Baseline values are defined as the last observed value before the first dose of any study drug. 
6.1.1 
Study Definitions 
6.1.1.1 
Definition of Study Days 
Study Day 1 is defined as the date on which the patient is administered the first dose of any study 
drug.  
Other study days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and (Day 
- 1) being the day prior to Study Day 1.  
6.1.1.2 
Definition of Study Cycle 
The starting date of a new cycle is the date on which the dose of modakafusp alfa is 
administrated.  
6.1.1.3 
Definition of Study Visit Window 
All data will be categorized on the basis of the scheduled visit at which they are collected. These 
visit designators are predefined values that appear as part of the visit tab in the electronic case 
report form (eCRF). The analysis of PK data will be based on the actual elapsed time post dose. 
6.1.2 
Analysis Approach for Continuous Variables 
Continuous variables will be summarized by dose level by phase using summary statistics 
including mean, standard deviation, median, first and third quartiles.  
6.1.3 
Analysis Approach for Binary Variables and Categorical Variables 
For binary and categorical variables, frequency and percentage will be provided by dose level by 
phase. The 2-sided 95% CI will be calculated based on Clopper-Pearson method (exact method) 
(Clopper, C., Pearson, E.S, 1934). No formal statistical comparisons will be performed between 
dose levels.   
6.1.4 
Analysis Approach for Time-to-Event Variables 
Time to event endpoints will be estimated using the Kaplan-Meier (K-M) method (Kaplan, E.L, 
Meier, P., 1958). The K-M curves, the 25th, 50th (median) and 75th percentiles, alone with 
associated 2-sided 95% CIs based on Brookmeyer and Crowley method (Brookmeyer, R., 
Crowley, J., 1982). The K-M probability estimates with 95% CIs at appropriate times will be 
presented if data permits. The number of patients with events and the number of patients 


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censored will be summarized. No formal statistical comparisons will be performed between dose 
levels.   
6.2 
Disposition of Subjects 
Study information, including the date first subject signed informed consent form (ICF) for each 
phase, date of first subject dosed (for phase 1 dose escalation portion),  date of last subject dosed 
(for phase 1 dose escalation portion), date of first subject randomized (for phase 2a dose finding 
portion), date of last subject randomized (for phase 2a dose finding portion), date of last 
subject’s last visit/contact, date of last subject’s last procedure for collection of data for primary 
endpoint(s), data cut-off date for analysis, MedDRA version, NCI CTCAE version, WHO Drug 
version, and SAS version will be presented in listings. 
Screen failures as well as reasons will be summarized.  
Patient disposition will be summarized using counts and percentage of patients based on all 
enrolled patients. The disposition will include the following categories: 
• Treatment status (never treated (only applicable for phase 2a portion), ongoing, 
discontinued treatment) 
- Reasons for discontinuation of treatment 
• Study status (discontinued from study, ongoing in study) 
- Reason for discontinuation of study 
• Participating in PFS follow-up 
• Participating in OS follow-up 
The number and percentage of subjects in each population will be summarized. 
A table and listing of significant protocol deviations will be presented.   
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
All demographics will be summarized based on the safety population using descriptive statistics. 
Demographic data to be evaluated will include, but not limited to, age, sex, race, ethnicity, 
height, and weight.  
6.3.2 
Medical History and Concurrent Medical Conditions 
Medical history and concurrent medical conditions will be coded using the most recent version 
of MedDRA available at the time of coding. Concurrent medical conditions are the ones ongoing 
or started on or after the day informed consent is signed. Medical history and concurrent medical 
conditions will be summarized separately based on safety population by System Organ Class 
(SOC) and Preferred Term (PT) using counts and percentages. 
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 


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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. 
6.3.3 
Baseline Characteristics 
Baseline characteristics will be summarized using descriptive statistics based on the safety 
population. The characteristics include the following: 
Disease characteristics: 
• Years since initial diagnosis [ (date of first dose – date of diagnosis) / 365.25)]. 
• Type of Myeloma 
– IgG, IgA, IgD, IgM, Biclonal (if known, otherwise summarize with Light chain below). 
– Light Chain Kappa, Light Chain Lambda, Light chain Biclonal, Light Chain unknown. 
• Measurable disease 
– Measurable by both SPEP (baseline serum M-protein ≥0.5 g/dL) and UPEP (baseline 
urine M-protein ≥200 mg/24 hr) 
– Measurable by SPEP only  
– Measurable by UPEP only  
– Measurable by FLC only (met all three criteria below): 
1. Involved either Kappa or Lambda free light chain level at baseline ≥10 mg/dL;  
2. and FLC ratio (Kappa FLC/Lambda FLC) is abnormal (serum FLC ratio >1.65 or 
<0.26) 
3. and not measurable by SPEP or UPEP 
• International Staging System (ISS) at study entry. 
• Revised ISS (R-ISS) at study entry.  
• Evidence of Lytic Bone Disease at initial diagnosis. 
• Evidence of Extramedullary Disease at initial diagnosis. 
• Eastern Cooperative Oncology Group (ECOG) performance status. 
 
