Conditions: Refractory Multiple Myeloma Relapsed Multiple Myeloma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
This is a first-in-human Phase I, open-label, multicenter, global, dose-escalation study designed to evaluate the safety, tolerability, and pharmacokinetics of RO7297089 and make a preliminary assessment of anti-tumor activity in patients with R/R MM for whom no established therapy for MM is appropriate and available or who are intolerant to those established therapies.

Detailed description:

Arms:
arm 1: Participants in Arm A will receive the target dose of RO7297089 as a flat dose at each scheduled study drug administration visit arm 2: Participants in Arm B will receive the first target dose of RO7297089 as a split dose divided over two days (Days 1 and 2). The full target dose will be administered at subsequent study drug administration visits. arm 3: No participants enrolled. Enrollment for the GO41582 study was stopped in July 2021 due to limited activity as a single agent which did not meet the Sponsor's internal criteria for further clinical development. arm 4: No participants enrolled. Enrollment for the GO41582 study was stopped in July 2021 due to limited activity as a single agent which did not meet the Sponsor's internal criteria for further clinical development.

Interventions: intervention 1: RO7297089
Intervention descriptions: intervention 1: RO7297089 will be given via intravenous (IV) infusion

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
RO7297089—Genentech, Inc.
Protocol GO41582, Version 4
PROTOCOL
TITLE:
AN OPEN-LABEL, MULTICENTER, PHASE I TRIAL 
EVALUATING THE SAFETY AND 
PHARMACOKINETICS OF ESCALATING DOSES 
OF RO7297089 IN PATIENTS WITH RELAPSED 
OR REFRACTORY MULTIPLE MYELOMA
PROTOCOL NUMBER:
GO41582
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-003540-76
IND NUMBER:
To be determined
NCT NUMBER: 
NCT04434469
TEST PRODUCT:
RO7297089 (BPCT2605S)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below
 
10-Nov-2020 02:40:06
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7297089—Genentech, Inc.
2/Protocol GO41582, Version 4
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
4
See electronic date 
stamp on title page



3
18 September 2020



2
23 April 2020
Belgium
2
30 July 2020
Norway
2
10 May 2020
1
25 November 2019





RO7297089—Genentech, Inc.
3/Protocol GO41582, Version 4
PROTOCOL AMENDMENT, VERSION 4
RATIONALE
Protocol GO41582 has been amended to add the option to implement up to three 
dose-escalation arms in a given dose cohort to mitigate the risk of infusion-related
reactions (IRRs). These dose-escalation arms differ in the schedule of RO7297089 
administration in Cycle 1. In addition, this amendment modifies eligibility criteria related 
to serum monoclonal protein (M-protein) levels and serum calcium levels.  Changes to 
the protocol, along with a rationale for each change, are summarized below.
The following changes have been incorporated in Version 4:

Section 3.1.1 has been revised to add an option for up to three dose-escalation 
arms in a dose cohort.  These dose-escalation arms define the Cycle 1 
administration schedule for RO7297089 and include a flat-dose arm (Arm A), a split-
dose arm (Arm B), and a step-dose arm (Arm C). The criteria for the opening and 
enrollment into each of these arms are also described.

Additional changes regarding the dose-escalation arms are as follows:
–
Section 3.1.3 has been revised to specify that RO7297089 administration for 
the first cycle after intrapatient dose escalation may follow any administration 
schedule previously evaluated in the study.
–
Section 3.1.5 has been revised to specify that the Internal Safety Committee 
(ISC) will make decisions in consultation with study investigators regarding 
opening Arm B and/or Arm C for a given dose cohort.
–
Section 3.3.2 has been revised to include rationale for the dose-escalation 
arms.
–
Section 4.3.2.1 has been revised to include additional dosing instructions 
regarding the additional dose-escalation arms.
–
Section 4.5.5 has been revised to include additional vital sign monitoring 
instructions regarding the additional dose-escalation arms. 
–
Appendix 1 and Appendix 3 have been revised to reflect the additional 
timepoints and assessments regarding the additional dose-escalation arms.

Section 4.1.1 has been revised to update the inclusion criterion for serum M-protein 
concentration from 1.0 g/dL (10 g/L) to 0.5 g/dL (5 g/L).  This revision was 
made on the recommendation of investigators based on the patient population for 
this study.  Additionally, at least three historical values for serum M-protein (or 
serum free light chains [SFLC], if light chainonly disease) from the end of prior 
therapy to the initiation of study treatment with RO7297089 will be collected if 
available (Section 4.5.6 and Appendix 1).


RO7297089—Genentech, Inc.
4/Protocol GO41582, Version 4

Section 4.1.1 has been revised to update the inclusion criterion for serum calcium 
concentration (corrected for albumin) from a threshold of the upper limit of normal 
(ULN) to a threshold of 11.5 mg/dL (2.9 mmol/L).  This new threshold is consistent 
with NCI CTCAE v5.0 guidelines for hypercalcemia and removes the threshold 
variability that occurs when local laboratory ranges are used.

Section 4.1.2 has been revised to clarify the exclusion criterion regarding previous 
treatment with systemic immunosuppressive medications.  

Section 5.1.1.1 has been revised to provide recent information regarding IRR events 
in this study and to reiterate premedication instructions accordingly.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


RO7297089—Genentech, Inc.
5/Protocol GO41582, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Multiple Myeloma.......................................... 28
1.2
Background on RO7297089 .................................................. 28
1.3
Study Rationale and BenefitRisk Assessment..................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
2.1
Safety Objective (Primary Study Objective)........................... 32
2.2
Pharmacokinetic Objectives .................................................. 33
2.3
Activity Objectives ................................................................. 33
2.4
Immunogenicity Objectives.................................................... 33
2.5
Biomarker Objective .............................................................. 34
2.6
Additional Objective............................................................... 34
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of the Study......................................................... 34
3.1.1
Dose-Escalation Stage .......................................................... 36
3.1.1.1
Definition of Dose-Limiting Toxicity........................................ 39
3.1.1.2
Dose-Escalation Rules .......................................................... 41
3.1.2
Continued Dosing Beyond the Dose-Limiting 
Toxicity Observation Period (Cycles ≥2)................................ 41
3.1.3
Intrapatient Dose Escalation.................................................. 42
3.1.4
Expansion Stage ................................................................... 42
3.1.5
Internal Safety Committee ..................................................... 42
3.2
End of Study and Length of Study......................................... 43
3.3
Rationale for Study Design.................................................... 43
3.3.1
Rationale for Patient Population ............................................ 43
3.3.2
Rationale for RO7297089 Dose and Schedule...................... 44
3.3.3
Rationale for Dose-Escalation Plan....................................... 45
3.3.4
Rationale for PK Sampling Schedule..................................... 46
3.3.5
Rationale for Biomarker Assessments................................... 46
4.
MATERIALS AND METHODS .................................................................... 47


RO7297089—Genentech, Inc.
6/Protocol GO41582, Version 4
4.1
Patients.................................................................................. 47
4.1.1
Inclusion Criteria.................................................................... 48
4.1.2
Exclusion Criteria................................................................... 50
4.2
Method of Treatment Assignment.......................................... 53
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 53
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 53
4.3.1.1
RO7297089 ........................................................................... 53
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 53
4.3.2.1
RO7297089 ........................................................................... 53
4.3.3
Investigational Medicinal Product Accountability ................... 55
4.3.4
Continued Access to RO7297089 ......................................... 56
4.4
Concomitant Therapy ............................................................ 57
4.4.1
Permitted Therapy................................................................. 57
4.4.2
Cautionary Therapy ............................................................... 58
4.4.2.1
Medications Given with Precaution due to Effects 
Related to CYP Enzymes ...................................................... 58
4.4.2.2
Herbal Therapies................................................................... 58
4.4.3
Prohibited Therapy ................................................................ 58
4.5
Study Assessments............................................................... 59
4.5.1
Informed Consent Forms and Screening Log........................ 59
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 60
4.5.3
Physical Examinations........................................................... 60
4.5.4
ECOG Performance Status ................................................... 60
4.5.5
Vital Signs.............................................................................. 60
4.5.6
Disease-Specific Assessments.............................................. 61
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.8
Electrocardiograms................................................................ 67
4.5.9
Blood Samples for Whole Genome Sequencing.................... 68
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 69


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4.5.10.1
Overview of the Research Biosample Repository.................. 69
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 69
4.5.10.3
Sample Collection.................................................................. 70
4.5.10.4
Confidentiality........................................................................ 70
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 71
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 71
4.5.10.7
Monitoring and Oversight....................................................... 72
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 72
4.6.1
Study Treatment Discontinuation........................................... 72
4.6.1.1
Survival and Subsequent Anti-Cancer Therapy 
Follow-Up .............................................................................. 73
4.6.2
Patient Discontinuation from the Study.................................. 73
4.6.3
Study Discontinuation............................................................ 73
4.6.4
Site Discontinuation............................................................... 74
5.
ASSESSMENT OF SAFETY....................................................................... 74
5.1
Safety Plan ............................................................................ 74
5.1.1
Potential Risks Associated with RO7297089......................... 75
5.1.1.1
Infusion-Related Reactions/Cytokine-Release 
Syndrome .............................................................................. 75
5.1.1.2
Immunogenicity ..................................................................... 76
5.1.1.3
Infection................................................................................. 77
5.1.1.4
Blood Pressure Decrease...................................................... 77
5.1.1.5
Tumor Lysis Syndrome.......................................................... 78
5.1.1.6
Lymphopenia......................................................................... 79
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 79
5.1.2.1
Dose Modifications and Interruptions .................................... 79
5.1.2.2
Management Guidelines for Infusion-Related 
Reactions/Cytokine-Release Syndrome ................................ 80
5.1.2.3
Management of Increases in QT Interval............................... 81
5.2
Safety Parameters and Definitions ........................................ 82


RO7297089—Genentech, Inc.
8/Protocol GO41582, Version 4
5.2.1
Adverse Events ..................................................................... 82
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 83
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 84
5.2.4
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor)...................................................................... 84
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 84
5.3.1
Adverse Event Reporting Period ........................................... 85
5.3.2
Eliciting Adverse Event Information....................................... 85
5.3.3
Assessment of Severity of Adverse Events ........................... 85
5.3.4
Assessment of Causality of Adverse Events ......................... 86
5.3.5
Procedures for Recording Adverse Events............................ 87
5.3.5.1
Infusion-Related Reactions and Cytokine-
Release Syndrome................................................................ 87
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 88
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 88
5.3.5.4
Persistent or Recurrent Adverse Events................................ 88
5.3.5.5
Abnormal Laboratory Values ................................................. 89
5.3.5.6
Abnormal Vital Sign Values ................................................... 89
5.3.5.7
Abnormal Liver Function Tests.............................................. 90
5.3.5.8
Deaths ................................................................................... 90
5.3.5.9
Preexisting Medical Conditions.............................................. 91
5.3.5.10
Lack of Efficacy or Worsening of Multiple 
Myeloma................................................................................ 91
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 91
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 92
5.3.5.13
Safety Biomarker Data........................................................... 93
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 93
5.4.1
Emergency Medical Contacts................................................ 94


RO7297089—Genentech, Inc.
9/Protocol GO41582, Version 4
5.4.2
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities......................................................... 94
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 94
5.4.2.2
Events That Occur after Study Drug Initiation........................ 94
5.4.3
Reporting Requirements for Pregnancies.............................. 95
5.4.3.1
Pregnancies in Female Patients............................................ 95
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 95
5.4.3.3
Abortions ............................................................................... 96
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 96
5.5
Follow-Up of Patients after Adverse Events .......................... 96
5.5.1
Investigator Follow-Up........................................................... 96
5.5.2
Sponsor Follow-Up ................................................................ 97
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 97
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 97
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98
6.1
Determination of Sample Size ............................................... 98
6.2
Summaries of Conduct of Study............................................ 98
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 98
6.4
Safety Analyses..................................................................... 99
6.4.1
Analyses of Exposure, Adverse Event, 
Laboratory, and Vital Sign Data........................................... 100
6.5
Pharmacokinetic Analyses................................................... 100
6.6
Activity Analyses.................................................................. 101
6.7
Immunogenicity Analyses.................................................... 101
6.8
Interim Analyses .................................................................. 102
7.
DATA COLLECTION AND MANAGEMENT ............................................. 102
7.1
Data Quality Assurance....................................................... 102
7.2
Electronic Case Report Forms............................................. 103
7.3
Source Data Documentation................................................ 103


RO7297089—Genentech, Inc.
10/Protocol GO41582, Version 4
7.4
Use of Computerized Systems ............................................ 104
7.5
Retention of Records........................................................... 104
8.
ETHICAL CONSIDERATIONS.................................................................. 104
8.1
Compliance with Laws and Regulations .............................. 104
8.2
Informed Consent................................................................ 105
8.3
Institutional Review Board or Ethics Committee.................. 106
8.4
Confidentiality...................................................................... 106
8.5
Financial Disclosure ............................................................ 107
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 107
9.1
Study Documentation .......................................................... 107
9.2
Protocol Deviations.............................................................. 107
9.3
Site Inspections ................................................................... 107
9.4
Administrative Structure....................................................... 108
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 108
9.6
Protocol Amendments ......................................................... 109
10. REFERENCES ......................................................................................... 110
LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
RO7297089................................................................................. 55
Table 2
Vital Sign Monitoring................................................................... 61
Table 3
Management Guidelines for Infusion-Related Reactions ............ 81
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 86
Table 5
Causal Attribution Guidance ....................................................... 87
LIST OF FIGURES
Figure 1
Study Design............................................................................... 36
Figure 2
Dose-Escalation Arms:  Study Drug Administration for 
Cycle 1 ........................................................................................ 38


RO7297089—Genentech, Inc.
11/Protocol GO41582, Version 4
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 113
Appendix 2
Schedule of Activities:  Post-Treatment Follow-Up ................... 119
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples................................................................... 120
Appendix 4
Guidelines for the Determination of Prior Lines of Therapy ...... 124
Appendix 5
International Myeloma Working Group Uniform Response 
Criteria (2016)........................................................................... 125
Appendix 6
Modified CockcroftGault Equation (Using Ideal Body Mass 
Instead of Mass) ....................................................................... 128
Appendix 7
Recommended Anaphylaxis Management ............................... 129
Appendix 8
Examples of Sensitive In Vivo CYP Substrates and CYP 
Substrates with Narrow Therapeutic Range ............................. 130
Appendix 9
Modified Cytokine-Release Syndrome Grading System ........... 131
Appendix 10
Management Guidelines for Cytokine-Release Syndrome ....... 132
Appendix 11
Modified Continuous Reassessment Method with Escalation 
with Overdose Control Design .................................................. 138
Appendix 12
Diagnosis and Management of Hemophagocytic 
Lymphohistiocytosis (HLH) and Macrophage Activation 
Syndrome (MAS) ...................................................................... 146
Appendix 13
AIDS-Defining Illnesses ............................................................ 148
Appendix 14
Criteria for Identifying Multiple Myeloma Patients at High 
Risk for Tumor Lysis Syndrome................................................ 149
Appendix 15
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 150


RO7297089—Genentech, Inc.
12/Protocol GO41582, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, MULTICENTER, PHASE I TRIAL 
EVALUATING THE SAFETY AND 
PHARMACOKINETICS OF ESCALATING DOSES 
OF RO7297089 IN PATIENTS WITH RELAPSED OR 
REFRACTORY MULTIPLE MYELOMA
PROTOCOL NUMBER:
GO41582
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-003540-76
IND NUMBER:
To be determined
NCT NUMBER:
NCT04434469
TEST PRODUCT:
RO7297089 (BPCT2605S)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please retain a copy of 
the signed form as instructed by the Sponsor.


RO7297089—Genentech, Inc.
13/Protocol GO41582, Version 4
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, MULTICENTER, PHASE I TRIAL EVALUATING 
THE SAFETY AND PHARMACOKINETICS OF ESCALATING 
DOSES OF RO7297089 IN PATIENTS WITH RELAPSED OR 
REFRACTORY MULTIPLE MYELOMA
PROTOCOL NUMBER:
GO41582
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-003540-76
IND NUMBER:
To be determined
NCT NUMBER:
NCT04434469
TEST PRODUCT:
RO7297089 (BPCT2605S)
PHASE:
I
INDICATION:
Relapsed or refractory multiple myeloma
SPONSOR:
Genentech, Inc.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety and pharmacokinetics of RO7297089 in patients with 
relapsed or refractory (R/R) multiple myeloma (MM) and make a preliminary assessment of 
anti-tumor activity.  Specific objectives and corresponding endpoints for the study are outlined 
below.
Safety Objective (Primary Study Objective)
The safety objective for this study is to evaluate the safety of RO7297089, including estimation 
of the maximum tolerated dose (MTD) and characterization of dose-limiting toxicities (DLTs), on 
the basis of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) and the Modified Cytokine-Release Syndrome Grading 
System

Change from baseline in targeted vital signs

Change from baseline in targeted ECG parameters

Change from baseline in targeted clinical laboratory test results

Relationship between RO7297089 dose and safety, pharmacokinetic (PK), activity, and 
immunogenicity endpoints
Pharmacokinetic Objectives
The PK objective for this study is to characterize the RO7297089 PK profile on the basis of the 
following endpoints:

Serum concentration of RO7297089 at specified timepoints

PK parameters for RO7297089
The exploratory PK objectives for this study are as follows:

To evaluate potential relationships between drug exposure and the safety and activity of 
RO7297089 on the basis of the following endpoints:


RO7297089—Genentech, Inc.
14/Protocol GO41582, Version 4

Relationship between serum concentration or PK parameters for RO7297089 and 
safety endpoints

Relationship between serum concentration or PK parameters for RO7297089 and 
activity endpoints

To evaluate potential relationships between selected covariates and exposure to 
RO7297089 on the basis of the following endpoint:

Relationship between selected covariates and serum concentration or PK parameters 
for RO7297089
Activity Objectives
The activity objective for this study is to make a preliminary assessment of the activity of 
RO7297089 on the basis of the following endpoints:

Objective response rate, defined as a stringent complete response, complete response, 
very good partial response, or partial response, as determined by the investigator according 
to International Myeloma Working Group (IMWG) Uniform Response Criteria

Duration of response, defined as the time from the first occurrence of a documented 
objective response to disease progression or death from any cause (whichever occurs first), 
as determined by the investigator according to IMWG Uniform Response Criteria
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to RO7297089 
on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and safety, PK, biomarker, or activity endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to RO7297089 (i.e., predictive biomarkers), are early surrogates of 
activity, are associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), are associated with acquired resistance to RO7297089, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of RO7297089 activity (i.e., 
pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoint:

Relationship between biomarkers in blood and tissue samples (listed in the protocol) and 
safety, PK, activity, immunogenicity, or other biomarker endpoints
Additional Objective
An additional objective for this study is to identify a recommended Phase II dose (RP2D) and 
regimen for RO7297089 on the basis of the following endpoint:

Relationship between RO7297089 exposure and safety, PK, activity, and immunogenicity 
endpoints
STUDY DESIGN
Description of Study
This is a first-in-human Phase I, open-label, multicenter, global, dose-escalation study designed 
to evaluate the safety, tolerability, and pharmacokinetics of RO7297089 and make a preliminary 
assessment of anti-tumor activity in patients with R/R MM for whom no established therapy for 
MM is appropriate and available or who are intolerant to those established therapies.  The study 
consists of a screening period of up to 28 days and a minimum follow-up period of 90 days after 
treatment.  Following confirmation of eligibility, patients will receive RO7297089 by IV infusion.  
Patients will be enrolled in two stages:  a dose-escalation stage and an expansion stage.  To 
mitigate the risk of infusion-related reactions (IRRs), up to three dose-escalation arms that 


RO7297089—Genentech, Inc.
15/Protocol GO41582, Version 4
differ in the RO7297089 administration schedule for Cycle 1 may be enrolled in a 
dose-escalation cohort.  The study will enroll approximately 3050 patients during the dose-
escalation stage and approximately 30 patients during the expansion stage at approximately 12 
sites globally.  
Patients who do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of two screenings per participant) at the 
investigator's discretion.  Patients must re-sign the consent form prior to re screening.  The 
investigator will record reasons for screen failure in the screening log.
All patients will be closely monitored for adverse events throughout the study and for at least 
90 days after the final dose of study treatment.  Adverse events will be graded according to the 
NCI CTCAE v5.0, with the exception of cytokine-release syndrome (CRS), which will be graded 
according to the Modified Cytokine-Release Syndrome Grading System.
Patients may continue treatment with RO7297089 until disease progression as determined by 
the investigator using IMWG Uniform Response Criteria, unacceptable toxicity, start of new 
anti-cancer therapy, or withdrawal from study participation, whichever occurs first. 
Dose-Escalation Stage
Approximately 3050 patients will be enrolled in the dose-escalation stage.  The dose-
escalation stage of the study will assess the safety, tolerability, and pharmacokinetics of 
RO7297089 administered by IV infusion.  The cycle length is 14 days.  
To mitigate the risk of IRRs, up to three dose-escalation arms may be enrolled in a given dose 
cohort.  These arms differ in the RO7297089 administration schedule for Cycle 1:

Arm A (Flat Dose-Escalation Arm).  Patients in Arm A will receive the Cycle 1 target 
dose of RO7297089 as a flat dose independent of body weight on Day 1 and Day 8.  
Dosing for Cycle 2 and beyond will follow the same administration schedule. The DLT 
assessment window for Arm A is 14 days (Cycle 1, Days 114).

Arm B (Split Dose-Escalation Arm).  Patients in Arm B will receive the first dose in 
Cycle 1 as a split dose.  The initial target dose of RO7297089 will be divided over 2 days 
(Days 1 and 2), and the full target dose will be administered on Day 8.  
Initially, the dose will be divided such that 50% of the target dose is administered on 
Day 1 and the remaining 50% on Day 2.  If the Day 1 dose is associated with a 
Grade ≥2 IRR, the ratio may be adjusted for subsequent patients so that a smaller 
percentage of the dose is administered on Day 1, with the remainder of the dose 
administered on Day 2.  For example, 25% of the target dose administered on Day 1 
and the remaining 75% administered on Day 2.
If a patient does not receive the full planned dose on Day 1 because of scheduling 
reasons but has received at least 75% of the intended Day 1 dose, the patient may 
proceed with the Day 2 infusion to receive the remainder of the full target dose.
For Cycle 2 and beyond, RO7297089 will be administered on Day 1 and Day 8 of each 
14-day cycle.  The DLT assessment window for Arm B is 14 days (Cycle 1, Days 114).

Arm C (Single-Step Dose-Escalation Arm).  Patients in Arm C will receive the first 
cycle of RO2797089 as a single-step dose escalation.  The Cycle 1, Day 1 dose will be 
60 mg, followed by the full target dose on Day 8.  For Cycle 2 and beyond, the target dose 
of RO7297089 will be administered on Day 1 and Day 8 of each 14-day cycle.  The DLT 
assessment window for Arm C is 14 days (Cycle 1, Day 8 to Cycle 2, Day 7, to allow for 
two target doses); the window excludes the Cycle 1, Day 1 60-mg dose, which has already 
cleared.    
For all arms, the target dose refers to the highest dose administered in Cycle 1; this target 
dose will be administered on Day 1 and Day 8 of subsequent cycles.  
Enrollment in the dose-escalation arms will be managed as follows:

For new dose cohorts, all patients will enroll in Arm A unless criteria have been met for 
opening Arms B or C in a previous cohort.


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
Arm B may open if the planned infusion time for Arm A exceeds 4 hours on Cycle 1, 
Day 1.  Arm C may open if 2 or more patients in Arm B of that dose cohort experience 
any grade IRR that precludes the patient from receiving the full target dose during 
Cycle 1, Day 1 and Day 2.  

Once Arm B is open, Arm A for that dose cohort may close to further enrollment and may 
not open for subsequent dose cohorts.  Similarly, once Arm C is open, Arm B for that dose 
cohort may close to further enrollment and may not open for subsequent dose cohorts.