Baseline disease characteristics– laboratory values 
• 
2
-microglobulin category (<2.5, 2.5-5.5, >5.5 mg/L). 
• Serum albumin category (<3.5, ≥3.5 mg/dL). 
• Serum creatinine category (≤2, >2 mg/dL). 
• Calculated creatinine clearance category (<30, 30 - <60, 60 - <90, ≥90 mL/min). 
Creatinine clearance will be calculated using the Cockcroft-Gault formulas as follows: 
For male patients:  
 
[mg/dL])
creatinine
(serum
72
weight[kg]
Age[yrs])
(140
clearance
creatinine


−
=


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For female patients multiply by 0.85. 
• Hemoglobin (g/L). 
• Platelet count (10^9/L). 
• Absolute neutrophil count (10^9/L). 
• Lactate dehydrogenase (LDH) > Upper limit of normal (ULN). 
 
Baseline Bone Marrow Evaluation 
• Baseline bone marrow aspirate/biopsy performed and adequate for interpretation. 
• Percent plasma cells in bone marrow (if both biopsy and aspirate were performed use larger 
value; unable to detect is considered as zero). 
 
Cytogenetics 
• Cytogenetic testing performed. 
The number and percentage of patients with each type of chromosomal aberration or abnormality 
will be presented including but not limited to the following:  
• high risk cytogenetics [del 17, t(4;14) or t(14;16)]. 
• expanded high risk cytogenetics [del 17, t(4;14), (14;16), or 1q21 amplification/gain]. 
• del 17. 
• t(4:14). 
• t(14:16). 
• 1q21 amplification/gain. 
(percentages are based on the number of patients with cytogenetic testing performed) 
 
Extramedullary Disease Assessment (imaging) 
• Imaging lytic lesions (yes, no, indeterminate). 
• Imaging extramedullary plasmacytomas (yes, no, indeterminate). 
• Location of plasmacytomas. 
• Number of plasmacytomas (1, 2, ≥3). 
• Skeletal survey results (normal, abnormal not clinically significant, abnormal clinically 
significant, and not done). 
• Skeletal survey lytic lesions (yes, no, indeterminate). 
 
Prior therapy 
• Prior radiation (yes, no). 
• Prior surgery (yes, no). 
• Prior bone marrow transplant or stem cell transplant. 


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– Type of stem cell transplant (autologous, allogeneic, syngeneic, unknown). 
• Prior systemic therapy (yes, no). 
• Lines of prior therapy (descriptive statistics and categorical summary: 1, 2, 3, 4, 5, 6, >6). 
• Lines of prior therapy initiated within 12 months of first dose of modakafusp alfa (categorical 
summary). 
• Type of prior therapy may include (if data permits) but not limited to: 
– Anti-CD38 monoclonal antibody (i.e. Daratumumab, Isatuximab). 
– CAR-T. 
– Anti-BCMA. 
– T-Cell engager. 
– IMiD. 
– Proteasome inhibitor (PI). 
– Anti-SLAMF7 (i.e. Elotuzumab). 
• Type of last line of prior therapy. 
• Best response to any prior anti-CD38. 
• Best response to last line of prior therapy 
• Refractory to prior therapy may include but not limited to: 
- 
Refractory to BCMA agents.  
- 
Refractory to anti-CD38. 
- 
Refractory to IMiD. 
- 
Refractory to PI. 
- 
Refractory to IMiD and PI. 
- 
Refractory to IMiD, PI, and anti-CD38. 
- 
Refractory to last line of prior therapy. 
Refractory to therapy is defined as: best response of the treatment is stable disease or disease 
progression on treatment or date of progression is no more than 60 days from the end date of the 
last agent (start date to be imputed where only year or month/year are entered). 
 
6.4 
Medication History and Concomitant Medications  
Medication history and concomitant medications will be coded using the latest World Health 
Organization (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 


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only stop date is missing, then medication will be assumed to continue after treatment 
discontinuation. 
6.4.1 
Prior Therapy 
Prior medication is defined as the anticancer medication stopped before the date of first dose of 
any study drug. Prior medication will be coded by preferred term using the latest World Health 
Organization (WHO) Drug Dictionary.  
The safety population will be used for the analysis of prior therapy.  
6.4.2 
Concomitant Medications 
Concomitant medication is defined as the medication ongoing at the time of the first dose of any 
study drug or medications started on or after the first dose of any study drug. Concomitant 
medications will be coded using the latest WHO Drug Dictionary. The number and percentage of 
patients taking concomitant medications will be tabulated by Anatomical Therapeutic Chemical 
(ATC) classification pharmacological subgroup and WHO standardized medication name.   
The safety population will be used for the analysis of concomitant medications. 
6.5 
Study Drug Exposure and Compliance 
The exposure to study drugs (modakafusp alfa and daratumumab) will be characterized based on 
safety population by summaries and descriptive statistics of duration of treatment in weeks, 
number of treated cycles (1, 2, 3, 4, 5, 6, 7-12, 13-18, 19-24, >24 and summary statistics), and 
relative dose intensity (<50%, 50% - <80%, 80% - <100%, 100%, >100%, and summary 
statistics).  
 
The algorithm/calculation details will be documented in the analysis dataset specifications.  
 
Action on Study Drug 
The reason for treatment discontinuation and dose modification (e.g. dose increased, dose 
reduced, interrupted, withdrawn, delayed, infusion rate increased, infusion rate reduced, drug 
infusion interrupted) of the study drug will be summarized based on safety population. 
 
6.6 
Efficacy Analysis 
All efficacy endpoints are based on investigator’s assessment, if applicable.  
6.6.1 
Primary Endpoint Analysis 
The primary efficacy endpoint for phase 2a is investigator-assessed ORR. 


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6.6.1.1 
Derivation of Endpoint(s) 
ORR is defined as the proportion of patients who achieved a confirmed response of PR or better 
per IMWG criteria.  
6.6.1.2 
Main Analytical Approach 
Investigator-assessed ORR will be analyzed as the primary endpoint and calculated based on the 
safety population.  
ORR at the primary analysis will be analyzed based on the confirmed responses, details of which 
is described as follows.  
 
Confirmation of Response: 
To confirm a response of sCR, CR, VGPR, PR, or MR, it requires 2 consecutive adequate 
assessments made at any time before the initiation of subsequent anti-cancer therapy. There is no 
requirement on the time interval between the two visits.  
Below are some exceptions:  
1. One or two consecutive occurrences of “not done” (ND) or “not evaluable” (NE) between 
responses can be skipped when confirming a response. For example,  
 
PR → NE → PR:  PR is considered to be confirmed in this case. 
 
CR → ND → CR: CR is considered to be confirmed in this case. 
2. Bone marrow assessments do not need to be confirmed.  
 
Confirmation of PD: 
It also requires 2 consecutive adequate assessments made at any time before the initiation of 
subsequent anti-cancer therapy to confirm PD. If only one PD value is recorded in the middle of 
responses better than PD, it will not be counted as a confirmed PD and therefore not an event for 
DOR, TTP, and PFS analyses. For example, the following case is not a confirmed PD:  
           BL → SD → PD → SD → SD → Subsequent anti-cancer therapy/End 
Below are some exceptions:  
• If only one PD is recorded as the last available assessment, then  
1) If this PD is due to imaging (plasmacytomas or bone lesion), then it can be considered 
as a confirmed PD. 
2) If this PD is the last available assessment prior to the subsequent anti-cancer therapy 
or is the reason for End of Treatment (EOT), then it can be considered as a confirmed 
PD. 
3) Otherwise, the PD is considered as unconfirmed.  


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Best Overall Response 
Best overall response (BOR) is defined as the best response recorded after the first dose of study 
drug. The number and percentage of patients as well as corresponding 95% exact CIs with BOR 
in the following response categories will be summarized by dose level: sCR, CR, VGPR, PR, 
MR, SD, PD, and NE/ND. A list of investigator-assessed response at each visit will be provided. 
 
Only the assessments from the start of treatment up to the earlier of confirmed disease 
progression or the start of subsequent anti-cancer therapy will be considered. Only subsequent 
systemic anti-cancer drugs are considered as anti-cancer therapy (radiotherapy and surgeries are 
not considered as systemic anti-cancer therapy for the purpose of this analysis). However, 
assessment after the treatment discontinuation will be considered. Subjects with only 
assessments of “Not Evaluable” or missing response will be treated as non-responders, i.e., they 
will be included in the denominator when calculating the percentage. 
 
6.6.1.3 
Sensitivity Analysis 
The primary analysis of ORR will be based on the safety population. Sensitivity analyses for 
ORR include, but not limited to: 
1. ORR assessed by investigator will be analyzed using the ITT population. 
2. ORR assessed by investigator will be analyzed using the per protocol population if patients 
excluded due to major protocol deviation are deemed to have significant impact on the 
analysis of primary endpoints. 
3. ORR assessed by investigator will be analyzed using the response-evaluable population. 
 
For the primary endpoint ORR, subgroup analysis will be performed in the following selected 
subgroups and presented using forest plot within each treatment arm. Additional subgroups of 
clinical interest may also be considered if data permits, but not required by this SAP. 
  