A minimum of 3 patients must complete the DLT assessment period for a given arm 
(Arm A, B, or C) before dose escalation for that arm may occur.
Dose escalations will be guided by the modified continual reassessment method of escalation 
with overdose control (mCRM-EWOC) model (Neuenschwander et al. 2008).  All cohorts will 
enroll a minimum of 3 patients.  Enrollment of the first 2 patients in each arm of each dose-
escalation cohort will be staggered such that the respective Cycle 1, Day 1 treatments are 
administered 72 hours apart.  The maximal dose escalation increment recommended by the 
model will be 3-fold.  In addition, the relevant demographic, adverse event, laboratory, dose 
administration, and available PK data will be reviewed prior to dose-escalation decisions, which 
will be made by an Internal Safety Committee (ISC) in consultation with the investigator.  
Evidence of clinical activity at a given dose level (e.g., decrease in serum monoclonal protein 
[M-protein]) or PD activity (e.g., NK cell activation) may ungate backfill cohorts at doses that 
have already completed DLT assessment and have been found not to exceed the MTD in 
escalation cohorts.  DLT information from patients in these back-fill cohorts will be used to 
inform the mCRM-EWOC model.  
Patients will be closely monitored for adverse events during a DLT assessment window
(14 days), as defined above for each arm.  Adverse events identified as DLTs, as defined below, 
will be reported to the Sponsor within 24 hours.
Patients who discontinue from the study prior to completing the DLT assessment window for 
reasons other than a DLT will be considered non-evaluable for dose-escalation decisions and 
MTD assessments and will be replaced by an additional patient at that same dose level.  
Patients must receive two planned target doses of RO7297089 during the DLT assessment 
window to be considered DLT-evaluable.  Treatment delays during the first cycle of RO7297089 
will be allowed if they are less than one cycle (i.e., <14 days); under these circumstances, the 
DLT assessment window may be extended up to an additional 7 days in order to capture two 
planned target doses of treatment.  Patients who receive supportive care during the DLT 
assessment window that confounds the evaluation of DLTs (not including supportive care 
described below as part of the DLT definition) may be replaced at the discretion of the Medical 
Monitor. 
As described below, the ISC will additionally review cumulative safety data and make 
recommendations regarding overall study conduct to ensure patient safety while receiving study 
treatment.  These recommendations include suspending patient enrollment based on the overall 
benefit-risk profile of RO7297089 during dose escalation.
Definition of Dose-Limiting Toxicity
All adverse events, including DLTs, will be reported according to instructions in the protocol and 
graded according to the NCI CTCAE v5.0, with the exception of CRS, which will be graded 
according to the Modified Cytokine-Release Syndrome Grading System.  DLTs will be treated 
according to clinical practice and will be monitored through their resolution.  Any one of the 
following events will be considered a DLT if it occurs during the DLT assessment window 
(Days 114 of Cycle 1 for Arms A and B; Cycle 1, Day 8 to Cycle 2, Day 7 for Arm C) unless 
clearly attributed to another identified etiology by the investigator (e.g., cancer progression):

Any Grade 4 or 5 adverse event

Grade 3 febrile neutropenia lasting 3 days


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
Grade 3 elevation of serum hepatic transaminase (ALT or AST) lasting 7 days
Any Grade 3 AST or ALT elevation that occurs in the context of Grade 2 CRS 
(as defined by the criteria established by Lee et al. [2019]) and resolves to Grade 1 
within 3 days will not be considered a DLT.

Grade 3 elevation of serum bilirubin (total)

Any increase in hepatic transaminase (ALT or AST) 3baseline in combination with either 
an increase in direct bilirubin 2upper limit of normal (ULN) or clinical jaundice, in the 
absence of cholestasis or other contributory factors (e.g., concomitant exposure to known 
hepatotoxic agent, or documented infectious etiology)
This is suggestive of potential drug-induced liver injury (according to Hy’s Law). 

Grade 3 non-hematologic, non-hepatic major organ adverse event, with the following 
exceptions:

Grade 3 nausea, vomiting, or diarrhea that improves to Grade 2 with standard-of-care 
therapy in 3 days will not be considered a DLT. 
Grade 3 nausea or vomiting that requires total parenteral nutrition or 
hospitalization is not excluded and should be considered a DLT.

Grade 3 fatigue that improves to Grade 2 within 7 days will not be considered a DLT. 

Grade 3 infection that resolves within 7 days to Grade 2 and does not require 
intensive care unit will not be considered a DLT. 

Grade 3 fever (as defined by 40ºC) for 48 hours will not be considered a DLT. 

Grade 3 laboratory abnormalities that are asymptomatic, resolve to Grade 1 or 
baseline within 7 days, and are considered by the investigator not to be clinically 
significant will not be considered a DLT. 

Fractures of any grade at site of lytic bone disease will not be considered a DLT.

Grade 3 IRRs will not be considered a DLT, as generally IRRs are not considered to be 
dose-related events on the basis of experience with monoclonal antibodies.  
Precautions will be taken if IRRs Grade 2 occur.  
Grade 4 IRRs or re-occurrence of an IRR event in a patient that precluded the 
administration of the full dose or the administration of the next scheduled dose of 
study drug will be considered a DLT. 
Anemia, neutropenia, lymphopenia, leukopenia, and thrombocytopenia are anticipated in the 
study population due to the extensive prior therapy and myeloma involvement in the R/R MM 
population.  Investigator assessment of causality and change from pre-treatment baseline will 
be important to characterize the effect of RO7297089 on cytopenias.  In addition, infection is a 
common occurrence in R/R MM due to prior therapy and hypogammaglobulinemia.  Hence, 
infection that recovers as expected with appropriate therapy (as per above) will not be 
considered a DLT.
Dose-Escalation Rules
The starting dose of RO7297089 will be 60 mg, administered IV weekly for Cohort 1.
Dose escalations will be guided by the mCRM-EWOC model.  The MTD is defined as the dose 
that maximizes the probability of a DLT being in the targeted toxicity interval in the range of 
20%35%, subject to the probability of the DLT being in the excessive toxicity interval in the 
range of 35%100% being 25%.  For each cohort, patients will be followed through a 14-day 
DLT assessment window.  At each dose-escalation step, the dose can be escalated or 
de-escalated and/or an additional cohort at that same dose level could be enrolled.
If MTD is not reached, the RP2D will be determined based on the totality of data including 
clinical activity, safety, PK, and pharmacodynamics biomarkers.  Once the MTD or is RP2D 
determined, all patients in dose-escalation will be eligible to receive the RP2D, based upon ISC 
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In addition, different dosing regimens (e.g., every 2 weeks) may be explored in parallel, if 
warranted, on the basis of the safety and PK profile of RO7297089, with DLT periods specific 
for each regimen and starting dose not exceeding the weekly MTD.  Any evaluation of a 
different administration schedule will be based on the recommendation of the ISC and reviewed 
with study investigators.  Addition of different dosing regimens will require a protocol 
amendment.  For this new regimen, the mCRM-EWOC model and priors as defined in the 
protocol, as well as the simulations, will be reviewed and possibly modified and the DLT 
assessment period will be extended to 21 days to ensure that patients have received at least 
two doses of study drug.
Continued Dosing Beyond the Dose-Limiting Toxicity Observation Period (Cycles ≥2)
Nonclinical toxicology data supports RO7297089 treatment every 7 days.  The ethical conduct 
of a clinical study of cancer requires that patients have the opportunity to continue study 
treatment provided that the treatment is active and tolerable and patients comply with protocol 
requirements.  Therefore, dosing beyond Cycle 1 for patients with R/R MM will be allowed in the 
absence of unacceptable toxicity or objective evidence of disease progression as assessed by 
the treating study investigator and following a careful assessment and discussion of the 
potential risks and benefits with the patient.  Patients will continue study treatment until 
objective disease progression is documented or unacceptable toxicity, whichever occurs first.  
RO7297089 administration will be interrupted in patients who experience a DLT during the DLT 
assessment window.  Patients who experience a DLT during the first cycle and whose toxicity 
returns to baseline within 14 days may be restarted at a dose level tolerated by the prior cohort 
following discussion with the Medical Monitor.  A treatment delay beyond 14 days may be 
acceptable upon discussion with the Medical Monitor.
Intrapatient Dose Escalation
To maximize the collection of information at relevant doses and minimize the exposure of 
patients to sub-optimal doses of RO7297089, intrapatient dose escalation may be permitted.  
Within each assigned dose-escalation cohort, the dose of RO7297089 for an individual patient 
may be increased to the highest cleared dose level that is tolerated by completed cohorts 
through the DLT window.  Patients may be able to undergo intrapatient dose escalation after 
completing at least two cycles at their originally assigned dose level.  Subsequent intrapatient 
dose escalations may occur after at least one cycle of any subsequently higher cleared dose 
level without any adverse event that meets the definition of a DLT or necessitates post-
administration hospitalization.  Once the MTD is declared and the RP2D is determined, 
intrapatient dose escalation directly to the RP2D is permitted for patients who remain on study 
and continue to tolerate RO7297089.
At the discretion of the investigator and in consultation with the Medical Monitor, the 
RO7297089 administration schedule for the first cycle after intrapatient dose escalation may 
follow any administration schedule previously evaluated in the study.
Expansion Stage
After dose escalation has been completed, approximately 30 patients will be enrolled in the 
expansion stage.  Patients will be treated at the RP2D (at or below the MTD) to obtain 
additional safety, tolerability, and PK data, as well as preliminary evidence of clinical activity.  
The ISC will assess all safety data on an ongoing basis. At no time will the dose administered 
in the expansion stage exceed the highest dose level that qualified as an MTD in the dose 
escalation stage.
Internal Safety Committee
Given that this is a first-in-human trial, an ISC will be utilized during the study to make 
recommendations regarding study conduct on the basis of trial safety data to ensure enhanced 
patient safety monitoring while receiving study treatment.  The ISC will be formed before the 
first patient is enrolled into the study.
The ISC will include at a minimum the Medical Monitor, study Safety Scientist, study 
Biostatistician, and a Sponsor Medical Monitor not associated with the study.  Representatives 
from other Sponsor functional areas may be included as ad hoc members.


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In addition to the ongoing assessment of the incidence and nature of DLTs, adverse events, 
serious adverse events, adverse events of special interest, and laboratory abnormalities by the 
investigator and the Medical Monitor, the ISC will review cumulative data at regular intervals 
during the study.  This committee will make decisions in consultation with study investigators 
regarding opening Arm B and/or Arm C for a given dose cohort as well as dose escalations 
based on the plan described in the protocol.  The ISC, in consultation with study investigators, 
will also review the cumulative data from dose escalation prior to opening the dose expansion 
portion of the study and review data from the dose expansion at routine intervals.  In addition, 
the ISC will meet regularly and as needed at the request of the study Medical Monitor (e.g., 
based on unexpected safety signals).  The ISC may further make recommendations regarding 
study conduct, including, but not limited to, the following: performing additional safety analyses, 
amending the study protocol, holding patient enrollment pending further safety evaluations, 
enrolling additional patients at a specific dose level and schedule to obtain additional safety 
data, holding/discontinuing study treatment, or terminating the study.
Number of Patients
The study will enroll approximately 3050 patients during the dose-escalation stage and 
approximately 30 patients during the expansion stage. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
ECOG Performance Status of 2 due to MM may be eligible after discussion with the 
Medical Monitor.

Life expectancy of at least 12 weeks

Patients must have R/R MM for which no established therapy for MM is appropriate and 
available or be intolerant to those established therapies

Agreement to provide bone marrow biopsy and aspirate samples as detailed in the protocol

Adverse events from prior anti-cancer therapy resolved to Grade 1, with the following 
exceptions:

Any grade alopecia

Peripheral sensory or motor neuropathy that has resolved to Grade 2

Measurable disease, defined as at least one of the following:

Serum monoclonal protein (M-protein) 0.5 g/dL (5 g/L)

Urine M-protein 200 mg/24 hr

Serum free light chain (SFLC) assay:  Involved SFLC 10 mg/dL (100 mg/L) and an 
abnormal SFLC ratio (<0.26 or >1.65)

Laboratory values as follows:

Hepatic function: 
o
AST and ALT 3ULN
o
Total bilirubin 1.5ULN 
Patients with a documented history of Gilbert syndrome and in whom total bilirubin 
elevations are accompanied by elevated indirect bilirubin are eligible.

Hematologic function: 
o
Platelet count 50,000/mm3 without transfusion within 7 days of assessment 


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o
ANC 1000/mm3
o
Total hemoglobin 8 g/dL without transfusion within 14 days of assessment
Patients who do not meet criteria for hematologic function because of MM related 
cytopenias (e.g., due to extensive marrow involvement by MM) may be enrolled 
into the study after discussion with the Medical Monitor.  

Creatinine clearance 30 mL/min (either calculated using a modified Cockcroft-Gault 
calculation or per 24-hour urine collection; inulin or radionuclide-based methods may be 
used after discussion with Medical Monitor)  

Serum calcium (corrected for albumin) level 11.5 mg/dL (2.9 mmol/L)
Treatment of hypercalcemia is allowed and patient may enroll if hypercalcemia returns 
to normal with standard treatment.

For women of childbearing potential:  agreement to remain completely abstinent (refrain 
from heterosexual intercourse) or use contraception, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 28 days after the final dose of 
RO7297089.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, or copper intrauterine devices.
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drug and is consistent with the usual lifestyle of the patient.  The reliability of sexual 
abstinence should be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.  If required per local guidelines or regulations, 
locally recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain completely abstinent (refrain from heterosexual intercourse) 
or use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom with spermicide during the treatment period and for 
28 days after the final dose of RO7297089 to avoid exposing the embryo.  Men must 
refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.  If required per local 
guidelines or regulations, information about the reliability of abstinence will be 
described in the local Informed Consent Form.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
28 days after the final dose of study drug


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Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drug conjugate 
for the treatment of cancer within 4 weeks before first RO7297089 infusion

Prior treatment with systemic immunotherapeutic agents, including, but not limited to, 
cytokine therapy and anti-CTLA4, antiPD-1, and antiPD-L1 therapeutic antibodies, within 
12 weeks or 5 half-lives of the drug, whichever is shorter, before first RO7297089 infusion

Prior treatment with CAR-T therapy within 90 days before first study drug administration

Treatment with any chemotherapeutic agent, or treatment with any other anti-cancer agent 
(investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, 
prior to first RO7297089 infusion

Autologous stem cell transplantation within 100 days prior to first RO7297089 infusion

Allogeneic stem cell transplantation within 180 days prior to first RO7297089 infusion or 
requiring immunosuppression for treatment or prophylaxis of graft versus host disease

Primary or secondary plasma cell leukemia as defined by an absolute plasma cell count 
exceeding 2000/L or 20% of the peripheral blood white cells

Known cardiac amyloidosis 

History of severe allergic or anaphylactic reactions to monoclonal antibody therapy 
(or recombinant antibody-related fusion proteins) or any of the components of the 
RO7297089 drug product

Significant active pulmonary disease (e.g., chronic obstructive pulmonary disease with 
known forced expiratory volume in 1 second of less than 50% of predicted normal, severe 
persistent asthma) that may limit a patient's ability to adequately respond to an IRR event in 
the investigator’s assessment

History of other malignancy that could affect compliance with the protocol or interpretation 
of results, with the following exceptions:

Patients with history of curatively basal or squamous cell carcinoma of the skin or in situ 
carcinoma of the cervix

Localized prostate cancer Gleason Grade 6 AND with stable prostate-specific antigen 
levels off treatment

Patients with a malignancy that has been treated with curative intent will also be 
allowed if the malignancy has been in remission for 2 years prior to first RO7297089 
infusion. 

Acute or chronic hepatitis C virus (HCV) infection
Patients who are positive for the HCV antibody must be negative for HCV by PCR to 
be eligible for study participation.

Positive serologic or PCR test result for acute or chronic hepatitis B virus (HBV) infection
Patients whose HBV infection status cannot be determined by serologic test results 
must be negative for HBV by PCR to be eligible for study participation.
Antiviral prophylaxis for patients at risk of HBV reactivation is permitted.

Known HIV infection unless the patient meets all the following criteria:

CD4 count 350 cells/L prior to enrollment

No history of AIDS-defining illness in the last 12 months prior to study enrollment 

Must be on established antiretroviral therapy for at least 4 weeks and have an HIV viral 
load 400 copies/mL prior to enrollment

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV anti-microbial therapy within 14 days prior to first RO7297089 
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
Administration of a live, attenuated vaccine within 4 weeks before first RO7297089 infusion 
or anticipation that such a live, attenuated vaccine will be required during the study
Influenza vaccine should be given during influenza season (approximately October to 
May in the Northern Hemisphere; approximately May to October in the Southern 
Hemisphere).  Patients must not receive live, attenuated influenza vaccine at any time 
during the study period.
Investigators should review the vaccination status of potential study patients being 
considered for this study and follow the local guidelines for adult vaccination with any 
other non-live vaccines intended to prevent infectious diseases prior to study.

Received systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor 
agents) within 2 weeks prior to the first dose of RO7297089, with the following
exceptions:
Patients who received acute, systemic immunosuppressant medications (e.g., single 
dose of dexamethasone for nausea, prophylactic corticosteroids to prevent allergic 
reaction to CT contrast) may be enrolled in the study after discussion with the Medical 
Monitor.
The use of corticosteroids for anti-cancer treatment is permitted prior to the first 
dose of RO7297089; washout requirements for anti-cancer therapies are defined 
above.
The use of corticosteroid treatment of 10 mg/day prednisone or equivalent is 
permitted.
The use of inhaled corticosteroids is permitted.
The use of mineralocorticoids for management of orthostatic hypotension is permitted.
The use of physiologic doses of corticosteroids for management of adrenal 
insufficiency is permitted.

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s 
judgment

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study

Significant cardiovascular disease (such as, but not limited to, New York Heart Association 
Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable 
arrhythmias, or unstable angina)

Current CNS involvement by MM
Patients with a history of CNS involvement must have at least 6 months of remission in 
the CNS without interval CNS directed therapies prior to first RO7297089 infusion.
Patients with a history of CNS involvement must have a magnetic resonance imaging 
of the brain and lumbar puncture during screening to confirm that CNS is clear.

Recent major surgery within 4 weeks prior to first RO7297089 infusion or anticipation of 
need for a major surgical procedure during the course of the study
Protocol-mandated procedures (e.g., tumor biopsies and bone marrow biopsies) and 
superficial lymph node biopsies for diagnosis are permitted.
Prophylactic orthopedic intervention to long bones to prevent fracture is permitted 
within 2 weeks prior to first RO7297089 infusion.

Uncontrolled tumor-related pain
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment.


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Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not currently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to enrollment.
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.  The end of the study is expected to occur approximately 
1 year after the last patient is enrolled.  In addition, the Sponsor may decide to terminate the 
study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 3 years.
INVESTIGATIONAL MEDICINAL PRODUCT
The investigational medicinal product for this study is RO7297089 (BPCT2605S).  Dosing 
independent of body weight will be used for RO7297089.  The dose of RO7297089 for each 
patient will depend on the dose level assignment as detailed in the protocol.  Patients will 
receive RO7297089 by IV infusion.
STATISTICAL METHODS
Primary Analysis
The safety analysis population will consist of all patients who received at least one dose of 
study drug.  Statistical summaries will be descriptive in nature (e.g., incidence rates, means, 
and percentiles).
Primary Safety Model (mCRM-EWOC)
An mCRM-EWOC model will be utilized to inform decision-making about the dose of 
RO7297089.  All patients will be followed through the DLT window (2 weeks) and be enrolled in 
a sequential manner.  Patients within a cohort will be sequentially enrolled in cohorts of three 
patients each, which, if required, can be expanded with additional patients. 
The dose-toxicity relationship will be described by a two-parameter logistic regression model, 
which can be updated anytime by incorporating available information from all patients.  
A minimal informative prior will be used.
The Sponsor and Investigators will evaluate the next dose recommended by the mCRM-EWOC 
design and agree on the dose for the subsequent cohort.  At each dose-escalation step, the 
dose can be escalated, de-escalated, or an additional cohort at that same dose level could be 
enrolled. 
The mCRM will continue until a maximum of approximately 40 patients, or all rules in a 
pre-defined set of MTD precision criteria, have been reached; or if it is concluded that the RP2D 
has been defined, using multiple parameters of safety, PD, and efficacy data. 
The set of MTD precision criteria is: 

At least 9 patients have accrued overall;

At least 6 patients have been accrued near the MTD dose where “near” is defined as being 
within 20% of the MTD;

The probability that the MTD lies within the target toxicity interval is above 40%.
After the dose-escalation phase, a tentative RP2D, which will guide the recommended dose in 
expansion, will be defined.  The final RP2D will be estimated based on the DLT occurrence rate 
in all patients evaluable for DLTs in the dose-escalation and dose-expansion parts of the study.  
The model will be implemented by R and Jags software.


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All patients from the safety analysis population who follow the protocol-specified dose regimen 
within the DLT observation period and have undergone the scheduled safety evaluations, or 
who discontinued earlier due to a DLT, will be included in the MTD-determined analysis.
Clinical judgment can always override the Bayesian adaptive design recommendations in the 
dose-selection process.
Analyses of Exposure, Adverse Event, Laboratory, and Vital Sign Data
Safety will be assessed through summaries of exposure to study treatment, adverse events, 
changes in laboratory test results, and changes in vital signs and ECGs.
Study treatment exposure (such as treatment duration, total dose received, and number of 
cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and adverse event severity will be graded according to NCI 
CTCAE v5.0.  All adverse events, serious adverse events, adverse events leading to death, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment (i.e., treatment emergent 
adverse events) will be summarized by mapped term, appropriate thesaurus level, and severity 
grade.  For events of varying severity, the highest grade will be used in the summaries.  Deaths 
and cause of death will be summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, and temperature), 
and ECG data will be displayed by time, with grades identified where appropriate.  Additionally, 
a shift table of selected laboratory tests will be used to summarize the baseline and maximum 
post-baseline severity grade.  Changes in vital signs and ECGs will be summarized.
Determination of Sample Size
Sample size of the dose-escalation study is based on the mCRM-EWOC design and not based 
on statistical power calculations.  A minimum of 9 evaluable patients and approximately 
3050 evaluable patients will be enrolled for dose-escalation.  A simulation study has been 
conducted to evaluate the sample size.  Approximately 30 patients may be enrolled in the 
expansion cohort to better characterize PK, PD, and preliminary activity signals at the presumed 
RP2D.
A sample size of thirty patients is a reasonable size for the expansion cohort in order to obtain 
an estimate of the response rate; with a sample size of 30 and an observed response rate of 
20%, the 90% confidence interval for the true response rate is (8%, 32%), corresponding with 
2 and 10 responses, and the expected number of responses is 6.
Interim Analyses
Continuous safety monitoring and interim analyses will be performed for the expansion portion 
of the study to guide potential early stopping of enrollment in the event of unacceptable toxicity 
or a lower than expected response rate.
A Bayesian posterior probability approach (Thall and Simon 1994) with a uniform prior will be 
used to evaluate toxicity, including the rate of DLTs.  If at any time in the expansion cohort, the 
number of observed DLTs indicates that there is an approximately 80% chance that the true 
DLT rate is 20% (e.g., DLTs observed in 2/5, 3/10, 4/15, 5/20 patients), accrual to the cohort 
may be paused and the ISC will meet to determine whether further enrollment in the cohort 
should be halted taking into account feedback from study investigators.
A similar approach will be used to assess the response rate. Specifically, after approximately 
15 patients in the expansion cohort have completed their first tumor assessment, an interim 
analysis will be conducted to inform potential early stopping of enrollment if observed response 
rates are lower than expected.  Using the Bayesian posterior probability approach with a 
uniform prior, the cohort may be stopped if the objective response rate is less or equal to 25% 
with a probability greater or equal to 60%.  This would be the case for example if 2 or fewer out 
of the first 15 patients have an objective response.  At each interim analysis, the ISC will review 
the response data and decide whether to recommend an early decision to stop enrollment in the 
subgroup due to futility.  Additional futility analyses may be conducted in periodic review of 
efficacy data.  In all cases, decisions to stop enrollment into the expansion cohort will be made 
in consultation with study investigators.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody-dependent cellular phagocytosis
AUC
area under the concentration–time curve
BCMA
B-cell maturation antigen
CAR-T
chimeric antigen receptor T cell
Cmax
maximum concentration observed
Cmin
minimum concentration observed
CR
complete response
CrCl
creatinine clearance
CRO
contract research organization
CRS
cytokine-release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ECOG
Eastern Cooperative Oncology Group
EOI
end of infusion
EWOC
escalation with overdose control
FACS
fluorescence-activated cell sorting
Fc
fragment crystallizable
FDA
Food and Drug Administration
FISH
fluorescence in situ hybridization
G-CSF
granulocyte colony-stimulating factor
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HLH
hemophagocytic lymphohistiocytosis
ICH
International Council for Harmonisation
IFN-
interferon-
IL
interleukin
IMiD
immunomodulatory drug
IMP
investigational medicinal product
IMWG
International Myeloma Working Group
IND
Investigational New Drug (Application)


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Abbreviation
Definition
IRB
Institutional Review Board
IRR
infusion-related reaction
ISC
Internal Safety Committee
IVIg
intravenous immunoglobulin
IxRS
interactive voice or web-based response system
MAS
macrophage activation syndrome
mCRM
modified continual reassessment method
MM
multiple myeloma
MMC
multiple myeloma cell
M-protein
monoclonal protein
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0
NK
natural killer (cell)
NOAEL
no observed adverse-effect level
ORR
objective response rate
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
PR
partial response
QTcF
QT interval corrected through use of Fridericia's 
formula
RBR
Research Biosample Repository
RP2D
recommended Phase II dose
R/R
relapsed or refractory
sBCMA
soluble B-cell maturation antigen
sCR
stringent complete response
SFLC
serum free light chain
SIFE
serum protein electrophoresis
SPEP
serum protein electrophoresis
tmax
time to maximum concentration observed
TLS
tumor lysis syndrome
TNF-
tumor necrosis factor-
UIFE
urine immunofixation electrophoresis
ULN
upper limit of normal
UPEP
serum protein electrophoresis
USM
Urgent Safety Measure
USPI
U.S. Package Insert


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Abbreviation
Definition
VGPR
very good partial response
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON MULTIPLE MYELOMA 
Multiple myeloma (MM) is a neoplasm characterized by the proliferation and 
accumulation of malignant plasma cells.  Worldwide, approximately 160,000 people are 
diagnosed with MM annually (Bray et al. 2018).  End-organ damage resulting from MM 
includes hypercalcemia, renal insufficiency, anemia, and lytic bone lesions.  MM remains 
incurable despite advances in treatment, with an estimated median survival of 
810 years for standard-risk myeloma and 23 years for high-risk disease, despite 
receipt of an autologous stem-cell transplant (Mikhael et al. 2013).  Increased survival 
has been achieved with the introduction of proteasome inhibitors such as bortezomib 
(VelcadeU.S. Package Insert [USPI] and Summary of Product Characteristics 
[SmPC]), immunomodulatory drugs (IMiDs) such as lenalidomide (RevlimidUSPI and 
SmPC), and monoclonal antibodies such as daratumumab (DarzalexUSPI and SmPC).  
The successful use of monoclonal antibodies in MM (e.g., daratumumab and 
elotuzumab) provides evidence that antibody-dependent cell-mediated cytotoxicity 
(ADCC) is an important therapeutic mechanism for MM.  Nevertheless, most patients (if 
not all) eventually relapse, and the outcome of patients with MM after they become 
refractory, or ineligible to receive a proteasome inhibitor or an IMiD, is quite poor, with 
survival less than 1 year (Usmani et al. 2016).  Therefore, relapsed or refractory (R/R) 
MM continues to constitute a significant unmet medical need, and novel therapeutic 
agents are still necessary.  
1.2
BACKGROUND ON RO7297089 
RO7297089 (BPCT2605S) is a bispecific, tetravalent antibody targeting B-cell 
maturation antigen (BCMA) and CD16a.  The molecule consists of a humanized 
anti-BCMA antibody with two identical light and heavy chains of human IgG1 isotype and 
two anti-CD16a single chain variable fragments derived from light and heavy variable 
domains of human origin fused to the C-terminal end of the IgG1 heavy chain. The 
bispecific antibody also contains amino acid changes in the fragment crystallizable (Fc) 
region to impair its binding to human Fc gamma-receptors (FcRs) and thus attenuates 
normal Fc-mediated effector functions (Lund et al. 1996; Borrok et al. 2017; RO7297089 
Investigator’s Brochure). 


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BCMA is exclusively expressed on plasmablasts and plasma cells, but it is absent on 
cells in earlier stages of B-cell development (e.g., pro- and pre-B cells, naive and 
memory B cells, as well as resting and activated B cells) and other normal tissues (Cho 
et al. 2019). BCMA is essential for the survival of long-lived bone marrow plasma cells,
is over-expressed in malignant plasma cells in patients with MM, and its expression level 
is reported to be associated with disease progression (Lee et al. 2016; Seckinger et al. 
2017; Tai and Anderson 2019). CD16a, also known as FcRIIIa, is expressed on 
macrophages, natural killer (NK) cells, and monocyte subsets as a transmembrane 
receptor (Ravetch and Perussia 1989; Wong et al. 2011). Engagement of BCMA and 
CD16a by RO7297089 results in the target-specific killing of BCMA-positive tumor 
plasma cells by CD16a-positive immune effector cells such as NK cells and 
macrophages. Therefore, RO7297089 is a potential therapeutic treatment for MM.
No clinical studies have been conducted with RO7297089 to date. Nonclinical in vivo 
safety and pharmacokinetic (PK)/pharmacodynamic (PD) studies with RO7297089 were 
conducted in cynomolgus monkeys.  No in vivo efficacy studies have been performed
due to lack of any relevant efficacy model in rodents or other species.
Nonclinical characterization of RO7297089 activity to confirm its mechanism of action 
was performed. In vitro pharmacological activity of RO7297089 requires binding to both 
CD16a-positive immune cells and BCMA-positive tumor cells. Simultaneous binding 
results in target-dependent NK cell activation, potent killing of target cells (MM cell lines
and normal plasma cells), without any significant NK cell fratricide. RO7297089 was 
shown to induce both ADCC and antibody-dependent cellular phagocytosis (ADCP) with 
the use of peripheral blood mononuclear cells (PBMCs) and macrophages, respectively, 
as effector cells in BCMA-positive MM cell lines.
An in vitro cytokine release assay was performed to evaluate the potential for acute 
cytokine-release syndrome (CRS) following RO7297089 administration to patients. 
RO7297089 led to minimal increases in TNFα and IFN-γ levels, and no change in the
15 other cytokines tested, including IL-6. Importantly, in vitro cytokine release was 
comparable between RO7297089 and daratumumab at the same concentrations; 
daratumumab has not been associated with CRS in patients, therefore risk of 
RO7297089-induced CRS in patients is considered to be low.  Published results for 
similar in vitro cytokine assays conducted for a CD3 bispecific molecule show robust 
increase in cytokines consistent with mechanism of action and known clinical effect of 
T-cell engaging molecules (Li et al. 2019). Results with RO7297089 suggest low risk for
CRS and are consistent with a mechanism of action of engaging CD16a-positive 
immune cells (e.g., NK cells).  
RO7297089 has high affinities for recombinant cynomolgus monkey CD16 and BCMA
as well as recombinant human CD16a and BCMA, but does not bind to recombinant 
mouse CD16. RO7297089 functionally activates cynomolgus or human PBMCs, 
resulting in killing of cynomolgus or human cell lines. 


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Therefore, cynomolgus monkey was selected as the relevant animal species to assess 
the PK, toxicokinetic, PD, and safety profiles of RO7297089.  The nonclinical toxicology 
program consisted of a single-dose IV toxicity study and a 4-week repeat-dose, IV, Good 
Laboratory Practice (GLP) toxicology study in cynomolgus monkeys, including a core 
battery of safety pharmacology (cardiovascular and neurological) endpoints. 
RO7297089 was well tolerated in cynomolgus monkeys at doses of up to 50 mg/kg IV
(5 weekly doses), and there were no RO7297089-related adverse findings.  Cytokines 
were also monitored in the toxicity studies. There were no RO7297089-related changes 
in cytokines observed at up to 50 mg/kg in monkeys.  Minimal non-adverse decreases in 
blood pressures were observed at 50 mg/kg following the fifth administered dose. The 
no observed adverse-effect level (NOAEL) was assessed as 50 mg/kg.  Increases in 
soluble BCMA (due to binding to RO7297089) and monocytes along with decreases in 
IgM and mRNA levels of plasma cell markers were notable changes in cynomolgus 
monkeys. These changes were considered evidence of pharmacological activity of 
RO7297089 and they were seen at both the 15 mg/kg and 50 mg/kg dose levels.
The totality of in vitro and in vivo data with RO7297089 support that the potential for 
CRS is low.  This is consistent with the mechanism of action of engaging 
CD16a-immune cells (e.g., NK cells, monocytes) and differentiated from data seen with 
T-cell engaging molecules.  Additionally, the lack of CRS seen in the Phase I study with 
AFM13 (anti-CD30/CD16a) in Hodgkin lymphoma (Rothe et al. 2015) supports a low 
potential for CRS with RO7297089.  
The recommended safe starting dose in patients is 60 mg RO7297089, which was 
determined based on an integrated analysis of the nonclinical data including the in vitro
cytokine release assay and the repeat-dose GLP toxicity study in cynomolgus monkeys
(see Section 3.3.2).
Collectively, the data from the nonclinical program with RO7297089 provide a scientific 
basis for investigating RO7297089 for the treatment of MM and support the proposed
first-in-human Phase I trial.
Refer to the RO7297089 Investigator's Brochure for details on nonclinical studies and 
starting dose rationale.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
MM that is R/R to standard-of-care therapies, including intensive induction/stem cell 
transplant, proteasome inhibitors, and IMiDs, represents an indication with a significant 
unmet clinical need.  Clinical activity seen with antibodies, such as daratumumab and 
elotuzumab, provides strong evidence that ADCC is an important therapeutic 
mechanism for treating MM.  NK cells are cytotoxic effector cells that play a potent role 
in ADCC by binding to FcRIIIA (CD16a).  BCMA has been demonstrated to be a 
validated target in MM with compelling early clinical activity reported from BCMA-specific 
chimeric antigen receptor T cells (CAR-Ts) (Raje et al. 2019), BCMA antibody-drug 


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conjugate (Trudel et al. 2018), and BCMA-CD3 bispecific T-cell engager (Topp et al. 
2019).  Promising early clinical data from these agents support that BCMA is a valid
target for immune-based therapies in MM.  However, significant toxicities related to 
cytokine release in T cellbased therapies and ocular toxicities related to cytotoxic 
payload in antibody-drug conjugates have been noted with other agents.  Targeting 
BCMA with a different mechanism of action may provide clinical benefit with an improved 
safety profile.
A bispecific anti-CD30/CD16a antibody construct, AFM13, has shown early promising
data in R/R Hodgkin lymphoma and demonstrates superior cytotoxicity to other 
CD30-targeting antibodies in vitro (Rothe et al. 2015).  In the Phase I dose-escalation 
study, 28 patients were treated at doses of 0.01 to 7 mg/kg body weight.  Treatment with 
this agent was generally well-tolerated and the maximum tolerated dose (MTD) was not 
reached.  Most adverse events were Grades 1 and 2 and largely related to 
infusion-related reactions (IRRs), which were managed through standard supportive 
care, without the need for premedication in the single-agent Phase I study.  CRS was 
not reported.  PD markers in the clinical study included dose-dependent transient 
decrease of circulating NK cells, likely due to margination and dose-dependent 
increases in the proportion of NK cells expressing the activation marker CD69.  
Quantifiable serum cytokine levels could only be measured for IL-6, IL-8, IL-10, and 
TNF-.  Data on cytokine release were inconclusive regarding a correlation with dose or 
activity of AFM13.
While there are no clinical data available with NK cellengaging agents in R/R MM, the 
data in R/R Hodgkin lymphoma with AFM13 is encouraging for further development of 
these agents with different antigen targets in other malignancies.  Given the poor 
prognosis of patients with R/R MM who have failed standard-of-care therapies, prior 
clinical studies demonstrating the efficacy and tolerability of the NK cellengaging agent 
in Hodgkin lymphoma, and the favorable nonclinical toxicity profile observed with 
RO7297089 treatment, the anticipated benefitrisk balance of a clinical study of 
RO7297089 is proposed to be acceptable.  Based on the mechanism of action and the 
nonclinical safety profile of RO7297089, the anticipated potential safety risks of 
RO7297089 include IRR/CRS, immunogenicity, infection, tumor lysis syndrome (TLS),
lymphopenia, and blood pressure decrease (see Section 5.1.1).  The study safety 
monitoring and mitigation plan will be implemented to manage and mitigate these 
potential toxicities (see Section 5.1). 
Patients with R/R MM who have failed standard-of-care therapies have a poor 
prognosis, with survival less than 1 year (Usmani et al. 2016; Gandhi et al. 2019). The 
nonclinical studies conducted in support of the clinical trial application of RO7297089 
demonstrate biologically effective activity and a favorable toxicity profile for the clinical 
dose level. The available clinical data with other BCMA-directed therapies in MM
provide a supporting rationale for the clinical development of RO7297089 based on 
validation of BCMA as a target in MM.  In addition, strong clinical benefit and tolerability 


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demonstrated in combination studies with approved monoclonal antibodies 
(e.g., daratumumab and elotuzumab) with proteasome inhibitors and in combination with 
IMiDs suggest that a future combination of RO7297089 and a proteasome inhibitor or an 
IMiD may provide additional treatment options for patients. Preclinical data exists for the 
role of IMiDs in augmenting NK cell cytotoxicity (Hayashi et al. 2005).  Novel
combinations with immune agents that enhance or augment NK function may also offer 
opportunities to enhance the activity of RO7297089.
RO7297089 may provide a potential therapeutic option, either alone or in combination 
with other therapies, in R/R MM, which continues to constitute a significant unmet need.  
RO7297089 has not been studied in humans, and therefore its clinical benefit or safety 
profile as a single agent or in combination is unknown.  
This Phase I study will enroll patients with R/R MM to assess safety, tolerability, and 
pharmacokinetics and to make a preliminary assessment of anti-tumor activity of 
RO7297089.  Given the relatively poor prognosis and limited treatment options for these
patients, this population is considered appropriate for early-stage trials of novel 
therapeutic candidates, and the benefitrisk ratio of a clinical study of RO7297089 is 
considered acceptable.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety and pharmacokinetics of RO7297089 in patients with 
R/R MM and make a preliminary assessment of anti-tumor activity.  Specific objectives 
and corresponding endpoints for the study are outlined below.
2.1
SAFETY OBJECTIVE (PRIMARY STUDY OBJECTIVE)
The safety objective for this study is to evaluate the safety of RO7297089, including 
estimation of the MTD and characterization of dose-limiting toxicities (DLTs), on the 
basis of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0 (NCI CTCAE v5.0) and the Modified Cytokine-Release 
Syndrome Grading System (Appendix 9)

Change from baseline in targeted vital signs

Change from baseline in targeted ECG parameters

Change from baseline in targeted clinical laboratory test results

Relationship between RO7297089 dose and safety, PK, activity, and 
immunogenicity endpoints


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2.2
PHARMACOKINETIC OBJECTIVES 
The PK objective for this study is to characterize the RO7297089 PK profile on the basis 
of the following endpoints:

Serum concentration of RO7297089 at specified timepoints

PK parameters for RO7297089
The exploratory PK objectives for this study are as follows:

To evaluate potential relationships between drug exposure and the safety and 
activity of RO7297089 on the basis of the following endpoints:
Relationship between serum concentration or PK parameters for RO7297089
and safety endpoints
Relationship between serum concentration or PK parameters for RO7297089
and activity endpoints

To evaluate potential relationships between selected covariates and exposure to 
RO7297089 on the basis of the following endpoint:
Relationship between selected covariates and serum concentration or PK 
parameters for RO7297089 
2.3
ACTIVITY OBJECTIVES
The activity objective for this study is to make a preliminary assessment of the activity of 
RO7297089 on the basis of the following endpoints:

Objective response rate (ORR), defined as a stringent complete response (sCR), 
complete response (CR), very good partial response (VGPR), or partial response 
(PR), as determined by the investigator according to International Myeloma Working 
Group (IMWG) Uniform Response Criteria (Appendix 5)

Duration of response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause 
(whichever occurs first), as determined by the investigator according to IMWG 
Uniform Response Criteria
2.4
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
RO7297089 on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and safety, PK, biomarker, or activity endpoints


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2.5
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to RO7297089 (i.e., predictive biomarkers), 
are early surrogates of activity, are associated with progression to a more severe 
disease state (i.e., prognostic biomarkers), are associated with acquired resistance to 
RO7297089, are associated with susceptibility to developing adverse events or can lead 
to improved adverse event monitoring or investigation (i.e., safety biomarkers), can 
provide evidence of RO7297089 activity (i.e., PD biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoint:

Relationship between biomarkers in blood and tissue samples (listed in 
Section 4.5.7) and safety, PK, activity, immunogenicity, or other biomarker 
endpoints
2.6
ADDITIONAL OBJECTIVE
An additional objective for this study is to identify a RP2D and regimen for RO7297089
on the basis of the following endpoint:

Relationship between RO7297089 exposure and safety, PK, activity, and 
immunogenicity endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a first-in-human Phase I, open-label, multicenter, global, dose-escalation study 
designed to evaluate the safety, tolerability, and pharmacokinetics of RO7297089 and 
make a preliminary assessment of anti-tumor activity in patients with R/R MM for whom 
no established therapy for MM is appropriate and available or who are intolerant to those
established therapies.  The study consists of a screening period of up to 28 days and a 
minimum follow-up period of 90 days after treatment.  Following confirmation of 
eligibility, patients will receive RO7297089 by IV infusion.  Patients will be enrolled in two 
stages:  a dose-escalation stage and an expansion stage.  To mitigate the risk of IRRs, 
up to three dose-escalation arms that differ in the RO7297089 administration schedule 
for Cycle 1 may be enrolled in a dose-escalation cohort.  The study will enroll 
approximately 3050 patients during the dose-escalation stage and approximately 
30 patients during the expansion stage at approximately 12 sites globally. Figure 1
presents an overview of the study design.  
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator's discretion.  Patients must re-sign the consent form prior to 
re-screening.  The investigator will record reasons for screen failure in the screening log 
(see Section 4.5.1).


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All patients will be closely monitored for adverse events throughout the study and for at 
least 90 days after the final dose of study treatment. Adverse events will be graded 
according to the NCI CTCAE v5.0, with the exception of CRS, which will be graded 
according to the Modified Cytokine-Release Syndrome Grading System (Appendix 9).
Patients may continue treatment with RO7297089 until disease progression as 
determined by the investigator using IMWG Uniform Response Criteria (Appendix 5), 
unacceptable toxicity, start of new anti-cancer therapy, or withdrawal from study 
participation, whichever occurs first. 
A schedule of activities is provided in Appendix 1 and Appendix 2. To characterize the 
PK properties of RO7297089, blood samples will be taken at various timepoints before 
and after dosing (see Appendix 3).


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Figure 1
Study Design
Notes:  
RO7297089 is administered by IV infusion, with a cycle length of 14 days.  The Cycle 1 
administration schedule is dependent on the assigned treatment arm (see Figure 2). From 
Cycle 2 onwards, RO7297089 is administered on Days 1 and 8 of each cycle.
Cohort must clear the DLT assessment window to open next cohort.  The DLT assessment 
window is 14 days (see Figure 2).  
Backfill cohorts are ungated based on evidence of clinical activity (e.g., decrease in M-protein) 
and/or PD activity (e.g., NK cell activation).  Dose-escalation decisions are based on totality of 
data (clinical, safety, PK, biomarker).  Dose recommended will not exceed dose recommended 
by the mCRM-EWOC model.
DLT dose-limiting toxicity; mCRM-EWOCmodified continual reassessment method of 
escalation with overdose control; MTDmaximum tolerated dose; NKnatural killer; 
RP2Drecommended Phase II dose; PDpharmacodynamic; PKpharmacokinetic; TBDto be 
determined.
3.1.1
Dose-Escalation Stage
Approximately 3050 patients will be enrolled in the dose-escalation stage.  
The dose-escalation stage of the study will assess the safety, tolerability, and 
pharmacokinetics of RO7297089 administered by IV infusion.  The cycle length is 
14 days. 


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To mitigate the risk of IRRs, up to three dose-escalation arms may be enrolled in a
given dose cohort (see Figure 2). These arms differ in the RO7297089 administration 
schedule for Cycle 1:

Arm A (Flat Dose-Escalation Arm).  Patients in Arm A will receive the Cycle 1 
target dose of RO7297089 as a flat dose independent of body weight on Day 1 and 
Day 8.  Dosing for Cycle 2 and beyond will follow the same administration 
schedule. The DLT assessment window for Arm A is 14 days (Cycle 1,
Days 114).

Arm B (Split Dose-Escalation Arm).  Patients in Arm B will receive the first 
dose in Cycle 1 as a split dose.  The initial target dose of RO7297089 will be 
divided over 2 days (Days 1 and 2), and the full target dose will be administered on 
Day 8.  
Initially, the dose will be divided such that 50% of the target dose is 
administered on Day 1 and the remaining 50% on Day 2.  If the Day 1 dose is 
associated with a Grade ≥2 IRR, the ratio may be adjusted for subsequent 
patients so that a smaller percentage of the dose is administered on Day 1, 
with the remainder of the dose administered on Day 2.  For example, 25% of 
the target dose administered on Day 1 and the remaining 75% administered on 
Day 2.
If a patient does not receive the full planned dose on Day 1 because of
scheduling reasons but has received at least 75% of the intended Day 1 dose, 
the patient may proceed with the Day 2 infusion to receive the remainder of the 
full target dose.
For Cycle 2 and beyond, RO7297089 will be administered on Day 1 and Day 8 of 
each 14-day cycle.  The DLT assessment window for Arm B is 14 days (Cycle 1,
Days 114).

Arm C (Single-Step Dose-Escalation Arm).  Patients in Arm C will receive the 
first cycle of RO2797089 as a single-step dose escalation.  The Cycle 1, Day 1 dose 
will be 60 mg, followed by the full target dose on Day 8.  For Cycle 2 and beyond, 
the target dose of RO7297089 will be administered on Day 1 and Day 8 of each 
14-day cycle.  The DLT assessment window for Arm C is 14 days (Cycle 1, Day 8 
to Cycle 2, Day 7, to allow for two target doses); the window excludes the Cycle 1, 
Day 1 60-mg dose, which has already cleared.  
For all arms, the target dose refers to the highest dose administered in Cycle 1; this 
target dose will be administered on Day 1 and Day 8 of subsequent cycles.  
Enrollment in the dose-escalation arms will be managed as follows:

For new dose cohorts, all patients will enroll in Arm A unless criteria have been
met for opening Arms B or C in a previous cohort.

Arm B may open if the planned infusion time for Arm A exceeds 4 hours on Cycle 
1, Day 1.  Arm C may open if 2 or more patients in Arm B of that dose cohort
experience any grade IRR that precludes the patient from receiving the full target 
dose during Cycle 1, Day 1 and Day 2.  


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
Once Arm B is open, Arm A for that dose cohort may close to further enrollment
and may not open for subsequent dose cohorts. Similarly, once Arm C is open, 
Arm B for that dose cohort may close to further enrollment and may not open for 
subsequent dose cohorts.

A minimum of 3 patients must complete the DLT assessment period for a given
arm (Arm A, B, or C) before dose escalation for that arm may occur. 
Figure 2
Dose-Escalation Arms:  Study Drug Administration for Cycle 1 
D day; DLT dose-limiting toxicity; IRR infusion-related reaction.
Notes:  One treatment cycle is 14 days.  Target dose is the highest dose administered in 
Cycle 1. DLT window is 14 days.
a Arm B may open if the planned infusion time exceeds 4 hours on Cycle 1, Day 1.
b If the Day 1 dose is associated with Grade ≥2 IRR, the ratio may be adjusted so that a 
smaller percentage of the dose is administered on Day 1, with the remainder of the dose 
administered on Day 2. 
c
Arm C may open if more than one patient in Arm B of that dose cohort experiences an IRR 
that precludes the patient from receiving the full target dose during Cycle 1, Day 1 and 
Day 2.
Dose escalations will be guided by the modified continual reassessment method of 
escalation with overdose control (mCRM-EWOC) model (Neuenschwander et al. 2008; 
Appendix 11). All cohorts will enroll a minimum of 3 patients.  Enrollment of the 
first 2 patients in each arm of each dose-escalation cohort will be staggered such that the 
respective Cycle 1, Day 1 treatments are administered 72 hours apart.  The maximal 


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dose escalation increment recommended by the model will be 3-fold. In addition, the 
relevant demographic, adverse event, laboratory, dose administration, and available PK 
data will be reviewed prior to dose-escalation decisions, which will be made by an
Internal Safety Committee (ISC) in consultation with the investigator (see Section 3.1.5
for more information about the ISC).  
Evidence of clinical activity at a given dose level (e.g., decrease in serum monoclonal 
protein [M-protein]) or PD activity (e.g., NK cell activation) may ungate backfill cohorts at 
doses that have already completed DLT assessment and have been found not to exceed 
the MTD in escalation cohorts.  DLT information from patients in these back-fill cohorts 
will be used to inform the mCRM-EWOC model.  
Patients will be closely monitored for adverse events during a DLT assessment window
(14 days), as defined above for each arm.  Adverse events identified as DLTs, as defined 
below (see Section 3.1.1.1), will be reported to the Sponsor within 24 hours.
Patients who discontinue from the study prior to completing the DLT assessment window 
for reasons other than a DLT will be considered non-evaluable for dose-escalation 
decisions and MTD assessments and will be replaced by an additional patient at that 
same dose level.  Patients must receive two planned target doses of RO7297089 during 
the DLT assessment window to be considered DLT-evaluable.  Treatment delays during 
the first cycle of RO7297089 will be allowed if they are less than one cycle (i.e., 
<14 days); under these circumstances, the DLT assessment window may be extended 
up to an additional 7 days in order to capture two planned target doses of treatment.  
Patients who receive supportive care during the DLT assessment window that 
confounds the evaluation of DLTs (not including supportive care described below as part 
of the DLT definition) may be replaced at the discretion of the Medical Monitor.
As described in Section 3.1.5, the ISC will additionally review cumulative safety data and 
make recommendations regarding overall study conduct to ensure patient safety while 
receiving study treatment.  These recommendations include suspending patient 
enrollment based on the overall benefit-risk profile of RO7297089 during dose 
escalation.
3.1.1.1
Definition of Dose-Limiting Toxicity
All adverse events, including DLTs, will be reported according to instructions in 
Section 5.3.5 and graded according to the NCI CTCAE v5.0, with the exception of CRS, 
which will be graded according to the Modified Cytokine-Release Syndrome Grading 
System (Appendix 9).  DLTs will be treated according to clinical practice and 
will be monitored through their resolution.  Any one of the following events will be 
considered a DLT if it occurs during the DLT assessment window (Days 114 of Cycle 1


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for Arms A and B; Cycle 1, Day 8 to Cycle 2, Day 7 for Arm C) unless clearly attributed 
to another identified etiology by the investigator (e.g., cancer progression):

Any Grade 4 or 5 adverse event

Grade 3 febrile neutropenia lasting > 3 days

Grade 3 elevation of serum hepatic transaminase (ALT or AST) lasting 7 days
Any Grade 3 AST or ALT elevation that occurs in the context of Grade 2 CRS 
(as defined by the criteria established by Lee et al. [2019]; see Appendix 9) and 
resolves to Grade 1 within 3 days will not be considered a DLT.

Grade 3 elevation of serum bilirubin (total)

Any increase in hepatic transaminase (ALT or AST) 3baseline in combination 
with either an increase in direct bilirubin 2upper limit of normal (ULN) or 
clinical jaundice, in the absence of cholestasis or other contributory factors 
(e.g., concomitant exposure to known hepatotoxic agent, or documented 
infectious etiology)
This is suggestive of potential drug-induced liver injury (according to Hy’s Law).