Subgroups 
Categories 
Age group (at screening) 
18 to <65; 65 to < 75; ≥ 75 
Gender 
Male; female 
Race 
White; Black; Asian; Other 
Type of myeloma 
IgA; IgG; light chain only 
Cytogenetics risk 
High risk [defined as 17p-, t(4;14) and/or t(14;16)]; 
complementary standard risk (non-high risk) 
R-ISS 
I/II; III 
ISS 
I/II; III 


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Extramedullary disease 
Yes; no 
Prior treatment  
Naïve to anti-CD38; sensitive (non-refractory) to anti-CD38 
Number of prior lines of 
therapy 
1; 2/3 
Transplant status 
Transplanted; Non-transplanted 
 
If the percentage of subjects is small within a particular subgroup, then the subgroup categories 
may be refined prior to the database lock. 
 
6.6.2 
Secondary Endpoints Analysis 
6.6.2.1 
Phase 1 dose escalation 
For the phase 1 dose escalation, secondary efficacy endpoints include ORR, DOR, PFS, OS, 
MRD[-] CR rate, MRD[-] rate, and duration of MRD negativity.  
 
ORR 
ORR is defined in Section 6.6.1.1.  
The analysis of ORR will be based on the response-evaluable population.  
ORR will be summarized by frequencies, percentages, and 2-sided 95% exact binomial CIs.  
 
DOR 
DOR is defined as the time from the date of first documentation of a confirmed PR or better to 
the date of first documentation of confirmed progressive disease or death due to any cause, 
whichever occurs first. Responders without documentation of confirmed progressive disease or 
death will be censored at the date of last adequate disease assessment. The censoring rule for 
DOR is the same as for PFS. Please refer to Table 1 in Section 6.6.2.2 for the detailed censoring 
rules.  
DOR (months) = (earliest date of progression or death or censor – date of confirmed response + 
1)/30.4375 
The analysis of DOR will only include confirmed responders (PR or better) based on the safety 
population. 
DOR will be summarized using KM method. The K-M curves, the 25th, 50th (median) and 75th 
percentiles, alone with associated 2-sided 95% CIs based on Brookmeyer and Crowley method, 
and the K-M probability estimates with 95% CIs at 3, 6, 9 and 12 months (or later time points if 
applicable) will be presented. The number of patients with events along with the type of events 
(death or progressive disease) and the number of patients censored will be summarized.  


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PFS 
PFS is defined as the time from the date of the first dose administration of any study drug to the 
first documentation of confirmed progressive disease or death due to any cause, whichever 
occurs first. Patients without documentation of confirmed progressive disease or death will be 
censored at the date of last adequate disease assessment prior to the date of initiation of 
subsequent anti-cancer therapy. Patients with no post baseline response assessment will be 
censored on day 1 unless patient died without extended loss-to-follow-up time. Determination of 
dates of PFS event and date for censoring is summarized in Table 1 as follows. 
Table 1: PFS Event and Censoring Method 
Scenarios 
Event date/censoring date 
Event status 
No (or inadequate) baseline 
tumor assessments1 
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 
PFS Event 
No confirmed progression or 
death 
Date of last adequate disease 
assessment2 
Censored 
Subsequent anti-cancer 
therapy started (before 
documented confirmed 
progression or death)3 
Date of last adequate disease 
assessment2 (prior to the 
initiation of the subsequent 
anti-cancer therapy) 
Censored 
Death without extended loss-
to-follow-up time 
Death date 
PFS Event 
Death or progression after an 
extended loss-to-follow-up 
time (two or more missed 
cycles) 
Date of last adequate disease 
assessment2 (prior to missed 
assessments) 
Censored 
1. 
Adequate baseline assessment is defined as at baseline, a patient has at least one of the following measurements: 
a) 
Serum M-protein ≥ 0.5g/dL (≥500 mg/dL) or  
b) 
Urine M-protein ≥200 mg/24 hours or  
c) 
Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65) 
2. 
An adequate disease assessment is defined as an assessment where the investigator determined response is sCR, CR, VGPR, PR, MR, or 
SD prior to a subsequent anti-cancer therapy. An unconfirmed PD assessment is also considered as an adequate assessment.   
3. 
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. 
 


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PFS (months) = (earliest date of progression or death or censor – date of first dose + 1)/30.4375. 
The analysis of PFS will be based on the safety population. 
PFS will be summarized using KM method. The K-M curves, the 25th, 50th (median) and 75th 
percentiles, alone with associated 2-sided 95% CIs based on Brookmeyer and Crowley method, 
and the K-M probability estimates with 95% CIs at 3, 6, 9 and 12 months (or later time points if 
applicable) will be presented. The number of patients with events along with the type of events 
(death or progressive disease) and the number of patients censored will be summarized. The PFS 
follow-up time will be summarized and reported using the inverse KM methods.  
 
OS 
OS is defined as the time from the date of first dose administration of any study drug to the date 
of death from any cause. Patients without documentation of death at the time of analysis will be 
censored at the date last known to be alive.  
OS (months) = (date of death or censor – date of first dose + 1)/30.4375. 
The analysis of OS will be based on the safety population.  
OS will be summarized using KM method. The K-M curves, the 25th, 50th (median) and 75th 
percentiles, alone with associated 2-sided 95% CIs based on Brookmeyer and Crowley method, 
and the K-M probability estimates with 95% CIs at 3, 6, 9 and 12 months (or later time points if 
applicable) will be presented. The number of patients with events and the number of patients 
censored will be summarized. The OS follow-up time will be summarized and reported using the 
inverse KM method.  
 
MRD[-] CR Rate 
MRD[-] CR rate is defined as the proportion of patients who have achieved confirmed CR 
assessed by the investigator and MRD[-] status using a threshold of 10-5.  
The analysis of MRD[-] CR rate will be based on the response-evaluable population.  
MRD[-] CR rate will be summarized by frequencies, percentages, and 2-sided 95% exact 
binomial CIs.  
 
MRD[-] Rate 
MRD[-] rate is defined as the proportion of patients who have achieved MRD[-] status using a 
threshold of 10-5.  
The analysis of MRD[-] rate will be based on the response-evaluable population.  
MRD[-] rate will be summarized by frequencies, percentages, and 2-sided 95% exact binomial 
CIs.  
 


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Duration of MRD negativity 
Duration of MRD negativity is defined as the time from the date of first documentation of MRD 
negativity to the first documentation of MRD positivity or confirmed progressive disease, or 
death due to any cause, whichever occurs first. Patients without documentation of MRD 
positivity or confirmed progressive disease will be censored at the date last known to be MRD 
negative.  
Duration of MRD negativity (months) = (earliest date of MRD positivity or progression or death 
or censor – date of MRD negativity + 1)/30.4375.  
The analysis of duration of MRD negativity will include only patients who have achieved MRD 
negativity with a threshold of 10-5 based on the safety population.  
If data permits, duration of MRD negativity will be summarized using KM method. Otherwise, a 
listing will be generated.  
 
6.6.2.2 
Phase 2a dose finding 
Secondary efficacy endpoints include DOR, CBR, DCB, DCR, duration of disease control, TTP, 
TTR, TTNT, PFS, OS, MRD[-] CR rate, MRD[-] rate, and duration of MRD negativity.  
 
DOR 
DOR is defined in Section 6.6.2.1 and will be analyzed in the same way.  
 
CBR  
CBR is defined as the proportion of patients with a confirmed response of sCR, CR, VGPR, PR, 
or minimal response per IMWG criteria. 
The analysis of CBR will be based on the safety population.  
CBR will be summarized by frequencies, percentages, and 2-sided 95% exact binomial CIs.   
 
DCB 
DCB is defined as the time from the date of first documentation of a minimal response or better 
to the date of first documentation of confirmed progressive disease or death due to any cause, 
whichever occurs first. Patients without documentation of confirmed progressive disease or death 
will be censored at the censoring time point for PFS as specified in Table 1.  
DCB (months) = (earliest date of PD or death or censor – date of first minimal response or better 
+ 1)/30.4375. 


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The analysis of DCB is based on a subset of safety population that only includes patients who 
have achieved a minimal response or better.  
DCB will be summarized using KM method. The 25th, 50th (median) and 75th percentiles, alone 
with associated 2-sided 95% CIs based on Brookmeyer and Crowley method.  
 
DCR 
DCR is defined as the proportion of patients with a confirmed response of sCR, CR, VGPR, PR, 
minimal response, or SD per IMWG criteria.  
The analysis will be based on the safety population.  
DCR will be summarized by frequencies, percentages, and 2-sided 95% exact binomial CIs.   
 
Duration of disease control 
Duration of disease control is defined as the time from date of first documentation of SD or 
better to the date of first documentation of confirmed progressive disease or death due to any 
cause. Patients without documentation of confirmed PD or death will be censored following the 
same censoring rule for PFS as specified in Table 1. 
Duration of disease control (months) = (earliest date of PD or death or censor – date of first SD 
or better + 1)/30.4375. 
The analysis of duration of disease control will include only patients who have achieved SD or 
better based on the safety population. 
Duration of disease control will be summarized using KM method. The 25th, 50th (median) and 
75th percentiles, alone with associated 2-sided 95% CIs based on Brookmeyer and Crowley 
method.  
 
TTP 
TTP is defined as the time the date of randomization to the first documentation of confirmed PD 
per IMWG criteria, or death due to PD.   
TTP (months) = (earliest date of progression or death due to PD or censor – date of 
randomization + 1)/30.4375. 
The analysis of TTP will be based on the ITT population.  
TTP will be summarized using KM method. The K-M curves, the 25th, 50th (median) and 75th 
percentiles, alone with associated 2-sided 95% CIs based on Brookmeyer and Crowley method, 
and the K-M probability estimates with 95% CIs at 3, 6, 9 and 12 months (or later time points if 
applicable) will be presented. The number of patients with events and the number of patients 
censored will be summarized. Sensitivity analysis based on the safety population will also be 
provided.  