Grade 3 non-hematologic, non-hepatic major organ adverse event, with the 
following exceptions:
–
Grade 3 nausea, vomiting, or diarrhea that improves to Grade 2 with
standard-of-care therapy in 3 days will not be considered a DLT.
Grade 3 nausea or vomiting that requires total parenteral nutrition or 
hospitalization is not excluded and should be considered a DLT.
–
Grade 3 fatigue that improves to Grade 2 within 7 days will not be considered 
a DLT.
–
Grade 3 infection that resolves within 7 days to Grade 2 and does not require 
intensive care unit will not be considered a DLT.
–
Grade 3 fever (as defined by 40ºC) for 48 hours will not be considered a 
DLT.
–
Grade 3 laboratory abnormalities that are asymptomatic, resolve to Grade 1 or 
baseline within 7 days, and are considered by the investigator not to be 
clinically significant will not be considered a DLT.
–
Fractures of any grade at site of lytic bone disease will not be considered a 
DLT.
–
Grade3 IRRs will not be considered a DLT, as generally IRRs are not 
considered to be dose-related events on the basis of experience with 
monoclonal antibodies.  Precautions will be taken if IRRs Grade 2 occur (see 
Section 5.1.2.2).  
Grade 4 IRRs or re-occurrence of an IRR event in a patient that 
precluded the administration of the full dose or the administration of the
next scheduled dose of study drug will be considered a DLT.


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Anemia, neutropenia, lymphopenia, leukopenia, and thrombocytopenia are anticipated in 
the study population due to the extensive prior therapy and myeloma involvement in the 
R/R MM population (see Section 4.1).  Investigator assessment of causality and change 
from pre-treatment baseline will be important to characterize the effect of RO7297089 on 
cytopenias.  In addition, infection is a common occurrence in R/R MM due to prior 
therapy and hypogammaglobulinemia.  Hence, infection that recovers as expected with 
appropriate therapy (as per above) will not be considered a DLT.
3.1.1.2
Dose-Escalation Rules
The starting dose of RO7297089 will be 60 mg, administered IV weekly for Cohort 1.
Dose escalations will be guided by the mCRM-EWOC model (Appendix 11). The MTD 
is defined as the dose that maximizes the probability of a DLT being in the targeted 
toxicity interval in the range of 20%35%, subject to the probability of the DLT being in 
the excessive toxicity interval in the range of 35%100% being 25%.  For each cohort, 
patients will be followed through a 14-day DLT assessment window.  At each 
dose-escalation step, the dose can be escalated or de-escalated and/or an additional 
cohort at that same dose level could be enrolled.  Refer to Section 3.1.1 for additional 
information. If MTD is not reached, the RP2D will be determined based on the totality of 
data including clinical activity, safety, PK, and pharmacodynamics biomarkers.  Once the 
MTD or is RP2D determined, all patients in dose-escalation will be eligible to receive the 
RP2D, based upon ISC decision.
In addition, different dosing regimens (e.g., every 2 weeks) may be explored in parallel, if 
warranted, on the basis of the safety and PK profile of RO7297089, with DLT periods 
specific for each regimen and starting dose not exceeding the weekly MTD.  Any 
evaluation of a different administration schedule will be based on the recommendation of 
the ISC and reviewed with study investigators.  Addition of different dosing regimens will 
require a protocol amendment. For this new regimen, the mCRM-EWOC model and 
priors as defined in Appendix 11, as well as the simulations, will be reviewed and 
possibly modified and the DLT assessment period will be extended to 21 days to ensure 
that patients have received at least two doses of study drug.
3.1.2
Continued Dosing Beyond the Dose-Limiting Toxicity 
Observation Period (Cycles ≥2)
Nonclinical toxicology data supports RO7297089 treatment every 7 days.  The ethical 
conduct of a clinical study of cancer requires that patients have the opportunity to 
continue study treatment provided that the treatment is active and tolerable and patients 
comply with protocol requirements.  Therefore, dosing beyond Cycle 1 for patients with 
R/R MM will be allowed in the absence of unacceptable toxicity or objective evidence of 
disease progression as assessed by the treating study investigator and following a 
careful assessment and discussion of the potential risks and benefits with the patient. 
Patients will continue study treatment until objective disease progression is documented 
or unacceptable toxicity, whichever occurs first.  


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RO7297089 administration will be interrupted in patients who experience a DLT during 
the DLT assessment window (Section 3.1.1). Patients who experience a DLT during the 
first cycle and whose toxicity returns to baseline within 14 days may be restarted at a 
dose level tolerated by the prior cohort following discussion with the Medical Monitor. 
A treatment delay beyond 14 days may be acceptable upon discussion with the Medical 
Monitor (see Section 5.1.2).
3.1.3
Intrapatient Dose Escalation
To maximize the collection of information at relevant doses and minimize the exposure 
of patients to sub-optimal doses of RO7297089, intrapatient dose escalation may be 
permitted. Within each assigned dose-escalation cohort, the dose of RO7297089 for an 
individual patient may be increased to the highest cleared dose level that is tolerated by 
completed cohorts through the DLT window. Patients may be able to undergo 
intrapatient dose escalation after completing at least two cycles at their originally 
assigned dose level.  
Subsequent intrapatient dose escalations may occur after at least one cycle of any 
subsequently higher cleared dose level without any adverse event that meets the 
definition of a DLT or necessitates post-administration hospitalization (Section 3.1.1.1). 
Once the MTD is declared and the RP2D is determined, intrapatient dose escalation 
directly to the RP2D is permitted for patients who remain on study and continue to 
tolerate RO7297089. 
At the discretion of the investigator and in consultation with the Medical Monitor, the 
RO7297089 administration schedule for the first cycle after intrapatient dose escalation 
may follow any administration schedule previously evaluated in the study.
3.1.4
Expansion Stage
After dose escalation has been completed, approximately 30 patients will be enrolled in 
the expansion stage.  Patients will be treated at the RP2D (at or below the MTD) to
obtain additional safety, tolerability, and PK data, as well as preliminary evidence of 
clinical activity.  The ISC will assess all safety data on an ongoing basis. At no time will 
the dose administered in the expansion stage exceed the highest dose level that 
qualified as an MTD in the dose-escalation stage.
3.1.5
Internal Safety Committee
Given that this is a first-in-human trial, an ISC will be utilized during the study to make 
recommendations regarding study conduct on the basis of trial safety data to ensure 
enhanced patient safety monitoring while receiving study treatment.  The ISC will be 
formed before the first patient is enrolled into the study.
The ISC will include at a minimum the Medical Monitor, study Safety Scientist, study 
Biostatistician, and a Sponsor Medical Monitor not associated with the study. 


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Representatives from other Sponsor functional areas may be included as ad hoc 
members.
In addition to the ongoing assessment of the incidence and nature of DLTs, adverse 
events, serious adverse events, adverse events of special interest, and laboratory 
abnormalities by the investigator and the Medical Monitor, the ISC will review cumulative 
data at regular intervals during the study.  This committee will make decisions in 
consultation with study investigators regarding opening Arm B and/or Arm C for a given 
dose cohort as well as dose escalations based on the plan described in Section 3.1.1.  
The ISC, in consultation with study investigators, will also review the cumulative data 
from dose escalation prior to opening the dose expansion portion of the study and 
review data from the dose expansion at routine intervals.  In addition, the ISC will meet 
regularly and as needed at the request of the study Medical Monitor (e.g., based on 
unexpected safety signals).  The ISC may further make recommendations regarding 
study conduct, including, but not limited to, the following: performing additional safety 
analyses, amending the study protocol, holding patient enrollment pending further safety 
evaluations, enrolling additional patients at a specific dose level and schedule to obtain 
additional safety data, holding/discontinuing study treatment, or terminating the study.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of the study is expected 
to occur approximately 1 year after the last patient is enrolled.
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 3 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
This study will enroll patients with a history of R/R MM who meet the inclusion and 
exclusion criteria as outlined in Sections 4.1.1 and 4.1.2.  Confirmation of BCMA 
expression will not be required during eligibility screening prior to enrollment, but it will 
be evaluated retrospectively, based on the following rationale:

Nonclinical studies have demonstrated that RO7297089 is potent in cell killing in 
multiple human MM cell lines and primary human MM plasma cells with a wide 
range of BCMA expression levels, including cells with minimal BCMA expression, 
suggesting that even very low levels of BCMA expression may be sufficient for 
clinical activity (RO7297089 Investigator’s Brochure). 


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
BCMA is a cell surface antigen whose expression is restricted to plasma cells.  
It is expressed in all MM samples tested to date (Carpenter et al. 2013; Seckinger 
et al. 2017).
Bone marrow samples obtained from all patients will be retrospectively analyzed for 
BCMA expression with validated assays (e.g., quantitative reverse transcription-PCR, 
immunohistochemistry, and quantitative flow cytometry).  These data will be used to 
inform how best to utilize BCMA expression screening in subsequent studies.
Patients with prior BCMA therapy exposure will be permitted to enroll in the study.  
Based on experience with BCMA CAR-T treated patients, BCMA expression increases 
at time of disease progression (Cohen et al. 2019b).  In addition, limited data exists for 
successful sequencing of BCMA therapies (Cohen et al. 2019a).  
Eligibility criteria for this Phase I study additionally consider the totality of nonclinical 
toxicology studies of RO7297089, clinical safety data from agents targeting BCMA 
(e.g., GSK2857916, bb2121), and published clinical safety data from AFM13 
(anti-CD30/CD16a).
3.3.2
Rationale for RO7297089 Dose and Schedule
The recommended first-in-human starting dose of 60 mg IV is based on an integrated 
approach using both in vivo data from the repeat-dose toxicity study in cynomolgus 
monkeys and in vitro data from the cytokine assay. 
RO7297089 showed minimal increase of cytokines in in vitro assays with human 
BCMA-positive cell lines and PBMCs at concentrations up to 50 g/mL (250 nM).  There 
were no RO7297089-related toxicity findings in the single-dose and repeat-dose 
toxicology studies in cynomolgus monkeys, while clear pharmacologic activity (reflected 
by reduction of IgM and decreased expression of BCMA and J-chain mRNA) was 
observed in a repeat-dose GLP safety study at both 15 m/kg and 50 mg/kg.  These 
observations, in combination with the mechanism of action of RO7297089, which is 
similar to ADCC and ADCP, suggest that RO7297089 has a low likelihood of CRS in the 
clinic.  This is supported further with AFM13 clinical data, where no CRS was detected in 
doses of up to 7 mg/kg (Rothe et al. 2015). 
The recommended first-in-human starting dose of 60 mg IV is based on an integrated 
approach using both in vivo and in vitro data.  The dose of 60 mg is predicted to have 
exposure (Cmax and AUC) ≥10-fold lower than the exposure at 15 mg/kg in cynomolgus 
monkeys (lowest dose at which RO7297089 demonstrated clear pharmacological 
changes) and also achieves a projected Cmax of 19 g/mL that is approximately 2.5-fold 
lower than the highest concentration of 50 g/mL tested in the in vitro cytokine assay 
(where only minimal cytokine increases were observed). Overall, the proposed 
first-in-human dose of 60 mg has >40 safety margin (based on Cmax, AUC, and dose) 


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when compared to cynomolgus monkey NOAEL (50 mg/kg). Based on the totality of 
the nonclinical data, the recommended starting dose is expected to be safe.
A weekly dosing frequency is proposed based on the in vivo PK properties of 
RO7297089 and the clinical experience of other therapeutics for the treatment of MM 
(e.g., daratumumab). RO7297089 is proposed to be administered via IV infusion, a 
commonly used route of administration for large molecule anti-cancer therapeutics.  
Dedicated dose-escalation arms have been added to evaluate split-dose and step-dose 
administration schedules with regard to mitigating the risk of IRRs.  While the impact 
of these alternate dose administration schedules on the frequency and severity of IRR is 
unknown for RO7297089, similar interventions have been successful with other 
monoclonal antibody therapies.
Details of nonclinical studies described above, starting dose rationale, and human 
equivalent dose calculation can be found in RO7297089 Investigator’s Brochure.
3.3.3
Rationale for Dose-Escalation Plan
The mCRM-EWOC model will be used to guide dose escalation to determine the MTD.  
mCRM-EWOC has many favorable characteristics compared with a conventional 
33 design.  Such an adaptive Bayesian model-based design is one of the key 
elements of the U.S. Food and Drug Administration (FDA)’s Critical Path Initiative. 
The key advantages of the mCRM-EWOC design are as follows:
It adaptively fits a DLT dose-response curve by incorporating toxicity data from eligible 
patients among different cohorts. Thus, dose recommendations for the next cohort are 
decisions made according to multiple cohorts instead of a single cohort in context of a 
33 design, and preclinical information is contributable by building an 
informative/minimal informative prior distribution of the statistical model.
It locates the MTD efficiently without pre-specifying dose levels in each cohort. Dose 
selections are made based on the DLT dose-response curve measured by a 
two-parameter logistic model over the dose range, subject to clinical judgment and 
mandated safety constraints that limit the size of dose-increments. It has been 
suggested in multiple reports that the method exposes fewer patients to sub-therapeutic 
doses than the traditional 33 design (Le Tourneau et al. 2009).
It greatly reduces risks of exposing patients to overly toxic doses by utilizing the 
escalation with overdose control algorithm. The design will never recommend a dose 
with more than 25% likelihood of being in the excessive toxicity interval in which the DLT 
rate is above 35% according to the present DLT information.
The maximal increment for escalation is 3-fold.  Nonclinical data for RO7297089 and 
published clinical safety data for AFM13 (described in Section 1.3) supports this 


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approach (see Section 1.2 for a summary of nonclinical data and Section 5.1.1 for 
potential risks).  
Decision making with respect to patient dosing and dose-escalation is described in 
Section 3.1.  Furthermore, DLT criteria, stopping rules, monitoring and management 
guidelines of all potential toxicities and dose delay rules are included in this protocol 
(Sections 3.1 and 5.1.2). 
3.3.4
Rationale for PK Sampling Schedule 
The PK sampling schedule that follows RO7297089 administration is designed to 
capture data at a sufficient number of timepoints to inform the concentration-time curve 
and enable characterization of key PK parameters, including maximum serum 
concentration observed (Cmax ), minimum serum concentration observed (Cmin), area 
under the concentration-time curve (AUC), time to maximum concentration observed
(tmax), total clearance, volume of distribution at steady state, and half-life, as appropriate.  
These data will also be used to understand the relationship between dose, 
pharmacokinetics, safety, and activity to inform clinical dose selection. 
Exploratory PK samples are collected using a sparse sampling schedule to allow 
exploratory assessment of potential presence of drug fragments and in relative ratio to 
intact molecules.
3.3.5
Rationale for Biomarker Assessments 
Understanding the mechanism of action of RO7297089 and identifying prognostic and 
predictive biomarkers for safety and clinical activity in patients with R/R MM forms the 
underlying rationale for their assessment in this study.  
The biomarker sampling schedule (from peripheral blood, and bone marrow biopsies 
and aspirates) following RO7297089 administration is designed to provide a detailed 
profile of the following: 

Expression of phenotypic markers of NK cell and T-cell function and potential 
markers of resistance to RO7297089 therapy  
Examples of these include, but are not limited to, markers of NK/T-cell 
activation and proliferation as well as expression of T-cell immunoreceptor with 
Ig and ITIM domains (TIGIT) and other inhibitory molecules on NK cells.

Dynamic quantitative changes in NK cell, T-cell, and B-cell counts

Assessments of cytokine levels as clinically indicated in relation to RO7297089 
pharmacokinetics and clinical safety during and beyond the DLT assessment period 
These assessments will permit correlations with any chronic safety signals 
observed with RO7297089 treatment. 

Monitoring for minimal residual disease (MRD) by next-generation sequencing and 
establishing correlations with objective response


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In addition to biomarker sampling (as outlined in Appendix 3), bone marrow biopsies and 
aspirates will be obtained as detailed in Appendix 1.  Evaluating changes to the tumor 
immune microenvironment is important in understanding the mechanism of action of 
RO7297089, understanding potential mechanisms of RO7297089 resistance, and 
providing biologic rationale for combinations of RO7297089 with other anti-cancer 
therapies.  The sampling schedule is therefore designed to capture quantitative and 
functional changes in the immune cell infiltrate as well as changes to disease biology 
using both phenotypic and gene expression assays.
Contingent upon the review and approval of the exploratory research by each site's 
IRB/EC and, if applicable, an appropriate regulatory body (Section 4.5.9), tissue samples
will be collected for DNA extraction to enable whole genome sequencing (WGS) or 
whole exome sequencing (WES).  The aim of these analyses is to identify variants that 
are predictive of response to study drug, are associated with progression to a more 
severe disease state, are associated with acquired resistance to study drug, are 
associated with susceptibility to developing adverse events, can lead to improved 
adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Genomics is increasingly informing 
researchers’ understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.  Data will 
be analyzed in the context of this study but may also be explored in aggregate with data 
from other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
4.
MATERIALS AND METHODS 
4.1
PATIENTS
Approximately 6080 patients with R/R MM will be enrolled in this study.


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4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
ECOG Performance Status of 2 due to MM may be eligible after discussion with 
the Medical Monitor.

Life expectancy of at least 12 weeks

Patients must have R/R MM for which no established therapy for MM is appropriate 
and available or be intolerant to those established therapies

Agreement to provide bone marrow biopsy and aspirate samples as detailed in 
Appendix 1

Adverse events from prior anti-cancer therapy resolved to Grade 1, with the 
following exceptions:
–
Any grade alopecia
–
Peripheral sensory or motor neuropathy that has resolved to Grade 2

Measurable disease, defined as at least one of the following:
–
Serum monoclonal protein (M-protein) 0.5 g/dL (5 g/L)
–
Urine M-protein ≥ 200 mg/24 hr
–
Serum free light chain (SFLC) assay: Involved SFLC ≥ 10 mg/dL (≥ 100 mg/L) 
and an abnormal SFLC ratio (<0.26 or >1.65)

Laboratory values as follows:
–
Hepatic function:
o
AST and ALT 3 ULN
o
Total bilirubin 1.5 ULN 
Patients with a documented history of Gilbert syndrome and in whom 
total bilirubin elevations are accompanied by elevated indirect bilirubin 
are eligible.
–
Hematologic function:
o
Platelet count 50,000/mm3 without transfusion within 7 days of 
assessment
o
ANC 1000/mm3
o
Total hemoglobin 8 g/dL without transfusion within 14 days of 
assessment


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Patients who do not meet criteria for hematologic function because of MM 
related cytopenias (e.g., due to extensive marrow involvement by MM) may be 
enrolled into the study after discussion with the Medical Monitor.  

Creatinine clearance (CrCl) 30 mL/min (either calculated using a modified 
Cockcroft-Gault calculation or per 24-hour urine collection; inulin or radionuclide-
based methods may be used after discussion with Medical Monitor)  

Serum calcium (corrected for albumin) level 11.5 mg/dL (2.9 mmol/L)
Treatment of hypercalcemia is allowed and patient may enroll if hypercalcemia 
returns to normal with standard treatment.

For women of childbearing potential:  agreement to remain completely abstinent 
(refrain from heterosexual intercourse) or use contraception, and agreement to 
refrain from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 28 days after the final dose 
of RO7297089.  Women must refrain from donating eggs during this same 
period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, or copper intrauterine 
devices.
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study drug and is consistent with the usual lifestyle of the 
patient.  The reliability of sexual abstinence should be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.  If required per local guidelines or regulations, locally recognized 
acceptable methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain completely abstinent (refrain from heterosexual 
intercourse) or use a condom, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom with spermicide during the treatment 


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period and for 28 days after the final dose of RO7297089 to avoid exposing the 
embryo.  Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 28 days after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug.

Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drug 
conjugate for the treatment of cancer within 4 weeks before first RO7297089
infusion

Prior treatment with systemic immunotherapeutic agents, including, but not limited 
to, cytokine therapy and anti-CTLA4, antiPD-1, and antiPD-L1 therapeutic 
antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before 
first RO7297089 infusion

Prior treatment with CAR-T therapy within 90 days before first study drug 
administration

Treatment with any chemotherapeutic agent, or treatment with any other anti-cancer 
agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, 
whichever is shorter, prior to first RO7297089 infusion

Autologous stem cell transplantation within 100 days prior to first RO7297089
infusion

Allogeneic stem cell transplantation within 180 days prior to first RO7297089 
infusion or requiring immunosuppression for treatment or prophylaxis of graft versus
host disease

Primary or secondary plasma cell leukemia as defined by an absolute plasma cell 
count exceeding 2000/L or 20% of the peripheral blood white cells

Known cardiac amyloidosis 

History of severe allergic or anaphylactic reactions to monoclonal antibody therapy 
(or recombinant antibody-related fusion proteins) or any of the components of the 
RO7297089 drug product

Significant active pulmonary disease (e.g., chronic obstructive pulmonary disease 
with known forced expiratory volume in 1 second of less than 50% of predicted 


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normal, severe persistent asthma) that may limit a patient's ability to adequately 
respond to an IRR event in the investigator’s assessment

History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the following exceptions:
–
Patients with history of curatively basal or squamous cell carcinoma of the skin 
or in situ carcinoma of the cervix
–
Localized prostate cancer Gleason Grade 6 AND with stable prostate-specific 
antigen levels off treatment
–
Patients with a malignancy that has been treated with curative intent will also be 
allowed if the malignancy has been in remission for ≥ 2 years prior to first 
RO7297089 infusion. 

Acute or chronic hepatitis C virus (HCV) infection
Patients who are positive for the HCV antibody must be negative for HCV by 
PCR to be eligible for study participation.

Positive serologic or PCR test result for acute or chronic hepatitis B virus (HBV)
infection
Patients whose HBV infection status cannot be determined by serologic test 
results must be negative for HBV by PCR to be eligible for study participation.
Antiviral prophylaxis for patients at risk of HBV reactivation is permitted.

Known HIV infection unless the patient meets all the following criteria:
–
CD4 count 350 cells/L prior to enrollment
–
No history of AIDS-defining illness in the last 12 months prior to study 
enrollment (see Appendix 13 for a list of AIDS-defining illnesses)
–
Must be on established antiretroviral therapy for at least 4 weeks and have an 
HIV viral load < 400 copies/mL prior to enrollment

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV anti-microbial therapy within 14 days prior to 
first RO7297089 infusion

Administration of a live, attenuated vaccine within 4 weeks before first RO7297089
infusion or anticipation that such a live, attenuated vaccine will be required during 
the study
Influenza vaccine should be given during influenza season (approximately 
October to May in the Northern Hemisphere; approximately May to October in 
the Southern Hemisphere). Patients must not receive live, attenuated influenza 
vaccine at any time during the study period.
Investigators should review the vaccination status of potential study patients 
being considered for this study and follow the local guidelines for adult 
vaccination with any other non-live vaccines intended to prevent infectious 
diseases prior to study.


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
Received systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor agents) within 2 weeks prior to the first dose of RO7297089, with 
the following exceptions:
Patients who received acute, systemic immunosuppressant medications (e.g., 
single dose of dexamethasone for nausea, prophylactic corticosteroids to 
prevent allergic reaction to CT contrast) may be enrolled in the study after 
discussion with the Medical Monitor.
The use of corticosteroids for anti-cancer treatment is permitted prior to the 
first dose of RO7297089; washout requirements for anti-cancer therapies are 
defined above.
The use of corticosteroid treatment of 10 mg/day prednisone or equivalent is 
permitted.
The use of inhaled corticosteroids is permitted.
The use of mineralocorticoids for management of orthostatic hypotension is 
permitted.
The use of physiologic doses of corticosteroids for management of adrenal 
insufficiency is permitted.

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s 
judgment

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study

Significant cardiovascular disease (such as, but not limited to, New York Heart 
Association Class III or IV cardiac disease, myocardial infarction within the last 
6 months, unstable arrhythmias, or unstable angina)

Current CNS involvement by MM
Patients with a history of CNS involvement must have at least 6 months of 
remission in the CNS without interval CNS directed therapies prior to first 
RO7297089 infusion.
Patients with a history of CNS involvement must have a magnetic resonance 
imaging (MRI) of the brain and lumbar puncture during screening to confirm that 
CNS is clear.

Recent major surgery within 4 weeks prior to first RO7297089 infusion or 
anticipation of need for a major surgical procedure during the course of the study
Protocol-mandated procedures (e.g., tumor biopsies and bone marrow 
biopsies) and superficial lymph node biopsies for diagnosis are permitted.
Prophylactic orthopedic intervention to long bones to prevent fracture is 
permitted within 2 weeks prior to first RO7297089 infusion.

Uncontrolled tumor-related pain


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Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to enrollment.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment.
4.2
METHOD OF TREATMENT ASSIGNMENT 
This is a non-randomized, open-label study.  After initial written informed consent has 
been obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient’s 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS).
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is RO7297089 (BPCT2605S).
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
RO7297089
RO7297089 (BPCT2605S) will be supplied by the Sponsor (Genentech).  For 
information on the formulation, packaging and handling of RO7297089, refer to the 
pharmacy manual and the RO7297089 Investigator’s Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along
with any associated adverse events, should be reported as described in 
Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.2.1.
4.3.2.1
RO7297089
Dosing independent of body weight will be used for RO7297089.  The dose of 
RO7297089 for each patient will depend on the dose level assignment as detailed in the 
protocol.