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TTR 
TTR is defined as the time from the date of first dose administration of any study drug to the date 
of first documentation of confirmed PR or better.  
The analysis of TTR will include only responders (PR or better) based on the safety population.  
TTR will be summarized using descriptive statistics with mean and 95% CI.  
 
TTNT 
TTNT is defined as the time from the date of first dose administration of any study drug to the 
date of the first dose initiation of the next line of anticancer therapy for any reason or death from 
any cause, whichever occurs first. Patients who neither started the next-line therapy nor die will 
be censored at the date last known to be alive before subsequent anticancer therapy. Patients who 
do not have any post-baseline follow-up assessments and who have not died will be censored at 
the date of first dose administration.  
TTNT (months) = (earliest date of next line or death or censor – date of first dose + 1)/30.4375. 
The analysis of TTNT will be based on the safety population.   
TTNT will be summarized using KM method. The K-M curves, the 25th, 50th (median) and 75th 
percentiles, alone with associated 2-sided 95% CIs based on Brookmeyer and Crowley method, 
and the K-M probability estimates with 95% CIs at 3, 6, 9 and 12 months (or later time points if 
applicable) will be presented. The number of patients with events along with the type of events 
(death or next line of anticancer therapy) and the number of patients censored will be 
summarized.  
 
PFS 
PFS is defined as the time from the date of randomization to the date of confirmed disease 
progression or death due to any cause, whichever occurs first.  
Censoring rule would follow Table 1 except for replacing “the date of first dose” with “the date 
of randomization”.  
PFS (months) = (earliest date of progression or death or censor – date of randomization + 
1)/30.4375. 
PFS would be analyzed in the same way as described in Section 6.6.2.1 based on the ITT 
population. Sensitivity analysis based on the safety population may also be provided. 
 
OS 
OS is defined as the time from the date of randomization to the date of death due to any cause.  


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OS (months) = (date of death or censor – date of randomization + 1)/30.4375. 
OS would be analyzed in the same way as described in Section 6.6.2.1 based on the ITT 
population. Sensitivity analysis based on the safety population will also be provided. 
 
MRD[-] CR rate 
MRD[-] CR rate is defined in Section 6.6.2.1 and will be analyzed in the same way based on the 
safety population.   
 
MRD[-] rate 
MRD[-] rate is defined in Section 6.6.2.1 and will be analyzed in the same way based on the 
safety population.   
 
Duration of MRD negativity 
Duration of MRD negativity is defined in Section 6.6.2.1 and will be analyzed in the same way 
based on the safety population.   
 
6.6.3 
Exploratory Endpoints Analysis 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
6.6.4 
Subgroup Analyses 
Please see Section 6.6.1.3. 


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6.7 
Safety Analysis 
Safety will be evaluated by the frequency of AEs, severity and type of AEs, and by changes from 
baseline in patients’ vital signs, weights, ECOG performance status, ECG results, and clinical 
laboratory results.  
All safety analyses will be performed using the safety population. Unless otherwise specified, all 
safety analyses will be reported according to actual study treatment received. 
 
6.7.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0 or later (based on the version at time of database lock) with the severity graded by 
the NCI CTCAE Version 5.0 or later (based on the version at time of database lock). Treatment-
emergent is defined as any AE that occurs after administration of the first dose of any study drug 
through 30 days after the last dose of any study drug.  
Treatment-emergent AEs will be summarized by MedDRA system organ class (SOC) and 
preferred term (PT) by dose level. 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: 
 
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 
Lymphocyte count decreased 
Lymphopenia 
 
Summary tabulations will include the following categories by SOC/PT unless otherwise 
specified: 
• Treatment-emergent AEs (by PT as well). 
• Drug-related treatment-emergent AEs. 


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• Grade 3 or higher treatment-emergent AEs. 
• Grade 3 or higher drug-related treatment-emergent AEs. 
• Grade 3 and Grade 4 treatment-emergent AEs (based on maximum severity, by PT as well). 
• Grade 5 treatment-emergent AEs. 
• Grade 5 drug-related treatment-emergent AEs.  
• The most commonly reported treatment-emergent AEs (i.e., those events reported by >= 10% 
of all patients, by PT only). 
• Serious treatment-emergent adverse events (SAEs) (based on maximum severity). 
• Drug-related treatment-emergent SAEs. 
• Grade 3 or higher treatment-emergent SAEs. 
• Grade 3 or higher drug-related treatment-emergent SAEs. 
• Grade 3 and Grade 4 treatment-emergent SAEs (based on maximum severity). 
• Grade 3 and Grade 4 drug-related treatment-emergent SAEs (based on maximum severity). 
• Treatment-emergent AEs resulting in discontinuation of study drug. 
• Treatment-emergent AEs resulting in study drug modifications (including discontinuation, 
delay, reduction, and interruption). 
• Treatment-emergent AEs resulting in dose delays. 
• Treatment-emergent AEs resulting in dose reductions. 
• Treatment-emergent AEs resulting in infusion rate reductions 
• Treatment-emergent AEs resulting in drug interruptions. 
• Treatment-emergent AEs resulting in drug infusion interruptions. 
• Treatment-emergent AESI – all Grades (by PT as well). 
• Treatment-emergent AESIs Grade 3 or Grade 4. 
• Treatment-emergent AESIs Grade 5.  
• Serious treatment-emergent AESIs. 
All summaries will be by dose levels by phases (phase 1 escalation and phase 2a dose finding) 
for patients in the safety population.  
Patients with the same AE more than once will have that event counted only once within each 
SOC, and once within each preferred term. Patients with the same AE more than once will have 
only the maximum intensity of that event counted once within each SOC, and once within each 
preferred term. 


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Most commonly reported (at least 10% of all patients) treatment-emergent AEs will be presented 
by preferred term only. Patients with multiple occurrences of the same AE will have that event 
counted only once within each preferred term. 
An overall summary treatment-emergent AE table will include numbers and percentages of 
patients who had any treatment-emergent AE, drug-related treatment-emergent AE, Grade 3 or 
higher treatment-emergent AE, grade 3 or higher drug-related treatment-emergent AE, serious 
treatment-emergent AE, drug-related serious treatment-emergent AE, serious treatment-emergent 
AE leading to study drug discontinuation, treatment-emergent AE resulting in study drug 
discontinuation, and on-study deaths. 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 
more than 30 days after the last dose of study drug but are assessed as study drug-related.  
A by-patient listing of DLTs as identified by the investigator that occur during Cycle 1 of 
treatment will be presented by dose levels for all patients enrolled during the phase 1 dose 
escalation portion of this study. 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.  
A by-patient listing of all deaths regardless of whether on study or not will also be presented. In 
this listing, on-study deaths will be flagged. 
6.7.2 
Adverse Events of Special Interest 
AE of special interest from a scientific and medical perspective (AESI) will be reported by SOC 
and preferred terms. In this study, infusion-related reactions (IRR) are considered as AESIs. The 
IRR signs and symptoms will be counted with other AEs in the treatment-emergent AE tables 
with other AEs, and also reported separately in AESI tables.  
 
6.7.3 
Clinical Laboratory Evaluations 
For the purposes of summarization in both the tables and listings, all laboratory values 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. Laboratory test results will be summarized according to the scheduled 
sample collection time point. Change from baseline will be presented. Scheduled laboratory 
along with unscheduled lab test results will be listed. Unscheduled laboratory test results will be 
included in the laboratory shift tables.  
Lab parameters to be analyzed are as follows: 
• Hematology: Hematocrit, Hemoglobin, Platelet count, Leukocytes with differential, 
Neutrophils (ANC). 


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• Chemistry: albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen, calcium, 
bicarbonate (HCO3) or carbon dioxide (CO2), creatinine, standard C-reactive protein, 
chloride, glucose, lactate dehydrogenase, magnesium, phosphate, potassium, sodium, 
urate, thyroid function test. 
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
Version 5.0. 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 dose level. Mean values over time for platelets and ANC will be produced. 
6.7.4 
Vital Signs 
For dose escalation cohorts, descriptive statistics for vital sign results (diastolic and systolic 
blood pressure, respiratory rate, pulse rate, oxygen saturation and body weight) will be 
summarized by 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. 
 
 
6.7.5 
12-Lead ECGs 
ECG data (ventricular rate, RR interval, PR interval, QT interval, and QTcF interval) will be 
summarized by 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- 


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<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. 
 
6.7.6 
Other Observations Related to Safety 
Shifts from baseline to the worst post-baseline ECOG score will be tabulated. 
 