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In this study, RO7297089 will be administered to patients by IV infusion using standard 
syringes and syringe pumps or IV bags where applicable. The drug product will be 
delivered by syringe pump via an IV infusion set or IV bag with a final RO7297089
volume determined by the dose.  The specific RO7297089 dose will determine the 
appropriate dosing concentrations, volumes, and infusion times, and will also dictate the 
specific, appropriate, administration apparatus (i.e., peripheral catheter vs. syringe pump 
vs. IV bags) to be used.  Premedication with oral acetaminophen or paracetamol 
(e.g., 5001000 mg), an antihistamine (2550 mg diphenhydramine or equivalent), and a 
corticosteroid (minimum equivalent of 80 mg IV methylprednisolone) will be administered 
as prophylaxis for IRR prior to first administration of RO7297089 for Arms A and B, and 
prior to the first two doses of RO7297089 for Arm C, unless contraindicated.  
Administering premedication on the day prior to infusion may also be considered 
and/or implemented to mitigate IRR.  Premedication may be given prior to subsequent 
infusions at the discretion of the investigator.  All RO7297089 doses should be 
administered to well-hydrated patients.
Recommended management of IRR is detailed in Section 5.1.2.2.
Infusion of RO7297089 will be administered as per Table 1, but no higher than 14 mg 
per kg of body weight per hour (14 mg/kg/hr). The reason for the restriction in infusion 
time is due to the use of sucrose as a protein stabilizing agent in the drug product. 
Sucrose is used as a protein stabilizer in many IV formulations of therapeutics and is 
generally excreted unchanged in the urine with no detrimental effect to humans. It was 
commonly used as a stabilizer in various formulations of intravenous Ig (IVIg); however, 
in 1999, the U.S. FDA issued a “Dear Doctor Letter” noting several cases of renal 
dysfunction and renal failure with IVIg, and a disproportionate number of cases 
correlated with sucrose containing formulations of IVIg. The FDA recommended that 
infusions of IVIg containing sucrose not exceed 3 mg of sucrose/kg/min to avoid renal 
complications. While this correlation was seen in IVIg formulations, this infusion rate has 
been extrapolated to any IV product containing sucrose. The amount of sucrose present 
in the formulated RO7297089 drug product is approximately 61.56 mg of sucrose per 
milliliter of drug product. Thus, to keep the sucrose infusion rates 3 mg/kg/min, 
RO7297089 will be infused at a rate no higher than 14 mg/kg/hr. Please refer to the 
pharmacy manual for additional details on administering RO7297089.
Initially, RO7297089 will be administered over a minimum of 2 hours or longer
depending on the patient’s body weight.  The minimum infusion time may be increased
if needed to mitigate IRRs.  The infusion may be slowed or interrupted for patients 
experiencing IRRs (see Section 5.1.2.2).  Patients will be observed at least 240 minutes 
(4 hours) for fever, chills, rigors, hypotension, nausea, or other signs and symptoms of 
IRRs after the first RO7297089 infusion.  For Arm B (split dose), patients will be 
observed at least 240 minutes (4 hours) after the Day 1 infusion and for at least 
120 minutes (2 hours) after the Day 2 infusion. At the discretion of the investigator, 
patients may be hospitalized overnight to accommodate a longer infusion or extend the 


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observation period (see Sections 5.3.3 and 5.3.5.11 regarding the reporting 
requirements for such events).  Patients who experience any sign or symptom of an IRR 
during the first infusion or at any time during the observation period that does not resolve 
to Grade 1 by the end of the observation period should be observed for at least 24 
hours in a hospital setting. In the absence of IRRs, the infusion time of RO7297089 for 
subsequent infusions may be reduced as described in Table 1, to a minimum of 
30 minutes.  Both of these infusion times will also be dependent on patient’s body weight 
to meet the 14 mg/kg/hr infusion rate limit.  If the first full dose was tolerated, the 
observation period may also be reduced for subsequent infusions as described in 
Table 1.
Patients who undergo intrapatient dose escalation (see Section 3.1.3) should receive the 
first higher dose of RO7297089 over a minimum of 2 hours and be observed for at least 
240 minutes (4 hours) for fever, chills, rigors, hypotension, nausea, or other signs and 
symptoms of IRR.
Management of IRRs and guidelines for dosage and schedule modification and 
treatment interruption or discontinuation are provided in Section 5.1.2.
Table 1
Administration of First and Subsequent Infusions of RO7297089 
RO7297089
Cycle 1, Day 1
Cycle 1, Day 2
Cycle 1, Day 8
Cycle 2, Day 1 
and Beyond
Arm A (flat dose)
Minimum infusion time
120 min 
N/A
60 min 
30 min 
Monitoring window
240 min
N/A
60 min
30 min
Arm B (split dose)
Minimum infusion time
120 min 
120 min
120 min 
30 min 
Monitoring window
240 min
120 min
120 min
30 min
Arm C (step up dose)
Minimum infusion time
120 min 
N/A
240 min 
60 min a
Monitoring window
240 min
N/A
240 min
30 min
N/A not applicable.
Notes:  These infusion and observation times may be longer to meet the 14 mg/kg/hr infusion limit.  
In addition, these times assume that no infusion-related adverse events occurred during or within 24 
hours after the prior infusion.  For patients who develop infusion-related adverse events, see 
Section 5.1.2 for management guidelines.
a After Cycle 2, Day 1, the minimum infusion time may be reduced to 30 minutes provided the 
previous infusions were tolerated.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of IMPs supplied by the Sponsor, by returning the 


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appropriate documentation form to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site’s method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to RO7297089
The Sponsor (Genentech, a member of the Roche Group) will offer continued access to 
Genentech IMP RO7297089 free of charge to eligible patients in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, as 
outlined below.
A patient will be eligible to receive Genentech IMP RO7297089 after completing the 
study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Genentech IMP treatment for his or her well-being.

There are no appropriate alternative treatments available to the patient.

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.
A patient will not be eligible to receive Genentech IMP RO7297089 after completing the 
study if any of the following conditions are met:

The Genentech IMP is commercially marketed in the patient’s country and is 
reasonably accessible to the patient (e.g., is covered by the patient’s insurance or 
wouldn’t otherwise create a financial hardship for the patient).

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for MM.

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
MM.

Provision of the Genentech IMP is not permitted under the laws and regulations of 
the patient’s country.
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


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4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 
7 days prior to initiation of study drug to the end-of-treatment visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy may continue their use.
Concomitant use granulocyte colony-stimulating factor (G-CSF) (filgrastim, 
pegfilgrastim), hematopoietic growth factors such as erythropoietin, 
granulocyte/macrophage colony-stimulating factor (sargramostim), or thrombopoietin 
(oprelvekin, eltrombopag) is permitted.  Transfusion of red blood cells and platelets are 
permitted.  
Anti-infective prophylaxis for viral, fungal, bacterial, or pneumocystis infections is 
permitted and should be instituted per institutional practice.  Immunoglobulin therapy is 
permitted.
Patients who experience RO7297089 infusion-related symptoms may be treated 
symptomatically as described in Section 5.1.2.2.
Palliative radiotherapy is permitted.  Study drug treatment may be continued during 
palliative radiotherapy.  Bisphosphonates and denosumab are permitted.
Patients experiencing a mixed response requiring local therapy (e.g., surgery, 
stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of lesions 
may still be eligible to continue study treatment, at the discretion of the investigator and 
after discussion with the Medical Monitor.
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), corticosteroids, or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists).  Refer to Section 5.1.2.2 for further guidance for 
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4.4.2
Cautionary Therapy
4.4.2.1
Medications Given with Precaution due to Effects Related to 
CYP Enzymes
The transient release of cytokines may be observed with RO7297089 which may 
suppress CYP450 enzymes and cause drugdrug interactions.  This risk is anticipated to 
be low based on nonclinical data but will be informed by clinical data during this Phase I
study.  Patients receiving concomitant medications that are CYP450 substrates and 
have a narrow therapeutic index (see Appendix 8) may have the highest risk of a 
drugdrug interaction.  
The list of medications in Appendix 8 is not necessarily comprehensive.  The investigator 
should consult the prescribing information when determining whether a concomitant 
medication can be safely administered with study treatment.  In addition, the investigator 
should contact the Medical Monitor if questions arise regarding medications not listed 
above.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer may be 
used during the study at the discretion of the investigator with Medical Monitor approval.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) for various 
time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2) and during study treatment

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, immunotherapy, radiotherapy, and herbal therapy) for various 
time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 4.4.1 for 
details)

Hormone therapy for the treatment of cancer, whether approved by local regulatory 
authorities or investigational
Adjuvant endocrine therapy for non-metastatic prostate cancer and 
non-metastatic, hormone-receptor positive breast cancer is permitted.

Biologic agents other than hematopoietic growth factors, which are allowed 
if clinically indicated and used in accordance with instructions provided in the 
package inserts

Any therapies intended for the treatment of MM, whether approved by local 
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
Live, attenuated vaccines
Patients who require the use of any of these agents will be discontinued from treatment 
with RO7297089.  Patients who are discontinued from study treatment will be followed 
for safety outcomes for 90 days following the patient’s final dose of RO7297089 or until 
the patient receives another anti-cancer therapy, whichever occurs first.
The above list of medications is not necessarily comprehensive.  The investigator should 
contact the Medical Monitor if questions arise regarding medications not listed above.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
Screening and pretreatment tests and evaluations will be performed within 28 days 
preceding the first dose of RO7297089 with the following exceptions:

Pregnancy test must be done within 7 days of first dose of study drug (Cycle 1, 
Day 1)

Hematology and chemistry panels must be done within 14 days of first dose of study 
drug
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within appropriate window prior to Cycle 1, Day 1 may be used; these tests 
do not need to be repeated for screening.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  With the exception of the pretreatment bone 
marrow biopsy material, results of all screening evaluations must be submitted to the 
Genentech Medical Monitor before a patient may be enrolled in the study.  The 
pretreatment bone marrow biopsy may be performed after the patient has been cleared 
for enrollment into the study.  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening 
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4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and reproductive status will be 
recorded at baseline.  In addition, all medications (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 7 days prior to initiation of study treatment will be recorded.  At the 
time of each follow-up physical examination, an interval medical history should be 
obtained and any changes in medications and allergies should be recorded (see
Appendix 2).
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, performed during screening, should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems (including evaluation of mental status, cranial nerves, strength, 
sensation, and coordination) and should be documented in the patient chart.  Any 
abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), targeted symptom-directed physical
examinations should be performed. Targeted physical examinations should be limited to
systems of primary relevance (i.e., cardiovascular, respiratory, neurologic, and any
system that might be associated with tumor assessment [e.g., those systems associated
with symptoms], or potential drug-related toxicity; see Section 5.1.1). Changes from 
baseline abnormalities should be recorded in patient notes. New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF.
4.5.4
ECOG Performance Status
Performance status will be measured using the ECOG Performance Status Scale 
(Appendix 15).
4.5.5
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  Every 
effort should be made to ensure that vital signs are obtained from patients in a 
consistent manner/position. Record abnormalities observed at baseline on the General 
Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.


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Vital signs for patients should be obtained according to the schedule of activities in 
Appendix 1.  Details of the frequency of vital sign monitoring are provided in Table 2
below. Additional vital sign monitoring should be performed if clinically indicated or if 
symptoms occurred during the prior infusion.
Table 2
Vital Sign Monitoring
Arm A (flat)
Cycle 1, Day 1 a
Cycle 1, Day 8
Cycle 2, Day 1 and 
Beyond b
Pre-infusion 
Once
Once
Once
During infusion
Every 30 min (10 min) Every 30 min (10 min) 
Once
End of infusion
Once
Once
Once
Post-infusion
Every 60 min (10 min) 
for 240 min
Once 60 min after end 
of infusion
Once 30 min after end 
of infusion
Arm B (split)
Cycle 1, Day 1 and 
Day 2 a
Cycle 1, Day 8
Cycle 2, Day 1 and 
Beyond b
Pre-infusion 
Once
Once
Once
During infusion
Every 30 min 
(10 min)
Every 30 min 
(10 min)
Once
End of infusion
Once
Once
Once
Post-infusion
Every 60 min 
(10 min) during 
observation
Once 60 min after end 
of infusion
Once 30 min after end 
of infusion
Arm C (step)
Cycle 1, Day 1 a
Cycle 1, Day 8
Cycle 2, Day 1 and 
Beyond 
Pre-infusion 
Once
Once
Once
During infusion
Every 30 min 
(10 min)
Every 30 min 
(10 min)
Once
End of infusion
Once
Once
Once
Post-infusion
Every 60 min 
(10 min) for 240 min
Every 60 min 
(10 min) for 240 min
Once 30 min after end 
of infusion
a For any patient undergoing intrapatient dose escalation, the first infusion at a higher dose 
requires the same vital sign monitoring as Cycle 1, Day 1 (or Cycle 1, Day 1 and Day 2 for 
Arm B).
b Except for any first infusion of a higher dose for patients undergoing intrapatient dose 
escalation (as per above).
4.5.6
Disease-Specific Assessments
Patients will be evaluated for disease response and progression according to the IMWG 
Uniform Response Criteria (Appendix 5) during each cycle at timepoints identified in the 
schedules of activities (Appendix 1 and Appendix 2).
A bone marrow biopsy and aspirate are required prior to Cycle 1, Day 1 dosing, between 
Cycle 2, Day 8 and Cycle 3, Day 1, and at the time of confirmation of CR or at disease 


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progression.  The bone marrow sample scheduled prior to Cycle 1, Day 1 may be 
obtained after the patient's other screening procedures have been completed and 
enrollment of the patient has been confirmed by the Medical Monitor.
Patients who are re-screened after an initial screen failure (see Section 3.1) do not need 
to undergo a repeat bone marrow biopsy and aspirate if these assessments were 
completed during the initial screening period.
At least three historical values for M-protein (or SFLC if light chainonly disease) from 
the end of prior therapy to the initiation of study treatment with RO7297089 will be 
collected if available.
The following myeloma-specific tests will be at the beginning of every odd cycle and
processed by the Sponsor or the Sponsor's contracted specialty bioanalytical 
laboratories for analysis, starting with Cycle 1, Day 1:

Serum protein electrophoresis (SPEP) with serum immunofixation electrophoresis 
(SIFE) 

SFLCs
If SPEP/SIFE and SFLC analyses are additionally performed locally at sites, the results 
of these analyses should be provided to the Sponsor.  
Quantitative Ig levels should be performed locally.
The following myeloma-specific tests should be performed both centrally and locally at 
sites during screening and as needed (locally) to confirm a response:

A 24-hour urine protein electrophoresis (UPEP) with urine immunofixation 
electrophoresis (UIFE) for M-protein quantitation
The following confirmatory assessments are required for all response categories (sCR, 
CR, VGPR, PR, and minimal response):

If extramedullary disease was previously present, computed tomography (CT) scan 
or MRI with bidimensional measurements to confirm reduction in size per IMWG 
Uniform Response Criteria

If extramedullary disease was previously present, positron emission tomography 
(PET)-CT scan, CT scan, or MRI to confirm complete resolution

24-hour UPEP/UIFE (performed locally) to confirm VGPR even if a UPEP was not 
performed during screening
The following additional samples/assessments are required to confirm a sCR or CR:

SIFE

SFLC


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
24-hour UPEP/UIFE (performed locally) to confirm CR/sCR even if a UPEP was not 
performed during screening 

Bone marrow aspiration and biopsy

If extramedullary disease was previously present, PET-CT scan, CT scan, or MRI to 
confirm complete resolution
To confirm progressive disease, the following are required:

If progressive disease is suspected by rising M-protein, SPEP, UPEP, or SFLC 
analysis should be obtained on two consecutive assessments.

If progressive disease is suspected on development of new bone lesions or soft 
tissue plasmacytomas or an increase in size of existing bone lesions or soft tissue 
plasmacytomas, skeletal survey/CT scan/MRI should be obtained and compared 
with baseline imaging.

If progressive disease is suspected on hypercalcemia attributed solely to MM, local 
laboratory levels of serum calcium should be >11 mg/dL and confirmed on a second 
assessment.
Extramedullary Disease
All patients with clinically suspected extramedullary disease or known extramedullary
disease at the time of screening must undergo imaging during screening to evaluate for 
the presence/extent of extramedullary disease.  This can be performed by CT scan of 
the chest, abdomen, and pelvis (preferably with IV contrast if renal function is adequate), 
PET/CT, or whole-body MRI.  Patients who are found to have extramedullary disease 
will undergo repeat imaging (preferably the same modality as performed during
screening) every 12 weeks (7 days).  Imaging should also be performed upon clinical 
suspicion of progressive disease.  Chest X-ray or ultrasound of the abdomen/liver/spleen 
may be substituted for CT, PET/CT, or MRI if, per the investigator's assessment, 
patients are not able to safely tolerate these imaging modalities and the anatomic 
location of the extramedullary disease is compatible with these alternative imaging 
methods.
Skeletal Survey
A skeletal survey will be completed during screening and as clinically indicated.  The 
skeletal survey may be completed up to 28 days prior to Day 1 of Cycle 1.  Plain films and 
CT scans are both acceptable imaging modalities for assessing skeletal disease.  
Imaging should include the skull, long bones, chest, and pelvis.  If plasmacytomas are 
seen on skeletal survey, bidimensional tumor measurements should be recorded.  The 
skeletal survey may be omitted if a PET/CT scan or a low-dose, whole-body CT is 
performed as part of screening.


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4.5.7
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells [if present])

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, LDH, total and 
direct bilirubin, ALP, ALT, and AST

Coagulation:  INR, aPTT, and PT (optional)

HIV serology:  HIV-1/2 antibody

HBV serology:  hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), and (if HBsAg test is negative and total HBcAb test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test during
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test during screening, an HCV RNA 
test must also be performed to determine if the patient has an HCV infection.

Quantitative immunoglobulins:  IgA, IgG, and IgM

Pregnancy test
All women of childbearing potential will have a serum pregnancy test within 
7 days prior to initiation of study drug. Urine pregnancy tests will be performed 
on the first day of odd-numbered cycles.  If a urine pregnancy test is positive, 
patient dosing will be postponed until the result is confirmed by a serum 
pregnancy test.  Patients who become pregnant while on study must 
permanently discontinue study treatment as outlined in Section 4.6.1.

Standard-of-care assessments of bone marrow biopsies and aspirate for local 
clinical pathology assessment, which will include, but are not limited to, cytogenetic 
analysis by fluorescence in situ hybridization (FISH; including markers such as 
1q gain, del17, t(11:14), t(4;14), t(14; 16))
The results of these studies should be sent to the Sponsor when available 
(results should be redacted of patient identifiers other than protocol-assigned 
patient number).  

Serum -2 microglobulin
Samples for the following laboratory tests will be sent to one of several central 
laboratories for analysis:

Blood samples for leukocyte immunophenotyping/flow cytometry (fluorescence-
activated cell sorting [FACS] lymphocyte subsets) including, but not limited to, 


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enumeration of leukocyte subsets (
 
), and assessment NK-cell functional status (
 
) by flow 
cytometry

Blood sample for WGS, to be collected on Cycle 1, Day 1 (or at any time during the
study after Cycle 1, Day 1)

Plasma for cytokines, including, but not limited to, IL-6 and IFN-

Blood samples for biomarker assays for exploratory assessments that may predict 
response to RO7297089
Blood samples will be obtained for biomarker evaluation (including, but not 
limited to, biomarkers related to MM or tumor immune biology) from all eligible 
patients according to the schedule in Appendix 3.  Blood, plasma, and serum 
samples will be collected for the determination of changes in blood-based 
biomarkers.  Blood samples may be processed to obtain PBMCs and their 
derivatives (e.g., RNA and DNA) or cell-free DNA.

Serum samples for immunogenicity analysis  

Serum samples for PK analysis

Bone marrow aspirate and biopsy samples
Prior to Cycle 1, Day 1 dosing; between Cycle 2, Day 8 and Cycle 3, Day 1 
dosing; and at the time of confirmation of CR or at disease progression, a bone 
marrow aspirate and trephine biopsy with an associated pathology report are 
required.  For bone marrow aspirate samples, please refer to the central 
laboratory manual for the volume of aspirate that should be collected.  
Trephine/core biopsy tissue samples should preferably be a minimum of 1.5 cm 
in length (2 cm is optimal).  If paraffin blocks or fresh tissue is unavailable, 
unstained slides should be sent to the Sponsor (see the laboratory 
manual for further details).  For bone marrow aspirates that unexpectedly clot, a 
paraffin block or 
 bone marrow aspirate unstained slides should be sent to 
the Sponsor or central laboratory per the laboratory manual. 

Analyses of bone marrow aspirate and biopsy samples may include, but are not 
limited to:
–
Changes in PD biomarkers, RO7297089 pharmacokinetics, and MRD status.  
Samples may be processed to obtain bone marrow mononuclear cells and their 
derivatives (e.g., RNA and DNA).
–
Leukocyte immunophenotyping/flow cytometry (FACS lymphocyte subsets) 
including, but not limited to, enumeration of leukocyte subsets (
 
), and 
assessment BCMAtarget cell depletion, NK-cell functional status (using 
markers including, but not limited to, 
) by flow 
cytometry
Fresh bone marrow aspirate may be used to confirm cytogenetic status at a 
central testing laboratory by FISH (during screening only).


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
In the rare instance that a bone marrow biopsy is not feasible, in patients with 
extramedullary disease tissue obtained from an extramedullary plasmacytoma is 
acceptable, but should meet the following criteria:  
–
If an excisional biopsy is performed, then a formalin-fixed, paraffin-embedded 
block (preferred) or a minimum of 15 serially sectioned, unstained slides is 
required.  If 10 serially sectioned slides are available, consult with the Medical 
Monitor.  For core-needle biopsy tissue specimens, at least three core tissue 
samples should be submitted for evaluation. 
–
Tumor tissue should be of good quality based on total and viable tumor content 
(sites will be informed if the quality of the submitted specimen is inadequate).  
Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage 
samples are not acceptable.
–
Acceptable samples include core needle biopsy tissue samples for deep tumor 
tissue or lymph nodes or excisional, incisional, punch, or forceps tissue sample 
biopsies for cutaneous, subcutaneous, or mucosal lesions.
–
Patients who are re-screened after an initial screen failure (see Section 3.1) do 
not need to undergo a repeat biopsy if this assessment was completed during 
the initial screening period.
Exploratory biomarker assays may include, but will not be limited to, flow cytometry, 
genes or gene signatures associated with tumor immunology, and cytokines associated 
with NK-cell activation.  Additional biomarkers may be assessed based on evolving 
clinical and nonclinical data. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Serum samples collected for PK and ADA analysis may be needed for additional 
immunogenicity characterization and for PK or immunogenicity assay development 
and validation; therefore, these samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed.

Blood, bone marrow aspirate, bone marrow biopsy samples and any derivatives 
thereof will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed.

Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health 
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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.8
Electrocardiograms
Triplicate ECG recordings will be obtained at specified timepoints, as outlined in the
schedule of activities (see Appendix 1).  Three interpretable ECG recordings 
(e.g., without artifacts) must be obtained at each timepoint (5 minutes).  The average 
of the three readings will be used to determine ECG intervals (e.g., PR, QRS, QT).  
Single ECG recordings may be obtained at the end of treatment visit and unscheduled 
timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  All ECGs as described above will be submitted to a Sponsor-
designated ECG central laboratory for storage and potential analysis. Detailed 
instructions on ECG acquisitions and transmissions to the ECG central laboratory will be 
provided in the ECG manual provided for this study. The following should be recorded in 
the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, uncorrected 
QT interval, and QT interval corrected through use of Fridericia's formula (QTcF) based 
on the machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory.


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If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another triplicate ECG must be recorded, ideally within the next 
5 minutes, and triplicate ECG monitoring should continue until QTcF has stabilized on 
two successive ECGs.  The Medical Monitor should be notified.  Standard-of-care 
treatment may be instituted per the discretion of the investigator.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained.  A decision 
on study drug discontinuation should be made, as described in Section 5.1.2.3.  The 
investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia).
4.5.9
Blood Samples for Whole Genome Sequencing 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  The samples may be 
sent to one or more laboratories for analysis.
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 4.5.9) will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/ECapproved Informed Consent Form and applicable laws (e.g., health 
authority requirements).


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Patient medical information associated with WGS specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
Refer to Section 4.5.7 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
4.5.10
Optional Samples for Research Biosample Repository 
4.5.10.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.10) 
will not be applicable at that site.


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4.5.10.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7297089, diseases, or 
drug safety:

Bone marrow aspirate and bone marrow tissue samples performed at the 
investigator's discretion during the study

Leftover blood, serum, plasma, PBMC, bone marrow aspirate, and bone marrow 
tissue samples and any derivatives thereof (e.g., DNA, RNA, proteins, peptides), 
including leftover tissue samples from medically indicated procedures performed at 
the investigator's discretion during the course of the study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods. Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB/EC
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.10.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 


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patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
informed that they are free to refuse to participate and may withdraw their consent at 
any time and for any reason during the storage period.  A separate, specific signature 
will be required to document a patient's agreement to provide optional RBR samples.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email
address:
global_rcr-withdrawal@roche.com


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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.10.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Use of an anticancer therapy not required per protocol

Symptomatic deterioration attributed to disease progression

Confirmed disease progression per investigator assessment according to IMWG 
Uniform Response Criteria (Appendix 5)

Patient decision 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced unless enrolled in the dose-escalation cohorts and discontinue prior to 
completion of the 14-day DLT assessment window.
Patients will return to the clinic for a treatment discontinuation visit 30 (10) days after 
the final dose of study drug (see Appendix 1 for additional details).  Additionally, patients 
who discontinue study treatment for reasons other than documented disease 
progression or relapse should continue to be followed as described in Appendix 2 until 
disease progression, start of new anti-cancer therapy, or withdrawal from study 
participation, whichever occurs first.


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4.6.1.1
Survival and Subsequent Anti-Cancer Therapy Follow-Up
Following study treatment discontinuation (initial or after re-treatment), patients may be 
followed for survival and subsequent anti-cancer therapy.  Survival and subsequent 
anti-cancer therapy follow-up information may be collected via telephone calls, patient 
medical records, and/or clinic visits approximately every 3 months until death, loss to 
follow-up, or study termination by the Sponsor unless the patient requests to be 
withdrawn from follow-up.  Information on subsequent anti-cancer therapies will include 
systemic therapies (e.g., chemotherapy, targeted therapy, hormonal therapy), surgery 
(e.g., resection of metastatic disease), and radiation procedures (radiotherapy to a tumor 
lesion).  If the patient withdraws from the study, the site's staff may use a public 
information source (e.g., county records) to obtain information about survival status only.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced unless enrolled in the dose-escalation 
cohorts and discontinue prior to completion of the 14-day DLT assessment window.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
This is the first study in which RO7297089 will be administered to humans.  As such, the 
actual risks are unknown.  The following information describing monitoring and 
management of potential safety risks is based on anticipated pharmacology and 
mechanism of action, results from nonclinical studies, and published data on similar 
molecules.  Please refer to the RO7297089 Investigator's Brochure for further safety 
information.
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (Sections 4.1.1 and 4.1.2) and close 
monitoring, as described below.  As described in Section 3.1.1, enrollment of the 
first patient in each arm in each dose-escalation cohort will be staggered such that the 
respective Cycle 1, Day 1 treatments are administered 72 hours apart.  
After each patient receives the first dose of RO7297089, the investigator should confirm 
with the Sponsor that the patient has been dosed and should provide a brief summary of 
the status of the patient in terms of safety and tolerability to RO7297089 (this will be 
communicated by email and/or telephone; as soon as reasonably possible).  In addition, 
regularly scheduled teleconferences will occur with the investigators and study team 
(including the Medical Monitor and Safety Scientist) to review the following for each 
patient: all relevant demographic, adverse event, laboratory, dose administration, 
available (radiographic) response, and available PK and PD data (e.g., imaging, plasma 
cytokines and markers of NK-cell activation).
All patients will be monitored closely for toxicity.  Patients will be assessed clinically for 
toxicity prior to each dose using the NCI CTCAE v5.0 grading scale, except for CRS, in 
which the Modified Cytokine-Release Syndrome Grading System will be used (see 
Appendix 9).  All adverse events and serious adverse events will be recorded during the 
trial and for up to 90 days after the final dose of study treatment or until the initiation of 
another systemic anti-cancer therapy, whichever occurs first.  To mitigate potential 


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unknown risks, at least in part, dosing beyond Cycle 1 will be limited to patients who do 
not demonstrate unacceptable toxicity or compelling evidence of disease progression 
(see Section 3.1.1.2).
Specific anticipated or potential toxicities associated with administration of RO7297089, 
as well as the measures taken to avoid or minimize such toxicities in this trial, are 
described in the following sections.
5.1.1
Potential Risks Associated with RO7297089
5.1.1.1
Infusion-Related Reactions/Cytokine-Release Syndrome
The mechanism of action of RO7297089 is engagement and activation of NK cells 
against cells expressing BCMA.  Therefore, a spectrum of events involving IRRs, CRS, 
and/or hypersensitivity with or without emergent ADAs, may occur.  These reactions may 
be mild in severity but can also be severe or even fatal.  Common signs and symptoms 
of these reactions could include fever; chills or rigors; alteration in heart rate and blood 
pressure; dyspnea or chest discomfort; back or abdominal pain; nausea, vomiting, 
and/or diarrhea; and various types of skin rash.  Severe reactions can also include 
hypotension, hypoxia, other organ dysfunction, and/or neurologic toxicity.
In nonclinical studies, cytokine release with RO7297089 was assessed both in vitro as 
well as in the toxicity studies in cynomolgus monkeys. Clinical findings consistent with 
CRS and/or increases in inflammatory cytokines associated with CRS (e.g., IL-6, TNF-, 
IFN-) due to RO7297089 were not observed in cynomolgus monkeys. IRRs were not 
observed in cynomolgus monkeys.  In vitro studies at clinically relevant concentrations of 
RO7297089 in the presence of human PBMCs and MMCs expressing BCMA
demonstrated minimal increases in inflammatory cytokines consistent with 
pharmacology.  The changes were similar in magnitude to that seen with daratumumab, 
and were far lower than levels seen with T-cell engaging bispecific antibodies in similar 
assays. 
Other bispecific antibody therapeutics involving NK-cell activation have been associated 
with IRRs in patients, though CRS was not demonstrated clinically. AFM13 is a 
tetravalent bispecific antibody with a mechanism of action similar to RO7297089, except 
that it engages NK cells to target CD30 expressed on B cells in patients with Hodgkin 
lymphoma and some types of non-Hodgkin lymphoma.  In patients with R/R Hodgkin 
lymphoma treated with single-agent AFM13 in a dose-escalation Phase I study, 
Grade 12 IRRs were seen in 4 patients (14%) and CRS was not reported (Rothe et al. 
2015).
Based on these nonclinical data, experience with molecules with a similar mechanism of 
action, and clinical experience with to RO7297089 date, RO7297089 has the potential 
to cause an IRR and/or CRS, but the likelihood of CRS appears very low (see 
Section 1.2). In this current first-in-human, dose-escalation Study GO41582, the 
observation of IRR events led to the release of an Urgent Safety Measure (USM) on 


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4 September 2020 and a subsequent protocol amendment to mandate premedication 
with corticosteroids.  At the time of the USM, 1 of 3 patients in Cohort 1 (60 mg) and 2
of 2 patients in Cohort 2 (180 mg) experienced a Grade 2 IRR in Cycle 1.  The IRR 
events, consisting of shivering/rigors and temperature elevation, occurred either during 
the infusion or during the post-infusion observation window. To minimize the risk of 
IRRs, patients will be premedicated prior to the first administration of RO7297089 for 
Arms A and B, and prior to the first two doses of RO7297089 for Arm C, unless 
contraindicated (see Section 4.3.2.1).  Administering premedication on the day prior to 
infusion may also be considered and/or implemented to mitigate IRR.  Patients will be
dosed slowly over a minimum of 2 hours to mitigate IRR and monitored closely for 
4 hours following their first infusion of RO7297089 (see Table 1), with frequent vital sign 
measurements (see Table 2) to identify potential IRR/CRS.  Patients who tolerate 
RO7297089 infusions well do not require as long an infusion time or observation period 
with subsequent infusions and will be observed post-infusion as described in Table 1.
Guidelines for management of patients who develop an IRR are summarized in Table 3, 
with grading according to NCI CTCAE v5.0. Management of Grade ≥3 IRR should be 
immediately discussed between the treating investigator and the Medical Monitor. Refer 
to Section 5.3.5.1 for adverse event reporting procedures related to IRRs. Guidelines for 
management of and grading of CRS according to the Modified Cytokine-Release 
Syndrome Grading System (Appendix 9) are summarized in Appendix 10.
5.1.1.2
Immunogenicity
Administration of therapeutic proteins may lead to the formation of ADAs.  The 
development of ADAs may have an impact on exposure and/or efficacy and can lead to 
hypersensitivity reactions, including immune complex-mediated responses. 
Serum samples will be collected at protocol-defined intervals to monitor for the
development of ADAs. Patients who have clinical sequelae that are considered
potentially related to an ADA response may also be asked to return for additional
follow-up testing.
ADAs to RO7297089 were observed in in cynomolgus monkeys in the toxicity studies, 
and while an effect on the pharmacokinetics was noted in cynomolgus monkeys, this 
does not always translate to an effect in humans.  There were no adverse findings 
related to ADA.
As seen with other therapeutic monoclonal antibodies, RO7297089 can form protein 
aggregates.  Non-covalent multimers (predominantly dimers) have been characterized 
during manufacturing.  The impact of non-covalent multimers or aggregates of 
RO7297089 is not known; however, there could be an increased potential for 
immunogenicity (Rosenberg 2006). 


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Patients will be monitored as described above after infusion for any IRR or 
hypersensitivity reactions, and at regular intervals for the development of ADAs. Any 
clinical signs and symptoms suggestive of a hypersensitivity reaction, in particular 
immune complex-mediated reaction possibly due to ADA formation, will be carefully 
investigated.
Please refer to the RO7297089 Investigator’s Brochure for additional details. 
5.1.1.3
Infection
Due to its anticipated mode of action resulting in plasma-cell depletion and, potentially, 
NK-cell depletion, RO7297089 may be associated with hypogammaglobulinemia and an 
increased risk of infections.  Serum Ig levels will be monitored in this study according to 
the schedule outlined in Appendix 1. Administration of IVIg should be considered for 
patients with hypogammaglobulinemia who are considered to be at increased risk for 
infection.
In the repeat-dose toxicity study in cynomolgus monkeys, decrease in plasma cells and 
hypogammaglobulinemia was not seen; however, decreases in serum IgM and mRNA 
expression levels of plasma cell markers were noted in all monkeys at all dose levels. 
This was considered a PD effect of the drug. 
RO7297089 should not be administered in the presence of active severe infections.  
Investigators should exercise caution when considering the use of RO7297089 in 
patients with history of recurring or chronic infections or with underlying conditions that 
may predispose patients to infections.  Signs and symptoms of infection should result in 
prompt evaluation and appropriate samples for bacteriological investigation prior to 
starting antibiotic or other treatment. 
Hepatitis B reactivation has been reported with B celldirected therapies.  While B cells 
are not expected to be effected by RO7297089, patients with a history of chronic 
hepatitis B infection or positive test results for active or chronic HBV infection (defined by 
HBsAg and/or positive total HBcAb and positive HBV PCR), or patients with HCV 
infection as assessed by PCR, will be excluded from this trial as a precaution (see 
Section 4.1.2).  Patients with positive HBV serology but undetectable HBV PCR will be 
allowed to enroll and may receive HBV prophylaxis at the investigator’s discretion.
Patients with known or suspected chronic active Epstein-Barr virus infection will be 
excluded from this trial due to the risk of secondary macrophage activation syndrome 
(MAS) or hemophagocytic lymphohistiocytosis (HLH) (see Section 4.1.2).
5.1.1.4
Blood Pressure Decrease
In the 4-week IV repeat-dose GLP toxicity study in cynomolgus monkeys, a core battery 
of safety pharmacology endpoints were assessed, including external multi-lead 
electrocardiogram (ECG) and non-invasive blood pressure measurements via tail cuff 


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measurements 24 hours after completion of infusion on Days 9 and 30 of the study. 
All ECG parameters were normal, as were measurements of pulse rate. The only 
findings were minimally decreased systolic, diastolic, and mean arterial pressures 
(19%, 27%, and 20%, respectively) compared to control animals. These changes were 
noted on Day 30 in the cohort receiving 50 mg/kg of RO7297089 approximately 24 hours
post administration of the fifth scheduled dose. These changes were considered 
non-adverse in the cynomolgus monkey based on the known variance using tail cuff 
measurements as a measure of blood pressure, lack of correlating cardiovascular 
parameters, and lack of clinical correlation in the monkeys; however, a relationship to 
RO7297089 was unable to be ruled out and, as such, a minimal decrease in blood 
pressure is considered a potential risk when dosing RO7297089 in humans.  
Blood pressure will be monitored during this study according to Section 4.5.5 and the 
schedule of activities (Appendix 1). This will include measurements of blood pressure 
during infusion of RO7297089 as well as measurements of blood pressure during 
post-infusion observation periods. In addition, patients will be educated on the potential 
for blood pressure decreases and will be instructed to inform their study physicians of 
any changes in blood pressure or clinical signs and symptoms that could indicate blood 
pressure decrease such as dizziness, lightheadedness, or syncope. 
5.1.1.5
Tumor Lysis Syndrome
TLS is a known PD effect of anti-tumor therapy in hematologic malignancies including 
MM (Fuente et al. 2004; Sezer et al. 2006).  TLS has been reported with some therapies 
for MM (Velcade USPI and SmPC; Kyprolis[carfilzomib] USPI and SmPC).  The 
inherent risk of TLS is dependent on the malignancy being treated and individual patient 
characteristics (Coiffier et al. 2008).  There is a theoretical risk of TLS if treatment with 
RO7297089 results in the rapid destruction of a large number of tumor cells. 
Due to the potential risk of TLS following RO7297089 administration, patients must have 
a CrCl 30 mL/min to participate in this trial (see Section 4.1.1).  Prior to dosing during 
Cycle 1 of RO7297089, the patient's serum chemistry and hematology laboratory 
samples should be obtained and reviewed and prophylactic measures initiated according 
to the guidelines described below.  Laboratory results should be reviewed and 
electrolyte values should not demonstrate any clinically significant abnormalities prior to 
the infusion of RO7297089 in Cycle 1 and beyond, otherwise the patient should receive 
additional prophylactic treatment and hydration prior to the initiation of dosing.  
Laboratory abnormalities suggestive of TLS should prompt immediate action by the 
treating clinicians, and TLS should be treated aggressively per institutional practice.  
Access to nephrologist and acute dialysis services must be available in the event of 
clinically significant TLS.  
Patients with elevated uric acid levels prior to RO7297089 treatment or who are 
considered to be at high risk for TLS as defined in Appendix 14 should receive 


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prophylaxis for TLS prior to each RO7297089 infusion during Cycle 1 as per institutional 
guidelines. 
5.1.1.6
Lymphopenia
Given the mode of action of RO7297089 mediating destruction of BCMA-expressing 
plasma cells via engagement of CD16A expressed on NK cells in a manner similar to 
ADCC, reduction in lymphocyte counts is a potential risk. 
In patients with R/R Hodgkin Lymphoma treated with single-agent AFM13, a transient 
dose-dependent decrease of circulating NK cells was observed. This was felt to be due 
to margination, but could possibly have been an effect of the drug given the mechanism 
of action (Rothe et al. 2015).
Patients receiving RO7297089 will be monitored for decreases in lymphocytes as 
described in Appendix 1. In addition, Grade 3 lymphopenia that also represents 
50% decrease from baseline (regardless of whether the event otherwise meets criteria 
for reporting of an abnormal laboratory value as an adverse event) will be considered an 
adverse event of special interest for this study. Patients with lymphopenia may be 
considered for antiviral and PCP prophylaxis as per institutional standard.
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications and Interruptions
All considerations of dose and schedule modifications should be discussed with the 
Medical Monitor.  The following guidelines regarding dose and schedule modifications 
should be followed:

In general, patients receiving RO7297089 who experience a Grade 4 
non-hematologic adverse event that is not considered by the investigator to be
attributable to another clearly identifiable cause should permanently discontinue all 
study treatment.  However, for patients with Grade 4 adverse events of 
asymptomatic laboratory changes, study treatment may be resumed upon resolution 
to Grade 1 or baseline with approval of the Medical Monitor. 

For patients who experience IRRs with the first dose of RO7297089, or are at 
increased risk of recurrent IRRs with subsequent doses, the infusion rate may be 
slowed by 50% (Section 5.1.2.2).  Modifications to infusion rate in these 
circumstances should be discussed with the Medical Monitor.

In general, patients who experience either an adverse event that meets the 
definition of a DLT or other Grade 3 adverse event that is not considered by the 
investigator to be attributable to another clearly identifiable cause (e.g., documented 
disease progression, concomitant medication, or pre-existing medical condition) will 
be allowed to delay dosing for up to 2 weeks (or longer if approved by the Medical 
Monitor) in order to recover from the toxicity.  Patients may continue to receive 
additional infusions of RO7297089, provided that the toxicity has resolved to 
Grade 1 (or for laboratory abnormalities, return to 75% of the baseline value), 
within 2 weeks.  


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–
A reduced dose for subsequent infusions of RO7297089 should be considered 
and discussed with the Medical Monitor.  Decisions on continued treatment 
following a DLT or other study treatmentrelated Grade 3 toxicity should be 
made following a careful assessment and discussion of risk versus benefit with 
the patient by the investigator and approval of the Medical Monitor, including in 
the following scenarios:
Patients with Grade 3 or 4 event of anemia if manageable by red blood cell 
transfusions as per institutional practice may continue without dose 
reduction with approval of the Medical Monitor.
Patients with Grade 3 or 4 events of thrombocytopenia or neutropenia if 
manageable by transfusions (platelets) or granulocyte colony-stimulating 
factor (GCSF) as per institutional practice may continue without dose 
reduction with approval of the Medical Monitor.
–
Any patient in whom similar toxicity recurs at a reduced dose should be 
discontinued from further RO7297089 treatment.

Patients who do not fulfill the criteria for dosing after the additional 2 weeks have 
elapsed will be discontinued from study treatment (unless a longer dose delay was 
approved by the Medical Monitor) and be followed for safety outcomes as described 
in Section 5.3.1.  Exceptions to this on the basis of ongoing clinical benefit may be 
allowed following investigator assessment of risk versus benefit with approval of the 
Medical Monitor.  In addition, delay of therapy because of toxicities not attributed to 
study drug may not require discontinuation and will be discussed with the Medical 
Monitor.
The dose of RO7297089 can be reduced up to two times for management of 
drug-related toxicities.  If further dose reduction is indicated after two dose reductions, 
the patient must discontinue RO7297089.  After dose reduction due to drug-related 
toxicity, the dose of RO7297089 may not be re-escalated.
Patients who discontinue study treatment for reasons other than progressive disease 
should continue to be followed according to the schedule in Appendix 3.
5.1.2.2
Management Guidelines for Infusion-Related 
Reactions/Cytokine-Release Syndrome
Guidelines for medical management of IRRs are provided in Table 3.  Guidelines for the 
medical management of CRS are provided in Appendix 10.


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Table 3
Management Guidelines for Infusion-Related Reactions
Event a
Management
IRR, Grade 1 
Reduce infusion rate to half the rate being given at the time of event onset.
After the event has resolved, the investigator should wait for 30 minutes 
while delivering the infusion at the reduced rate.
If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to the original 
rate.
IRR, Grade 2
Interrupt study treatment infusion.
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).
After symptoms have resolved to baseline, resume infusion at half the rate 
being given at the time of event onset.
For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics and monitor closely for 
IRRs.
IRR, Grade 3
Stop infusion.
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).
Subsequent infusions may be administered with premedication in 
consultation with and with approval of the Medical Monitor. b
Patients who experience Grade 3 wheezing, bronchospasm, or 
generalized urticaria at first occurrence must be discontinued from study 
treatment.
Notes:
If symptoms recur despite premedications with the same or greater 
severity at subsequent cycles, the infusion must be stopped immediately 
and patient permanently discontinued from study treatment.
IRR, Grade 4
Stop infusion.
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).
Permanently discontinue study treatment and contact Medical Monitor.
IRRinfusion-related reaction.
a Refer to NCI CTCAE v5.0 for the grading of symptoms
b Resumption of study treatment may be considered in patients who are deriving benefit and 
have fully recovered from the event.  Patients can be re-challenged with study treatment only 
after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor.
5.1.2.3
Management of Increases in QT Interval
RO7297089 should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value


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
Sustained absolute QTcF that is 515 ms

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  
In such a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients.  The Medical Monitor should be notified as soon as 
possible.
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9
and 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

DLTs

Grade ≥2 IRR

Any grade CRS

TLS (Grade ≥ 3 by definition)

Grade ≥ 3 infection

Grade 3 lymphopenia that also represents 50% decrease from baseline 
(regardless of whether the event otherwise meets criteria for reporting of an 
abnormal laboratory value as an adverse event, as described in Section 5.3.5.5)
5.2.4
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor)
During the DLT assessment window, adverse events identified as DLTs, as defined in 
Section 3.1.1.1, are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 90 days after the 
final dose of study drug or until initiation of new systemic anti-cancer therapy, whichever 
occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v 5.0) will be used for 
assessing adverse event severity, with the exception of CRS, which is graded according 
to the Modified Cytokine-Release Syndrome Grading System established by Lee et al. 
(2019) and is described in Appendix 9.  Patients who are hospitalized to extend the 
observation period following study drug administration, either at the discretion of the 
investigator or because the patient experienced an IRR during or following the first dose 
(see Section 4.3.2.1), should not automatically be considered to have had a Grade 3 
adverse event.  In such cases, the investigator should consider whether the adverse 
event required hospitalization due to the nature and severity of the symptoms when 
determining the severity of the adverse event.
Table 4 will be used for assessing severity for adverse events that are not specifically 
listed in the NCI CTCAE.


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Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age
appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life threatening;
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions and Cytokine-Release Syndrome
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., “infusion-related reaction” or “anaphylactic reaction”) on the Adverse Event eCRF.
Events that occur after the start of study drug administration and at any time during a 
given cycle, that are judged by the investigator to be consistent with CRS, should be 
recorded as “cytokine-release syndrome” on the Adverse Event eCRF.  If possible, for 
these events, avoid ambiguous terms such as "systemic reaction."  Associated signs, 
symptoms, and laboratory abnormalities should be recorded on the dedicated
Infusion-Related Reaction eCRF, or if CRS is suspected, on the dedicated Cytokine 
Release Syndrome eCRF. If a patient experiences both a local and systemic reaction to 
the same dose of study drug, each reaction should be recorded separately on the 
Adverse Event eCRF, with signs and symptoms also recorded separately on the 
dedicated Infusion-Related Reaction or Cytokine Release Syndrome eCRF as 
applicable.
In addition to documenting IRR and/or CRS on the Adverse Event eCRF, non-serious 
events of any grade CRS and Grade ≥2 IRR should be reported as a non-serious 
adverse event of special interest (see Section 5.2.3).


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5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 


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to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms


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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of Multiple Myeloma.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 


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reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of multiple myeloma, “multiple myeloma
progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Multiple Myeloma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization solely for coordination of care, including hospice arrangements

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


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
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
Patients who are hospitalized to extend the observation period following study 
drug administration, either at the discretion of the investigator or because the 
patient experienced an IRR during or following the first dose (see 
Section 4.3.2.1), should not automatically be considered to have had a serious 
adverse event.  In such cases, the investigator should consider whether the 
adverse event required hospitalization (regardless of the need for observation) 
or met seriousness criteria unrelated to hospitalization when determining 
whether an adverse event is serious.

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
5.3.5.12
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
RO7297089, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.


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In addition, all special situations associated with RO7297089, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

DLTs during the DLT assessment window (defined in Section 5.2.4; see 
Section 5.4.2 for details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)


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For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Genentech Medical Monitor contact information:
Medical Monitor:
, M.D.
Telephone No.:
(South San Francisco, CA, USA)
Email:
Alternate Medical Monitor Contact Information
CRO Medical Monitor contact information:
Medical Monitor:
, M.D.
Telephone No.:
(Belgium)
5.4.2
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest, and Dose-Limiting Toxicities
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the final dose of study drug.  DLTs will be 
reported during the DLT assessment window.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 


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system.  A report will be generated and sent to Safety Risk Management by the EDC 
system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 90 days after the final dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within
28 days after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 


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Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.


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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 90 days after the final
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
RO7297089
RO7297089 Investigator's Brochure 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
No formal hypothesis testing is planned. Descriptive statistics will be used to summarize
the safety, tolerability, pharmacokinetics, and clinical activity of RO7297089.  Data will 
be described and summarized as warranted by number of patients in question.  Listings 
will be used in place of tables for small numbers of patients. All analyses will be based 
on the safety-evaluable population, defined as all patients who receive any amount of 
study drug.
Continuous variables will be summarized using means, standard deviations, median and
ranges; categorical variables will be presented using counts and percentages. All
summaries will be presented by dose cohort to which a patient was originally assigned.
6.1
DETERMINATION OF SAMPLE SIZE
Sample size of the dose escalation study is based on the mCRM-EWOC design and not
based on statistical power calculations. A minimum of 9 evaluable patients and 
approximately 3050 evaluable patients will be enrolled for dose-escalation.
A simulation study has been conducted to evaluate the sample size (see Table 3 in
Appendix 11). Approximately 30 patients may be enrolled in the expansion cohort to 
better characterize PK, PD, and preliminary activity signals at the presumed RP2D.
A sample size of thirty patients is a reasonable size for the expansion cohort in order to 
obtain an estimate of the response rate; with a sample size of 30 and an observed 
response rate of 20%, the 90% confidence interval for the true response rate is 
(8%, 32%), corresponding with 2 and 10 responses, and the expected number of 
responses is 6.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. The study is open-label; 
therefore, no blinded treatment will be administered. Patients will be assigned to a 
dose/regimen rather than randomized.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race and ethnicity, 
weight, and disease characteristics such as duration of malignancy) will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented 
overall and by originally assigned dose level.