6.8 
Pharmacokinetic, 
, and Biomarker Analyses 
6.8.1 
Pharmacokinetic Analysis 
6.8.1.1 
Serum Modakafusp alfa Concentrations 
Blood samples will be collected at prespecified time points as described in the study protocol for 
the measurement of serum modakafusp alfa and daratumumab concentrations. Individual serum 
concentration data will be listed by patient, dose level, study day, and sampling time. Both 
nominal (scheduled) and actual sampling times will be presented in the listings. 
Serum modakafusp alfa and daratumumab concentrations will be summarized by nominal time 
post dose, grouped by dose level, nominal infusion duration, and study day by phases (escalation 
and dose finding). Summary statistics will be reported at nominal sampling times; means will be 
reported if the number of observations above the lower limit of quantitation (NALQ) is ≥50% 
of the number of patients. The summary statistics will consist of: N, NALQ, arithmetic mean, 
standard deviation (SD), coefficient of variation (CV), geometric mean, geometric CV, median, 
min, and max. The SD and CV will be reported on at least 3 non-missing values. Modakafusp 
alfa concentrations that are below the limit of quantitation (BLQ) will be set to zero for 
calculation of summary statistics, except for geometric means, where BLQ values will be 
considered missing. 
Concentration data that are considered anomalous may be excluded from the concentration 
summaries and plots. Evidence or explanations will be provided in the clinical study report to 
justify the exclusion of concentration data.  
Mean and individual modakafusp alfa and daratumumab serum concentration data will be plotted 
over nominal sampling time, grouped by dose level, nominal infusion duration, and study day on 
both linear and semi-logarithmic scales. Mean and individual serum concentrations will be 
plotted over time (labeled with cycle number), grouped by dose level on a linear scale by phases 
(escalation and dose finding). Visual inspection of the serum concentration-time plots will be 
used to make inferences regarding the attainment of PK steady-state by cycle. BLQ values will 
be plotted as zero on a linear scale and treated as missing on a semi-logarithmic scale. 


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6.8.1.2 
Serum PK Parameters (Phase 1 Dose Escalation) 
The serum PK concentration-time course data will be used to calculate standard PK parameters 
using noncompartmental methods with Phoenix WinNonlin.  
 
Actual sampling times will be used for the calculation of PK parameters. In the event that actual 
collection times are either unreliable or missing, nominal collection times will be used. For the 
calculation of PK parameters, serum concentrations of modakafusp alfa that are BLQ will be 
treated as zero prior to tmax, missing between tmax and the time of the last measurable 
concentration, and the concentration-time curve will be considered to have terminated at the time 
of the last measurable concentration. If measurable concentrations are near the lower limit of 
quantification (LLOQ) or imbedded between BLQ concentrations, these values may be excluded 
at the discretion of the Clinical Pharmacologist. Concentration data that are considered 
anomalous may not be used in the calculation of PK parameters; evidence or explanations will be 
provided in the clinical study report to justify the exclusion of data. In addition, patients with 
several missing samples around the expected Tmax and patients for whom AUC estimation was 
considered not be reliable due to several missing samples (50% or more of the data are missing) 
may be excluded from the PK parameter (Cmax and/or AUC) calculation and PK parameter 
summary. 
 
The following PK parameters for modakafusp alfa will be determined, as permitted by data: 
• Cmax. 
• tmax. 
• AUC∞. 
• AUClast. 
• λz. 
• t1/2z. 
• CL. 
• Vss. 
• Accumulation ratio based on AUClast.  
 
The following PK parameters for daratumumab will be determined, as permitted by data: 
• Cmax. 
• tmax. 
• 
Ctrough (for daratumumab) 
• AUC∞. 
• AUClast. 
 


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Individual PK parameters will be presented in listings, PK parameters for Cycle 1 Day 1, Cycle 1 
Day 15, Cycle 2 Day 1, and Cycle 2 Day 15, as appropriate, will be summarized and grouped by 
dose level, and study day by phases (escalation and dose finding). The SD and CV will be 
reported on at least 3 non-missing values. Except for tmax, the summary statistics will consist of: 
N, mean, SD, CV, geometric mean, geometric CV, median, min, and max. The summary 
statistics for tmax will consist of: N, median, min, and max. 
 
The PK data collected in this study (phase 1 dose escalation and phase 2 dose finding) are 
intended to contribute to future population PK analyses of modakafusp alfa. These population 
PK analyses may include data collected in other modakafusp alfa clinical studies. The analysis 
plan for the population PK analysis will be separately defined, and the results of these analyses 
will not be reported in the clinical study report. 
 
6.8.2 
 
 
 
  
 
 
 
 
 
 
 
6.8.3 
Immunogenicity Analysis 
The immunogenicity of modakafusp alfa will be assessed by determining anti–modakafusp alfa 
antibody (ADA) incidence and characteristics (eg, titer and specificity) and by determining 
neutralizing antibody (NAb) incidence. All ADA and NAb data will be listed. Percent of patients 
with positive ADA or NAb, percent of patients with positive ADA by domain specificity, and 
summary statistics of ADA titer at each timepoint will be summarized by dose levels by study 
phases (escalation and dose finding). Percent of patients with positive ADA and NAb at baseline 
and positive ADA (final result and by domain specificity) and NAb at any post-baseline time 
point during the study will be summarized. Additional summary of the ADA kinetics including 
transient- vs. persistent-ADA, preexisting ADA, treatment-induced, or treatment-boosted ADA 
will be summarized, as applicable. ADA titer distribution over time will be presented through a 
boxplot on a logarithmic scale. 
 


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7.0 
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