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6.4
SAFETY ANALYSES
The primary objective for this study is to evaluate the safety of RO7297089, including 
estimation of the MTD and characterization of DLTs, on the basis of the following 
endpoints:

Nature, frequency, severity, and timing of adverse events, including DLTs

Changes in vital signs, physical findings, and clinical laboratory results during and 
following RO7297089 administration
The safety analysis population will consist of all patients who received at least one dose 
of study drug.  Statistical summaries will be descriptive in nature (e.g., incidence rates, 
means, and percentiles).
Primary Safety Model (mCRM-EWOC)
An mCRM-EWOC model will be utilized to inform decision-making about the dose of 
RO7297089. All patients will be followed through the DLT window (14 days; see 
Figure 2) and be enrolled in a sequential manner. Patients within a cohort will be 
sequentially enrolled in cohorts of three patients each, which, if required, can be 
expanded with additional patients. 
The dose-toxicity relationship will be described by a two-parameter logistic regression 
model, which can be updated anytime by incorporating available information from all 
patients. A minimal informative prior will be used.
The Sponsor and Investigators will evaluate the next dose recommended by the 
mCRM-EWOC design and agree on the dose for the subsequent cohort. At each 
dose-escalation step, the dose can be escalated, de-escalated, or an additional cohort at 
that same dose level could be enrolled. 
The mCRM will continue until a maximum of approximately 40 patients, or all rules in a 
pre-defined set of MTD precision criteria, have been reached; or if it is concluded that 
the RP2D has been defined, using multiple parameters of safety, PD, and efficacy data. 
The set of MTD precision criteria is: 

At least 9 patients have accrued overall;

At least 6 patients have been accrued near the MTD dose where “near” is defined 
as being within 20% of the MTD;

The probability that the MTD lies within the target toxicity interval is above 40%.
After the dose-escalation phase, a tentative RP2D, which will guide the recommended 
dose in expansion, will be defined. The final RP2D will be estimated based on the DLT 
occurrence rate in all patients evaluable for DLTs in the dose-escalation and 
dose-expansion parts of the study.  The model will be implemented by R and Jags 
software.


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All patients from the safety analysis population who follow the protocol-specified dose 
regimen within the DLT observation period and have undergone the scheduled safety 
evaluations, or who discontinued earlier due to a DLT, will be included in the 
MTD-determined analysis.
Clinical judgment can always override the Bayesian adaptive design recommendations 
in the dose-selection process.
6.4.1
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Sign Data
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs.
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  All adverse events, serious adverse events, adverse 
events leading to death, adverse events of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, 
and temperature), and ECG data will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum post-baseline severity grade.  Changes in vital 
signs and ECGs will be summarized. 
6.5
PHARMACOKINETIC ANALYSES
Individual and mean serum RO7297089 concentration versus time data will be tabulated 
and plotted.  The serum pharmacokinetics of RO7297089 will be summarized by 
estimating the following:

AUC

Cmax

tmax

Cmin

Total clearance

Volume of distribution at steady state


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
Half-life (as appropriate for data collected)
Compartmental, non-compartmental, and/or population methods may be considered. 
Estimates for these parameters will be tabulated and summarized (mean, standard 
deviation, coefficient of variation, median, minimum, and maximum), as appropriate. 
Additional PK analyses may be conducted as appropriate.
6.6
ACTIVITY ANALYSES
Response assessment data and duration of response will be summarized for all patients
by cohort.
Objective response is defined as a sCR, CR, VGPR, or PR as determined by
investigator assessment using IMWG response criteria. Patients with missing or no
response assessments will be classified as non-responders. The objective response 
rate will be summarized for patients receiving the recommended Phase II dose.
Among patients with an objective response, duration of response will be defined as the 
time from the initial objective response to the time of disease progression or death. If a 
patient does not experience disease progression or death before the end of the study, 
duration of response will be censored at the day of the last tumor assessment. If no 
tumor assessments were performed after the time of first objective response, duration of 
response will be censored at the time of first objective response.
OS is defined as the time from the first day of study treatment (Day 1 of Cycle 1) to 
death.  If a patient has not experienced death, OS will be censored at the day of last 
contact.  Preliminary OS data may be tabulated and summarized using time-to-event 
analyses for patients receiving the RP2D.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of treatment emergent ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized by treatment group.  When determining 
postbaseline incidence, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all postbaseline samples are negative, or if they are ADA positive at 


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baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, activity, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
INTERIM ANALYSES
Continuous safety monitoring and interim analyses will be performed for the expansion
portion of the study to guide potential early stopping of enrollment in the event of
unacceptable toxicity or a lower than expected response rate.
A Bayesian posterior probability approach (Thall and Simon 1994) with a uniform prior
will be used to evaluate toxicity, including the rate of DLTs. If at any time in the
expansion cohort, the number of observed DLTs indicates that there is an approximately
80% chance that the true DLT rate is 20% (e.g., DLTs observed in 2/5, 3/10, 4/15, 
5/20 patients), accrual to the cohort may be paused and the ISC will meet to determine
whether further enrollment in the cohort should be halted taking into account feedback
from study investigators.
A similar approach will be used to assess the response rate. Specifically, after
approximately 15 patients in the expansion cohort have completed their first tumor
assessment, an interim analysis will be conducted to inform potential early stopping of
enrollment if observed response rates are lower than expected. Using the Bayesian
posterior probability approach with a uniform prior, the cohort may be stopped if the
objective response rate is less or equal to 25% with a probability greater or equal to 
60%. This would be the case for example if 2 or fewer out of the first 15 patients have 
an objective response. At each interim analysis, the ISC will review the response data 
and decide whether to recommend an early decision to stop enrollment in the subgroup 
due to futility. Additional futility analyses may be conducted in periodic review of efficacy 
data. In all cases, decisions to stop enrollment into the expansion cohort will be made in 
consultation with study investigators.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data and all non-CRF 
data types (i.e., ECG, IxRS, and sample results data) will be sent directly to the Sponsor, 


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using the Sponsor's standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.


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To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.


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8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 


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separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 


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permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Genentech, Inc.  
A CRO may provide clinical monitoring, data management, and medical monitoring 
support. Genentech will conduct CRO oversight, approve patient eligibility, make 
decisions regarding dosing levels and schedules, provide primary medical monitoring, 
and conduct statistical programming and analysis. 
EDC will be utilized for this study. An IxRS will be used to assign patient numbers. 
A central laboratory will be used for a subset of laboratory assessments as specified in 
Section 4.5; otherwise, local laboratories will be used. Central review facilities will be 
used to collect and analyze ECGs.
An ISC will be employed to monitor and evaluate patient safety throughout the study.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 


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proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Ravetch JV and Perussia B. Alternative membrane forms of Fc gamma RIII(CD16) on 
human natural killer cells and neutrophils. Cell type-specific expression of two 
genes that differ in single nucleotide substitutions. J Exp Med 1989;170:48197.
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2006;8:E5017.
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RO7297089—Genentech, Inc.
112/Protocol GO41582, Version 4
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RO7297089—Genentech, Inc.
113/Protocol GO41582, Version 4
Appendix 1
Schedule of Activities
Timepoint Screen a
Cycle 1
Cycle 2
Cycle ≥3
Cycle for First 
Dose of an 
Intrapatient Dose 
Escalation
End of 
Treatment 
Visit v
D1 b
D2
D3
D8 b
D9
D1 b
D8 b
D1 b
D8 b
D1 b
D8 b
Arm A (flat) 
Arm C (step)
Arm B 
(split)
Arms A and C:
4048 hr After EOI
Arm B: 
2024 hr After EOI
2024 
hr After 
EOI
2024 hr After 
EOI
Written informed consent
x c
Review inclusion/exclusion 
criteria
x
Medical history and 
demographic data
x
Height (screening only) 
and weight
x
x
x
x
x
x
x
x
x
x
Vital signs d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG performance status
x
x
x
x
x
x
Complete physical exam e
x
Targeted physical exam f
x
x
x
x
x
x
Concomitant medications g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECGs i
x
x
x
x
x
x
x
HBV, HCV, and HIV 
screening j
x


Appendix 1: Schedule of Activities
RO7297089—Genentech, Inc.
114/Protocol GO41582, Version 4
Timepoint Screen a
Cycle 1
Cycle 2
Cycle ≥3
Cycle for First 
Dose of an 
Intrapatient Dose 
Escalation
End of 
Treatment 
Visit v
D1 b
D2
D3
D8 b
D9
D1 b
D8 b
D1 b
D8 b
D1 b
D8 b
Arm A (flat) 
Arm C (step)
Arm B 
(split)
Arms A and C:
4048 hr After EOI
Arm B: 
2024 hr After EOI
2024 
hr After 
EOI
2024 hr After 
EOI
Hematology k
x
x
x
x
x
x
x
x
x
x
x
x
Liver function test l
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry panel m
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation (aPTT, PT 
[optional], INR)
x
Pregnancy test n
x
x
(odd 
cycles)
x
(if odd 
cycle)
x
Serum -2 microglobulin
x
x
(odd 
cycles)
x
(if odd 
cycle)
Immunoglobulins (IgG, 
IgM, IgA)
x
x
x
(odd 
cycles)
x
(if odd 
cycle)
SPEP with SIFE o
x
x
x
(odd 
cycles)
x
(if odd 
cycle)
Serum free light chains o
x
x
x
(odd 
cycles)
x
(if odd 
cycle)


Appendix 1: Schedule of Activities
RO7297089—Genentech, Inc.
115/Protocol GO41582, Version 4
Timepoint Screen a
Cycle 1
Cycle 2
Cycle ≥3
Cycle for First 
Dose of an 
Intrapatient Dose 
Escalation
End of 
Treatment 
Visit v
D1 b
D2
D3
D8 b
D9
D1 b
D8 b
D1 b
D8 b
D1 b
D8 b
Arm A (flat) 
Arm C (step)
Arm B 
(split)
Arms A and C:
4048 hr After EOI
Arm B: 
2024 hr After EOI
2024 
hr After 
EOI
2024 hr After 
EOI
Historical values for 
multiple myeloma labs w
x
Bone marrow biopsy and 
aspirate o, p
x q
x 
(between 
C2D8 and 
C3D1)
Repeat as clinically indicated to confirm 
complete response and/or progression.
RO7297089 
administration r
x s
x s
x s
x
x
x
x
x s
x
Skeletal survey (28 to 
1 days relative to C1D1) t
x
Repeat as clinically indicated
Imaging (as needed) to 
assess extramedullary 
disease
x
If extramedullary disease is present at screening, repeat every 12 weeks and as needed to confirm response 
or progression.
24-hour UPEP with UIFE
x o, u
Repeat as clinically indicated to confirm response or progression.
Serum PK 
See Appendix 3 for PK collection schedule.
Serum ADA
See Appendix 3 for ADA collection schedule.
Biomarkers 
See Appendix 3 for biomarker collection schedule.
Whole blood for flow 
cytometry and PBMC 
isolation, cell-free DNA, 
WGS
See Appendix 3 for whole blood collection schedule.


Appendix 1: Schedule of Activities
RO7297089—Genentech, Inc.
116/Protocol GO41582, Version 4
CCycle; CMVcytomegalovirus; CT computed tomography; DDay; ECOGEastern Cooperative Oncology Group; eCRF electronic Case 
Report Form; EOI end of infusion; GGT gamma-glutamyl transpeptidase; HBcAbhepatitis B core antibody; HBsAbhepatitis B surface 
antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; hr hour; IRRinfusion-related reaction; 
minminute; M-protein monoclonal protein (M-protein); MRImagnetic resonance imaging; PBMCperipheral blood mononuclear cell; 
PCRpolymerase chain reaction; PET positron emission tomography; PKpharmacokinetic; Screenscreening; SFLC serum free light chains; 
SIFEserum immunofixation electrophoresis; SPEPserum protein electrophoresis; UIFEurine immunofixation electrophoresis; UPEPurine 
protein electrophoresis; WGSwhole genome sequencing.
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Cycle 1, Day 1 may 
be used; these tests do not need to be repeated for screening. Hematology panel, chemistry panel should be performed within 14 days of 
Cycle 1, Day 1.  SPEP and serum free light chains should be repeated on Day 1 of Cycle 1.
b On dosing days, all pre-infusion assessments are to be performed before RO7297089 infusion, unless otherwise specified; pre-infusion local 
laboratory samples should be drawn 024 hours prior to infusion for Cycles 1 and 2, and 072 hours for Cycles ≥3.  Prior to the initiation of 
RO7297089 dosing on C1D1, C1D2 (Arm B only), C1D8, C2D1, and C2D8, the results of local laboratory assessments should be reviewed by 
the investigator or a delegate.
c Written informed consent for participation in the study must be obtained before performing any study-related procedures (including screening 
evaluations).  Informed Consent Forms for enrolled patients and for patients who are not subsequently enrolled will be maintained at the study 
site.
d Includes systolic and diastolic blood pressure, respiratory rate, pulse rate, and body temperature while the patient is in a sitting or semi-supine 
position.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  Please refer to Table 2 in Section 4.5.5 for frequency of 
vital sign monitoring.
e A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.
f
Targeted physical examinations should be limited to systems of primary relevance (i.e., cardiovascular, respiratory, neurologic, and any system 
that might be associated with tumor assessment [e.g., those systems associated with symptoms] or potential drug-related toxicity; see 
Section 5.1.1).  Changes from baseline abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
g Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until the end of treatment visit.


Appendix 1: Schedule of Activities
RO7297089—Genentech, Inc.
117/Protocol GO41582, Version 4
h After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study drug or 
until initiation of another anti-cancer therapy, whichever occurs first.  After this period, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.3.4).  The investigator should 
follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related 
to study drug or trial-related procedures until a final outcome can be reported.
i
See Section 4.5.8 for details.  Obtain 12-lead digital ECG measurements in triplicate (immediately consecutive ECGs until three evaluable ECGs 
are recorded) at the following timepoints:  Screening; 3060 minutes pre-infusion on C1D1, C1D8, C3D1, and Day 1 of any first cycle with a 
higher dose for patients who undergo intrapatient escalation; and 030 minutes after end of infusion on C1D1 (Arms A and C), C1D2 (Arm B), 
C1D8, C3D1, and Day 1 of any first cycle with a higher dose for patients who undergo intrapatient dose escalation.  Obtain post-screening ECGs 
as close as possible to scheduled serum PK samples (see Appendix 3).  Perform non-triplicate ECGs at end of treatment and when clinically 
indicated in any patient with evidence of, or suspicion for, clinically significant signs or symptoms of cardiac dysfunction.
j
HBsAg, HBcAb, HCV antibody, and HIV serology are required.  Patients whose hepatitis B serology results cannot rule out acute or chronic HBV 
infection must be negative for HBV by PCR to be eligible for study participation.  Patients who are positive for HCV antibody must be negative for 
HCV by PCR to be eligible for study participation.  
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells [if present]).
l
Liver function tests include total and direct bilirubin, total protein, albumin, ALT, AST, ALP.
m Chemistry panel includes sodium, potassium, chloride, bicarbonate or total carbon dioxide (if considered standard of care for the region), 
glucose, BUN or urea, creatinine, calcium, phosphorous, LDH.
n All women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug.  Thereafter, 
perform a urine pregnancy test on the first day of odd-numbered cycles.  If a urine pregnancy test result is positive, patient dosing will be 
postponed until the result is confirmed by a serum pregnancy test.  Patients who become pregnant while on study must permanently discontinue 
study treatment as outlined in Section 4.6.1.
o Central testing is required for these assessments.
p See Section 4.5.7 and specific instructions and description of supplies in the laboratory manual regarding bone marrow sample harvesting.  
Unsuccessful attempts at marrow aspiration will not be considered a protocol violation.
q The screening bone marrow biopsy and aspirate may be performed after all other screening tests have been completed and after the Medical 
Monitor has confirmed that the patient is eligible for the trial.  Patients who are re-screened after an initial screen failure (see Section 3.1) do not 
need to undergo a repeat bone marrow biopsy and aspirate if these assessments were completed during the initial screening period.
r
For Cycles ≥2, study drug infusions should occur on Day 1 and Day 8 of each 14-day cycle but may be given up to 2 days from the scheduled 
date (with a minimum of 5 days between doses) for logistic/scheduling reasons.  All timepoints listed are relative to end of infusion unless 
otherwise noted.


Appendix 1: Schedule of Activities
RO7297089—Genentech, Inc.
118/Protocol GO41582, Version 4
s Patients should be monitored after each infusion as described in Table 1.  Patients undergoing intrapatient dose escalation should also be 
monitored following their first dose-escalated infusion(s) as described in Section 4.3.2.1.
t
Skeletal survey may be omitted if a PET/CT scan or a low-dose, whole-body CT is performed as part of screening. 
u The baseline 24-hr UPEP with UIFE will be analyzed both centrally and locally.  Any other 24-hr UPEP that is required to assess patient status 
will be done locally.  A 40-mL aliquot from a single 24-hr UPEP collection for both the local and central analyses is acceptable.  See specific 
instructions and description of supplies in the laboratory manual.
v Patients who complete the treatment period will return to the clinic for an end of treatment visit 30 (10) days after the last infusion of study drug.  
Patients who discontinue study drug prematurely will return to the clinic for a treatment discontinuation visit 30 (10) days after the last infusion 
of study drug.
w Regardless of M-protein or SFLC laboratory values used for screening, at least three historical values of M-protein (or SFLC if light 
chainonly disease) from the end of prior therapy to the initiation of study treatment with RO7297089 will be collected if available.


RO7297089—Genentech, Inc.
119/Protocol GO41582, Version 4
Appendix 2
Schedule of Activities: Post-Treatment Follow-Up
Assessments/Procedures
Post-Treatment Follow-Up a
Targeted physical examination b
Every 3 months
Vital signs (blood pressure, pulse rate, and 
body temperature)
Every 3 months
ECOG Performance Status
Every 3 months
Tumor assessments including SPEP with SIFE 
and SFLCs performed centrally; UPEP with 
UIFE and imaging performed locally as 
clinically indicated
Every 3 months
Total IgA, IgG, IgM
Every 3 months
Hematology c
Every 3 months 2, then every 6 months
Serum chemistry d
Every 3 months 2, then every 6 months
Bone marrow biopsy and aspirate e
As needed to confirm relapse
ADA anti-drug antibody; ECOG Eastern Cooperative Oncology Group; eCRF electronic 
Case Report Form; PK pharmacokinetic; SFLC serum free light chain; SIFE serum
immunofixation electrophoresis; SPEP serum protein electrophoresis; UIFE urine 
immunofixation electrophoresis; UPEP urine protein electrophoresis.
a Schedule corresponds to visit timepoints only for patients who do not discontinue the study 
due to progressive disease. Perform assessments until disease progression, start of new 
anti-cancer therapy, or withdrawal from study participation, whichever occurs first.  Continue to 
follow patients on this schedule timed from the treatment termination visit 30 days (10 days) 
after the last dose of RO7297089 administered.  The first 2 visits should occur within 7 days 
from the scheduled date, while subsequent visits should occur within 14 days from the 
scheduled date.
b Targeted physical examinations should be limited to systems of primary relevance 
(i.e., cardiovascular, respiratory, neurologic, and any system that might be associated with 
tumor assessment [e.g., those systems associated with symptoms], or potential drug-related 
toxicity; see Section 5.1.1). Changes from baseline abnormalities should be recorded in 
patient notes. New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF.
c Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells 
[if present]).
d Chemistry panel includes sodium, potassium, chloride, bicarbonate or total carbon dioxide 
(if considered standard of care for the region), glucose, BUN or urea, creatinine, calcium, 
phosphorous, LDH.
e Unsuccessful attempts at marrow aspiration will not be considered a protocol violation.


RO7297089—Genentech, Inc.
120/Protocol GO41582, Version 4
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples
Visit
Timepoint
Sample Type
Cycle 1, Day 1
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
Cell-free DNA (whole blood)
WGS (whole blood) b
PK (serum)
Exploratory PK (serum)
ADA (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
2 hr after end of 
infusion (30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
Cycle 1, Day 2
(Arms A and C)
2024 hr after end of 
C1D1 infusion
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Cycle 1, Day 2
(Arm B)
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Exploratory PK (serum)
ADA (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
2 hr after end of 
infusion (30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)


Appendix 3: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples
RO7297089—Genentech, Inc.
121/Protocol GO41582, Version 4
Visit
Timepoint
Sample Type
Cycle 1, Day 3
Arms A and C: 4048 
hr after end of C1D1 
infusion
Arm B: 2024 hr after 
end of C1D2 infusion
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Cycle 1, Day 8 
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Exploratory PK (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
2 hr after end of C1D8 
infusion (30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
Cycle 1, Day 9
2024 hr after end of 
C1D8 infusion
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Cycle 2, Day 1 
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Exploratory PK (serum)
ADA (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
Cycle 2, Day 8
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
PK (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)


Appendix 3: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples
RO7297089—Genentech, Inc.
122/Protocol GO41582, Version 4
Visit
Timepoint
Sample Type
Cycle 3, Day 1
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
Flow cytometry and PBMC 
isolation (whole blood)
PK (serum)
Exploratory PK (serum)
ADA (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
Cycle 3, Day 8
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
PK (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
Cycles 4, 6, and 8, Day 1
Pre-infusion
Peripheral biomarkers 
(plasma and serum)
Cell-free DNA (whole blood) c
ADA (serum)
PK (serum)
Cycle 14, Day 1, and Day 1 
every six cycles thereafter 
(i.e., Cycles 20, 26, 32, etc.) 
Pre-infusion
Peripheral biomarkers 
(plasma and serum)
PK (serum)
ADA (serum)
Day 1 of any intrapatient 
dose escalation
Pre-infusion a
Peripheral biomarkers 
(plasma and serum)
PK (serum)
Exploratory PK (serum)
ADA (serum)
End of infusion 
(30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
2 hr after end of 
infusion (30 min)
Peripheral biomarkers 
(plasma and serum)
PK (serum)


Appendix 3: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples
RO7297089—Genentech, Inc.
123/Protocol GO41582, Version 4
Visit
Timepoint
Sample Type
End of treatment visit
Any time
Flow cytometry and PBMC 
isolation (whole blood)
Cell-free DNA (whole blood)
Peripheral biomarkers 
(plasma and serum)
PK (serum)
ADA (serum)
ADAanti-drug antibody; C cycle; Dday; PBMCperipheral blood mononuclear 
cell; PKpharmacokinetic; WGSwhole genome sequencing.
Note:  Study assessments may be delayed or moved ahead of the window to 
accommodate holidays, vacations, and unforeseen delays.  
a Pre-infusion collection should be taken within 2 hours prior to infusion.
b Whole blood sample for WGS should be collected on Cycle 1, Day 1; however, it 
may be collected at any time during the study after Cycle 1, Day 1.
c Cell-free DNA will only be collected on Cycle 4, Day 1.


RO7297089—Genentech, Inc.
124/Protocol GO41582, Version 4
Appendix 4
Guidelines for the Determination of Prior Lines of Therapy
Source:  Rajkumar et al. 2014.
LINE OF THERAPY
A line of therapy is defined as 1 complete cycle of a single agent, combination regimen 
of several drugs, or a planned sequential therapy of various regimens (e.g., induction 
with a multi-agent regimen followed by autologous stem cell transplantation, 
consolidation and lenalidomide maintenance is considered one line).
NEW LINE OF THERAPY
A treatment is considered a new line of therapy if any one of the following three
conditions is met:
Definition of a New Line of Therapy
Comments
Discontinuation of one treatment regimen and 
start of another
A regimen is considered to have been 
discontinued if all drugs in that given regimen 
have been stopped.
The reasons for discontinuation, addition, 
substitution, or SCT do not influence how 
lines are counted.
Unplanned addition or substitution of one or 
more drugs in a regimen
Unplanned addition of a new drug or 
switching to a different drug (or combination 
of drugs) due to any reason is considered a 
new line of therapy.
In patients undergoing 1 SCT, each SCT is 
considered a new line of therapy
Except in the cases of a planned tandem 
SCT performed 6 months from the first SCT, 
each additional SCT is considered a new line 
of therapy.
SCT stem cell transplant.
INTERRUPTIONS AND DOSE MODIFICATIONS
If a regimen is interrupted or discontinued for any reason and the same drug or 
combination is restarted without any intervening regimen, then it should be counted as a 
single line.
If a regimen is interrupted or discontinued for any reason and then restarted at a later 
timepoint, but one or more other regimens were administered in between, or the regimen 
is modified through the addition of one or more agents, then it should be counted as two 
lines. 


RO7297089—Genentech, Inc.
125/Protocol GO41582, Version 4
Appendix 5
International Myeloma Working Group Uniform Response Criteria (2016)
Adapted from Durie et al. 2015 and Kumar et al. 2016.
COMPLETE RESPONSE AND OTHER RESPONSE CATEGORIES
Response 
Subcategory
Response Criteria
All response categories require two consecutive assessments made any time before starting any new therapy.
sCR
CR as defined below, plus:
Normal FLC ratio and absence of clonal cells in BM by immunohistochemistry (kappa/lamda ratio 4:1 or 1:2 for kappa and 
lambda patients, respectively after counting 100 plasma cells)  a
CR
No evidence of initial monoclonal protein isotype(s) on immunofixation of the serum and urine, b disappearance of any soft tissue 
plasmacytomas, and 5% plasma cells in BM
VGPR
Serum and urine M-protein detectable by immunofixation but not on electrophoresis; or 90% reduction in serum M-protein plus 
urine M-protein level 100 mg/24 hr
PR
50% reduction of serum M-protein and reduction in 24-hour urine M-protein by 90% or to 200 mg/24 hr

If the serum and urine M-protein are unmeasurable, a 50% decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria.

If serum and urine M-protein are unmeasurable and serum FLC assay is also unmeasurable, 50% reduction in plasma cells 
is required in place of M-protein, provided baseline BM plasma cell percentage was 30%

In addition to the above listed criteria, if present at baseline, a 50% reduction in the size (SPD) c of soft tissue plasmacytomas 
is also required.
MR
25% but 49% reductions of serum M-protein and reduction in 24-hour urine M-protein by 50%89%

In addition to the above criteria, if present at baseline, 25%49% reduction in the size (SPD) c of soft tissue plasmacytomas is 
also required.
SD
Not meeting criteria for MR, CR, VGPR, PR, or PD


Appendix 5: International Myeloma Working Group Uniform Response Criteria (2016)
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DISEASE PROGRESSION AND RELAPSE
Relapse 
Subcategory
Relapse Criteria
PD d, e
Any one or more of the following criteria:

Increase of 25% from lowest response value in one or more of the following:

Serum M-protein (absolute increase must be 0.5 g/dL)

Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥ 5 g/dL

Urine M-protein (absolute increase must be 200 mg/24 hr)

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)

In patients without measurable serum and urine M-protein levels and without measurable disease by FLC:  BM plasma cell 
percentage irrespective of baseline status (absolute % must be 10%) b

Appearance of 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

50% increase in circulating plasma cells (minimum 200 cells per microliter) if this is the only measure of disease
Clinical 
relapse
Requires one or more of the following:

Direct indications of increasing disease and/or end organ dysfunction (CRAB features) f related to the underlying clonal plasma 
cell proliferative disorder.  It is not used in calculation of time to progression or PFS but is listed here as something that can be 
reported optionally or for use in clinical practice.

Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression)

Definite increase in the size of existing plasmacytomas or bone lesions.  A definite increase is defined as a 50% (and 1 cm) 
increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion.

Hypercalcemia 11 mg/dL (2.65 mmol/L)

Decrease in hemoglobin of 2 g/dL (1.25 mmol/L) not related to therapy or other non-myeloma related conditions

Rise in serum creatinine by 2 mg/dL or more (177 mol/L or more) from the start of therapy and attributable to myeloma

Hyperviscosity related to serum paraprotein


Appendix 5: International Myeloma Working Group Uniform Response Criteria (2016)
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Relapse 
Subcategory
Relapse Criteria
Relapse from 
CR (to be 
used only if 
the endpoint 
studied is 
PFS) c
Any one or more of the following:

Reappearance of serum or urine M-protein by immunofixation or electrophoresis

Development of 5% plasma cells in the BM

Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or hypercalcemia)
BMbone marrow; CRcomplete response; CT computed tomography; FLCfree light chain; M-proteinmonoclonal protein; MRminimal 
response; MRImagnetic resonance imaging; PDprogressive disease; PET positron emission tomography; PFSprogression-free survival; 
PRpartial response; sCR stringent complete response; SDstable disease; SPDsum of the products of diameters; VGPRvery good partial 
response.
a Special attention should be given to the emergence of a different M-protein following treatment, especially in the setting of patients having 
achieved a conventional CR, often related to oligoclonal reconstitution of the immune system. These bands typically disappear over time, and in 
some studies, have been associated with a better outcome.  Also, appearance of IgGk in patients receiving monoclonal antibodies should be 
differentiated from the therapeutic antibody.
b In some cases it is possible that the original M-protein light-chain isotype is still detected on immunofixation, but the accompanying heavy-chain 
component has disappeared; this would not be considered a CR even though the heavy-chain component is not detectable, since it is possible 
that the clone evolved to one that secreted only light chains.  Thus, if a patient has IgA lambda myeloma, then to qualify as a CR there should be 
no IgA detectable on serum or urine immunofixation; if free lambda is detected without IgA, then it must be accompanied by a different heavy-
chain isotype (IgG, IgM, etc.).  Modified from Durie et al. 2006.  Requires two consecutive assessments to be carried out at any time before the 
institution of any new therapy (Durie et al. 2015).
c Plasmacytoma measurements should be taken from the CT portion of the PET/CT or MRI scans, or dedicated CT scans where applicable.  For 
patients with only skin involvement, the skin lesions should be measured with a ruler.  Measurement of tumor size will be determined by the SPD.   
d Positive immunofixation alone in a patient previously classified as achieving a CR will not be considered progression. Criteria for relapse from a 
CR should be used only when calculating disease-free survival.
e In the case where a value is felt to be a spurious result per investigator discretion (e.g., a possible laboratory error), that value will not be 
considered when determining the lowest value.
f
CRAB features calcium elevation, renal failure, anemia, lytic bone lesions. 


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Appendix 6
Modified CockcroftGault Equation (Using Ideal Body Mass 
Instead of Mass)
eCCr 
(140Age) IBM (kg) [0.85 if 
female]
72 serum creatinine (mg/dL)
Or, if serum creatinine is in mol/L:
eCCr 
(140Age) IBM (kg) [1.23 if male, 1.04 if 
female]
serum creatinine (mol/L)
(IBM) should be used:
IBM (kg) [(height in cm154) 0.9] (50 if male, 45.5 if female)
eCCR estimated creatinine clearance; IBM ideal body mass.


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Appendix 7
Recommended Anaphylaxis Management
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
The following equipment is needed in the event of a suspected anaphylactic 
reaction during study drug infusion:

Appropriate monitors (ECG, blood pressure, pulse oximetry)

Oxygen and masks for oxygen delivery

Airway management devices per standard of care

Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines 

Salbutamol (or albuterol or equivalent)

Antihistamines (H1 and H2 blockers)

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
The following are the procedures to follow in the event of a suspected 
anaphylactic reaction during study drug infusion:

Stop the study drug infusion.

Call for additional assistance.

Maintain an adequate airway.

Provide oxygen.

Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible.

Administer epinephrine first, followed by antihistamines, albuterol, or other 
medications as required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.


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Appendix 8
Examples of Sensitive In Vivo CYP Substrates and CYP 
Substrates with Narrow Therapeutic Range
CYP Enzymes a
Sensitive Substrates b
Substrates 
With Narrow 
Therapeutic Range c
CYP1A2
Alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tacrine, tizanidine
Theophylline, tizanidine
CYP2B6 d
Bupropion, efavirenz
CYP2C8
Repaglinide e
Paclitaxel
CYP2C9
Celecoxib
Warfarin, phenytoin
CYP2C19
Lansoprazole, omeprazole, S-mephenytoin
S-mephenytoin
CYP3A f
Alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, 
everolimus, felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, maraviroc, 
midazolam, nisoldipine, quetiapine, saquinavir, 
sildenafil, simvastatin, sirolimus, tolvaptan, 
tipranavir, triazolam, vardenafil
Alfentanil, astemizole, g
cisapride, g cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus, 
terfenadine g
CYP2D6
Atomoxetine, desipramine, dextromethorphan, 
metoprolol, nebivolol, perphenazine, 
tolterodine, venlafaxine
Thioridazine
AUCarea under the concentrationtime curve.
a Note that this is not an exhaustive list.  For an updated list, see the following 
link: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm080499.htm.
b Sensitive CYP substrates refer to drugs whose plasma AUC values have been shown to 
increase 5-fold or higher when co-administered with a known CYP inhibitor.
c CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of 
CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
d The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, 
but they represent the most sensitive substrates studied with available inhibitors evaluated to 
date.
e Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if 
the inhibition of OATP1B1 by the investigational drug has been ruled out.
f
Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of 
P-gp, the observed increase in exposure could be due to inhibition of both CYP3A and P-gp.
g Withdrawn from the United States market because of safety reason.


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Appendix 9
Modified Cytokine-Release Syndrome Grading System
Source:  Lee et al. 2019.
Grade a
Toxicity
Grade 1
Fever ≥ 38°C with or without constitutional symptoms
  
Grade 2
Fever ≥ 38ºC with either: 
Hypotension responding to fluids but not requiring vasopressors 
Hypoxia – requiring low-flow nasal cannula (≤6 L/min) or blow-by oxygen to 
maintain oxygen saturation
Organ toxicity: b  Grade 2
Grade 3
Fever ≥ 38ºC with either: 
Hypotension – requiring single vasopressor (with or without vasopressin) 
Hypoxia – requiring high flow nasal cannula (> 6 L/min), facemask, 
non-rebreather mask, or Venturi mask to maintain oxygen saturation
Organ toxicity: b  Grade 3 organ toxicity or Grade 4 transaminitis
Grade 4
Fever ≥ 38ºC with either:
Hypotension – requiring multiple vasopressors (excluding vasopressin)
Hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation and 
mechanical ventilation)
Organ toxicity: b Grade 4 (excluding transaminitis)
Grade 5
Death
CRScytokine-release syndrome.
a CRS grade is determined by the more severe event:  hypotension or hypoxia not attributable to 
any other cause (e.g., if a patient has a temperature of 39°C, is on 4 L/min of oxygen by nasal 
cannula, and has hypotension requiring the use one vasopressor, this would be considered 
Grade 3 CRS).
b Organ toxicities associated with CRS may be graded according to NCI CTCAE v5.0.


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Appendix 10
Management Guidelines for Cytokine-Release Syndrome
Guidelines for management of CRS are summarized in Table 1 below based on the 
modified grading scale as described in Appendix 9.  Management of Grade 3 IRR 
and/or CRS should be immediately discussed with the Medical Monitor.  As noted below, 
even moderate presentations of CRS in patients with extensive comorbidities should be 
monitored closely with consideration given to intensive care unit admission and 
therapeutic intervention. 
Refer to Section 5.3.5.1 for adverse event reporting procedures related to IRR and CRS.


Appendix 10:
Management Guidelines for Cytokine Release Syndrome
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Table 1
Management Guidelines for Cytokine-Release Syndrome
Toxicity a
Action to Be Taken
Grade 1
Fever b ≥ 38ºC with or 
without constitutional 
symptoms (such as: nausea, 
fatigue, headache, myalgia, 
malaise)
Immediate actions:

If infusion still ongoing, slow the infusion rate up to 50% or 
interrupt infusion.

Treat symptomatically as indicated, including 
antihistamines, antipyretics, and/or analgesics as needed.

Treat fever and neutropenia if present.

Monitor fluid balance; administer IV fluids as clinically 
indicated.
Restarting infusion:

If study medication infusion was interrupted, wait until 
30 minutes after the event has resolved before restarting 
the infusion at 50% of the original infusion rate.
Next cycle:

Pretreat with antihistamines and antipyretics/NSAIDS.
Grade 2
Fever b ≥ 38ºC with either: 
Hypotension - responding to 
fluids but no required
vasopressor and/or 
Hypoxia – requiring ≤6 L/min 
by nasal cannula or blow-by 
to maintain oxygen saturation
Organ toxicity:  Grade 2
Immediate actions:

Follow all Grade 1 recommendations.

Hold further study medication treatment until symptoms 
completely resolved.

Consider treatment with IV corticosteroids 
(methylprednisolone 2 mg/kg/day or, if neurologic 
symptoms are present, dexamethasone 10 mg).

Consider administering cytokine therapy.

Monitor cardiac and other organ function closely.

Provide hemodynamic support as indicated.

Provide oxygen for hypoxia.

Admit to ICU as appropriate.

If no improvement within 24 hours, manage as a Grade 3 
event:
–
Notify Medial Monitor.
–
Initiate work-up and assess for signs and symptoms 
of MAS/HLH. c
–
May receive the next dose of study medication if 
symptoms resolve to Grade 1 for 3 consecutive 
days with approval of Medical Monitor.


Appendix 10:
Management Guidelines for Cytokine Release Syndrome
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Table 1
Management Guidelines for Cytokine-Release Syndrome (cont.)
Event a
Action to Be Taken
Grade 2 (cont.)
Restarting infusion:

Wait until 30 minutes after the event has resolved before 
restarting the infusion at up to 25% of the original infusion 
rate.

If hypotension or hypoxia recurs, stop infusion immediately. 
Study medication should not be re-administered (re-
started) again during this cycle.
–
If hypotension or hypoxia recurs, manage as a 
Grade 3 event.
Next cycles:

May receive the next dose of study medication if symptoms 
resolve to Grade 1 for 3 consecutive days with approval 
of Medical Monitor, as follows:
–
Pretreat with antihistamines, antipyretics and/or 
analgesics as clinically indicated.
–
Pretreat with IV corticosteroids (methylprednisolone 
80 mg or dexamethasone 16 mg) at least 60 minutes 
prior to the administration of study medication
–
Administer study medication at 50% of the initial 
infusion rate of the previous cycle.
Subsequent cycles:

If there is an occurrence of IRR or CRS Grade ≥ 3 in any of 
the subsequent cycles, permanently discontinue study 
medication regardless of recovery (see Grade 3 
management guidelines).

If there is an occurrence of a Grade ≤ 2 CRS in subsequent 
cycles, manage as indicated by severity (see Grade 1 or 
Grade 2 management guidelines).


Appendix 10:
Management Guidelines for Cytokine Release Syndrome
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135/Protocol GO41582, Version 4
Table 1
Management Guidelines for Cytokine-Release Syndrome (cont.)
Grade a
Action to Be Taken
Grade 3
Fever b ≥ 38ºC with either: 
Hypotension – requiring a 
single vasopressor (with or 
without vasopressin) and/or 
Hypoxia – requiring > 6 L/min 
oxygen by nasal cannula, 
facemask, non-rebreather 
mask, or Venturi mask to 
maintain oxygen saturation
Organ toxicity:  Grade 3 
organ toxicity or Grade 4 
transaminitis
Immediate actions:

Stop further infusion of study medication

Admission to ICU is recommended  

Treat symptomatically as indicated, including 
antihistamines, antipyretics, and/or analgesics as needed.

Provide other supportive care as clinically indicated 
(e.g., fever and neutropenia, infection).

Monitor fluid balance; administer IV fluids as clinically 
indicated.

Treat with IV corticosteroids (methylprednisolone 
2 mg/kg/day or, if neurologic symptoms are present, 
dexamethasone 10 mg).

Consider anti-cytokine therapy.

Monitor cardiac and other organ function closely.

Provide oxygen for hypoxia.

Notify Medial Monitor.

Initiate work-up and assess for signs and symptoms of 
MAS/HLH. c
Restarting infusion:

Study medication should not be administered again during 
this cycle.


Appendix 10:
Management Guidelines for Cytokine Release Syndrome
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Table 1
Management Guidelines for Cytokine-Release Syndrome (cont.)
Grade a
Action to Be Taken
Grade 3 (cont.)
Next cycle:

If the patient had a Grade ≥ 2 IRR or CRS in any previous 
cycle, permanently discontinue study medication.

If patient does not recover (is febrile or still on 
vasopressors) within 8 hours after corticosteroid and 
anti-cytokine treatment, permanently discontinue study 
medication.

If patient recovers (is afebrile and off vasopressors) within 
8 hours following corticosteroid and anti-cytokine 
treatment, study medication can be administered in next 
cycle, as follows:
–
Pretreat with antihistamines, antipyretics and/or 
analgesics as clinically indicated.
–
Pretreat with IV corticosteroids (methylprednisolone 
80 mg or dexamethasone 16 mg) at least 60 minutes 
prior to the administration of study medication.
–
Hospitalize patient for 24 hours.
–
Administer study medication at 50% of the initial 
infusion rate of the previous cycle. d
Subsequent cycles:

If a Grade ≥3 CRS recurs, permanently discontinue study 
medication.

If there is an occurrence of a Grade ≤ 2 CRS in 
subsequent cycles, manage as indicated by severity (i.e., 
Grade 1 or Grade 2 management guidelines).


Appendix 10:
Management Guidelines for Cytokine Release Syndrome
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137/Protocol GO41582, Version 4
Table 1
Management Guidelines for Cytokine-Release Syndrome (cont.)
Grade a
Action to Be Taken
Grade 4
Fever b ≥ 38ºC with either: 
Hypotension – requiring 
multiple vasopressors 
(excluding vasopressin) 
and/or 
Hypoxia – requiring positive 
pressure (e.g., CPAP, BiPAP, 
intubation and mechanical 
ventilation) 
Organ toxicity: Grade 4 
(excluding transaminitis)
Immediate actions:

Follow all Grade 3 management guidelines.

Permanently discontinue study treatment.
CRS cytokine-release syndrome; HLH hemophagocytic lymphohistiocytosis; ICU intensive 
care unit; MAS macrophage activation syndrome.
a Modified CRS grading per ASTCT (Lee et al. 2019).  Refer to Appendix 9 for the complete 
description of grading of symptoms.
b Fever is defined as temperature ≥ 38ºC not attributable to any other cause.  In patients who 
have CRS and then receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, 
fever is no longer required to grade subsequent CRS severity.  CRS grade is determined by 
the more severe event:  hypotension or hypoxia not attributable to any other cause.
c Refer to Appendix 12 for HLH/MAS diagnostic criteria.
d If the patient does not experience CRS during the next infusion at the 50% reduced rate, the 
infusion rate can be increased to the initial rate in subsequent cycles upon discussion with 
Medical Monitor.  However, if this patient experiences another CRS event, the infusion rate 
should be reduced by 25%50% depending on the severity of the event.


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Appendix 11
Modified Continuous Reassessment Method with Escalation with Overdose Control Design
Details of the mCRM-EWOC design used in the study are descripted in this appendix. In addition, the design operating characteristics 
are evaluated through comprehensive simulations in this section. In this study, the MTD is defined as the dose maximizing the 
posterior probability that the DLT rate belongs to [0.20,0.35], while keeping the probability of overdose below 0.25. The details of the 
mCRM-EWOC design will be described below. Calculations are done using R package crmPack 0.1.9 
(https://cran.rproject.org/web/packages/crmPack/index.html). 
Dose-Response Model 
The probability of DLTs over doses (dose-DLT response curve) will be described by a two-parameter logistic regression model: 
where p(d) stands for the DLT rates under a dose level d, and d* is set to 1200 mg in the study as the reference dose. Thus, the
dose-DLT response curve follows a sigmoidal shape and can be flexibly adjusted by a parameter
It is common to assume such a sigmoidal curve since usually the DLT rate increases monotonically while dose levels go up, but not in 
a linear way because it has a minimal level 0 and will reach a plateau when dose is very high. It is anticipated that RO7297089 would 
have a similar dose-DLT relationship.


Appendix 11:
Modified Continuous Reassessment Method with Escalation with Overdose Control Design
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139/Protocol GO41582, Version 4
Prior Setting
In particular, a minimal informative multiple normal prior (Neuenschwander et al. 2008) is utilized for θ in the dose-escalation. It is 
conservatively assumed that it would be very unlikely (with a 95% confidence) that a 30% or higher and a 30% or lower DLT rates are
associated with the starting dose, i.e., 60 mg, and the 1650 mg dose, respectively. The parameters of the minimal informative prior 
are listed below:
 = (0.2098152, 0.7905444)
Σ = 2.3807734
0.32675892
0.3267589
0.07025577
The prior distribution is displayed in Figure 1, which is consistent with what is assumed: it would be unlikely that a 60 mg dose
corresponds to a 30% or higher DLT rate, and a 1650 mg dose corresponds to a 30% or lower DLT rate.


Appendix 11:
Modified Continuous Reassessment Method with Escalation with Overdose Control Design
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140/Protocol GO41582, Version 4
Figure 1
Prior Distribution of the mCRM-EWOC Design
Cohort Size
All cohorts will enroll at least 3 patients and may be expanded with additional patients in order to collect additional data on PK, PD or 
safety. For details see Section 3.1.1 of the protocol.
Maximum Allowable Dose Increments
The maximum allowable dose increment throughout the study is 200% or a 3-fold increase from the current dose.


Appendix 11:
Modified Continuous Reassessment Method with Escalation with Overdose Control Design
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Next Dose Selection
The selection dose for the next cohort will be guided by the mCRM-EWOC model, subject to clinical judgment and mandated safety 
constraints that limit the size of maximum allowable dose increments. Clinical judgment always overrides model estimates in the 
selection of the next dose. The Sponsor, in consultation with the Investigators, can modify the dose to be used in the next cohort of 
patients as deemed appropriate at any time during the trial.
Stopping Rules
The dose-escalation trial will continue until the recommended Phase II dose (RP2D) has been determined or the maximum sample 
size of ~40 is reached or pre-specified precision rules have been fulfilled:

At least 9 patients have accrued overall;

At least 6 patients have been accrued near the MTD dose where “near” is defined as being within 20% of the MTD;

The probability that the MTD lies within the target toxicity interval is above 40%.
The Sponsor in consultation with the Investigators may decide to stop the escalation prior to above stopping criteria are met if the
RP2D has been determined. 
The mCRM-EWOC Algorithm
Patients in the first cohort will be treated with the starting dose. Prior to open a new cohort, the available DLT data will be used to 
update the mCRM-EWOC model through a Bayesian approach. That is, the posterior probability of parameter θ from the logistic 
model will be estimated by using the DLT data from all eligible patients who complete the DLT observation period. A recommended 
dose, dr, for the next cohort will be calculated using the updated mCRM-EWOC model, i.e., P(dr)overdose < 25% and
dr=min(drmax,max{di:P(p(di)[0.2,0.35])}) where drmax is the highest next dose subject to the maximal increment rule.
Patients in the next cohort will be treated at the dose recommended by such an algorithm (possibly reduced based on clinical 
judgment). This process is repeated until the stopping criterion is met.


Appendix 11:
Modified Continuous Reassessment Method with Escalation with Overdose Control Design
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Hypothetical Trials
Several hypothetical trials are reported here to illustrate the behavior of the design in specific situations.
The first scenario illustrates how dose will be escalated assuming no DLTs are observed. The mCRM-EWOC model considered 
doses under a dose grid of every 5 mg from 60 mg to 100 mg and then every 10 mg up to 1650 mg. 
Table 1 shows the different levels suggested by the mCRM-EWOC design. The results show that, in the absence of observed DLTs, 
the design will reach high doses based in 4 cohorts.
Table 1
Dose Escalation Path in Absence of Observed DLTs
Current Cohort Dose (mg)
Recommended Next Dose Increment % If No 
DLTs In Current Cohort
60
200
180
178
500
136
1180
36
1600
3
1650
Additionally, the impact on dose-escalation of the occurrence of a first DLT is examined for all possible DLT frequencies (1 to 3, when 
the cohort size is 3) assuming that no DLTs occur until the given dose. The recommended next doses suggested by the design after 
the DLTs are reported in Table 2. 
The results show that the design will adequately adapt the dose in the presence of observed DLTs.




Appendix 11:
Modified Continuous Reassessment Method with Escalation with Overdose Control Design
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Figure 2 “True” Scenarios Used for Simulations
Each scenario uses 1000 simulated trials, analyzed by generating a MCMC chain run for 15000 iterations following a 5000-iteration 
burn-in period. Every one out of 2 iterations are saved after the burn-in i.e., step=2. Random manual checks revealed no significant 
MCMC convergence issues using standard convergence diagnostics. 
The design is evaluated using the following criteria: the MTD chosen, the number of subjects treated at doses higher than the MTD 
and the sample size of the trials. The following table demonstrates the simulation study result. 




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Appendix 12
Diagnosis and Management of Hemophagocytic 
Lymphohistiocytosis (HLH) and Macrophage Activation 
Syndrome (MAS)
CRS may lead to hemophagocytic lymphohistiocytosis (HLH) and macrophage activation 
syndrome (MAS).  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 1.


Appendix 12:
Diagnosis and Management of Hemophagocytic Lymphohistiocytosis 
(HLH) and Macrophage Activation Syndrome (MAS)
RO7297089—Genentech, Inc.
147/Protocol GO41582, Version 4
Table 1
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue study drug and contact Medical Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
REFERENCES
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.


RO7297089—Genentech, Inc.
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Appendix 13
AIDS-Defining Illnesses
Patients with a history of HIV should be carefully questioned regarding their history of 
opportunistic infections and other AIDS-defining illnesses in the past 12 months prior to 
study enrollment.  Patients with any history of HIV and an AIDS-defining illness listed in 
the table below are excluded from participating in the study. Contact the Medical 
Monitor regarding any uncertainty over illnesses listed below.
AIDS-Defining Illnesses
Candidiasis of the 
esophagus, bronchi, trachea, 
or lungs (excluding the 
mouth [thrush])
Cervical Cancer, invasive
Coccidioidomycosis, 
disseminated or 
extrapulmonary
Cryptococcus, 
extrapulmonary
Cytomegalovirus infection 
(other than liver, spleen, or 
lymph nodes)
HIV-related encephalopathy
Herpes Simplex: chronic 
ulcers 1 month duration, 
bronchitis, pneumonitis, or 
esophagitis
Histoplasmosis, 
disseminated or 
extrapulmonary
Isosporiasis, chronic 
intestinal (1 month 
duration)
Kaposi sarcoma
Lymphoma, Burkitt (or 
equivalent term)
Lymphoma, immunoblastic 
(or equivalent term)
Lymphoma, brain, primary
Mycobacterium avium 
complex of M. kansasii, 
disseminated or 
extrapulmonary
Mycobacterium tuberculosis, 
any site 
Mycobacterium, other 
species, disseminated or 
extrapulmonary
Pneumocystis pneumonia
Pneumonia, recurrent
Progressive multifocal 
leukoencephalopathy
Salmonella septicemia, 
recurrent
Toxoplasmosis of the brain
Wasting Syndrome due to 
HIV
Reference: Centers for Disease Control and Prevention. Appendix A: AIDS-Defining 
Conditions. MMWR. 2008;57(RR10):9.


RO7297089—Genentech, Inc.
149/Protocol GO41582, Version 4
Appendix 14
Criteria for Identifying Multiple Myeloma Patients at High Risk 
for Tumor Lysis Syndrome
Reference:  Minasyan and Henrici 2015.
Patients meeting any of the following criteria will be considered at high risk for tumor 
lysis syndrome (TLS):

Prior history of TLS caused by previous multiple myeloma therapy

Pre-existing renal insufficiency (serum creatinine 1.5 mg/dL, or CrCl 60 mL/min)

High tumor burden, defined as increased serum LDH (2ULN), increased beta-2 
microglobulin (5.5 mg/dL), hypercalcemia (serum Ca 12 mg/dL), or per 
investigator's clinical judgment (e.g., based on the magnitude of diffuse bone 
marrow disease and multiple lytic lesions)


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Appendix 15
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature; e.g., light housework or 
office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead