Clinical trial NCT05347485
Conditions: Multiple Myeloma
Sponsor: Janssen Scientific Affairs, LLC
Start date: 2022-05-13; Completion date: 2023-12-15
Enrollment: 86 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of cilta-cel out-of-specification (OOS).

Detailed description:

Arms: arm 1: Eligible participants will receive bridging therapy (that is, anti-plasma cell directed treatment) based on participant's clinical status and timing of availability of cilta-cel (JNJ-68284528) along with lymphodepleting chemotherapy (cyclophosphamide 300 milligrams per meter square \[mg/m\^2\] intravenous \[IV\] and fludarabine 30 mg/m\^2 IV daily, for 3 days). After 5 to 7 days of initiating lymphodepleting chemotherapy, participants will receive a single IV infusion of cilta-cel (JNJ-68284528) at a total targeted dose of 0.75\*10\^6 chimeric antigen receptor (CAR)-positive viable T cells per kilogram (cells/kg).
Interventions: intervention 1: Cilta-cel intervention 2: Lymphodepleting Therapy (Cyclophosphamide and Fludarabine)
Intervention descriptions: intervention 1: Cilta-cel will be administered as an IV infusion. intervention 2: Lymphodepleting therapy (cyclophosphamide and fludarabine) will be administered intravenously.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date:  02 September 2022
Janssen Scientific Affairs,LLC*
Clinical Protocol
A Safety and Efficacy Study of JNJ‐68284528 (ciltacabtagene autoleucel) Out‐of‐
Specification (OOS) for Commercial Release in Patients with Multiple Myeloma
Protocol 68284528MMY2005; Phase 2
AMENDMENT 2
JNJ-68284528 (ciltacabtagene autoleucel)
* Janssen Scientific Affairs, LLC is an organization that operates through different legal entities in
various countries/territories, including Janssen Research & Development, LLC. The legal entity acting as
the sponsor for studies of Janssen Scientific Affairs, LLC may vary. The term "sponsor" is used
throughout the protocol to represent these various legal entities.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
IND:  18080
Status: 
Approved
Date: 
02 September 2022
Prepared by: Janssen Scientific Affairs, LLC;
EDMS number: 
EDMS-RIM-145877, 4.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT05347485


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date:  02 September 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 2 
02-Sep-2022
Amendment 1 
26-May-2021
Original Protocol 
21-Jan-2021
Amendment 2 (02-Sep-2022)
Overall Rationale for the Amendment:  The overall reason for this amendment is to integrate an urgent
safety measure for this product into the protocol, to align with the USPI for this product, addressing
increased risk of COVID-19 for this product, and clarification in alignment with global protocol in order to
preclude redundant testing.
The changes made to the clinical protocol 68284528MMY2005 as part of Protocol Amendment 2 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.18, Appendix 18: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities 
(SoA) 
Footnote s was added: “If the time from consent to 
the start of lymphodepleting (LD) chemotherapy is
≤7 days, repeat assessments prior to administration
of LD chemotherapy are not required with exception
of weight and vitals.” 
Footnotes m and n were updated. In both 
footnotes, “8 weeks until 1 year” was revised to
“12 weeks until 1 year”.
To align with the visit schedule
.
To align with the visit schedule
1.3. Schedule of Activities 
(SoA) 
Footnote b was modified, the text “All 
participants who received cilta-cel OOS will continue 
to be monitored under a separate long-term follow-up 
(LTFU) safety study (68284528MMY4002) for up to
15 years after last dose of cilta-cel OOS”was
added.
Footnote m was modified, the text “ Additional
event-triggered testing immunophenotyping may be
conducted as clinically indicated.”was added.
The text containing “Outpatient administration: In 
consultation with and approval from sponsor
Appendix 10.16” was deleted from SoA table.
To comply with FDA mandate to
follow all CAR-T patients for 15
years.
To evaluate role of CARs in
AEs/SAEs.
To align with latest USPI.
1.3. Schedule of Activities 
(SoA), PK and Biomarker 
assessments 
Added “X” at prior to first dose of lymphodepleting 
chemotherapy at Replication competent Lentivirus 
assessment.
To compare with the baseline
value.
1.3. Schedule of Activities 
(SoA) 
The timing for Screening Phase was revised as 
“After cilta-cel out of specifications (OOS) is 
approved for exceptional release”; additional 
wording was added for Screening Phase to
specify “28 days from time of consent”the
timing; and footnote a was updated.
To be in line with exceptional
release process for OOS
products and for more clarity.


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date:  02 September 2022
Section Number
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities
(SoA), Review Protocol
Safety criteria
New row of “Review Protocol Safety criteria” 
was added. 
To specifically align the
increased risk of COVID-19
infection with use of the drug
product.
1.3. Schedule of Activities
(SoA), Infectious disease
testing
Deleted “Infectious disease testing” parameter 
from Schedule of Activities table as it seemed 
duplicate of Serology which covers infectious 
disease testing mandated by the study and
accordingly, footnotes from m to t were
updated.
The content was condensed into
previous “Serology” section to
eliminate duplication.
1.3. Schedule of Activities
(SoA), Coagulation
The timing for coagulation test was modified as 
“As clinically indicated, including participants 
who have fever (≥38°C) or other signs of
potential CRS”.
To align coagulation testing with
symptoms
1.3. Schedule of Activities
(SoA), Flow cytometry
The timing for flow cytometry (bone marrow 
aspirate-central laboratory) was updated from 
Day 28 to Day 56. Also the text “6 months after 
cilta cel OOS in participants who have not had a bone 
marrow within the last 3 months and” was deleted
for Day 100, Posttreatment Day 101, and EOS.
Bone marrow at Day 28 is often
acellular but sufficiently recover
at Day 56, such that these
assessments are more feasible
1.3. Schedule of Activities
(SoA), Flow cytometry,
MRD, 24-hour urine protein
electrophoresis sample
(SOC)
Day 56 was added as a timepoint and footnote h
was revised to reflect “For patients in CR/sCR
spot urine protein showing continued CR/sCR is
permitted”.
Bone marrow at Day 28 is often
acellular but sufficiently recover
at Day 56, such that these
assessments are more feasible
1.3. Schedule of Activities
(SoA),
ECOG, Bone marrow
aspirate and core biopsy
Added ‘X’ at Day 56 to indicate that Eastern
Cooperative Oncology Group (ECOG)
assessment is to be performed at Day 56.
Added Day 56 to specify that Bone marrow
aspirate and core biopsy should be performed at
Day 56.
To align with the visit schedule
1.3. Schedule of Activities
(SoA),
Assess extramedullary
Plasmacytomas
8.1.4. Documentation of
extramedullary
plasmacytomas
Revised the frequency for post Day 100
radiologic assessment from “every 16 weeks” to
"every 12 weeks".
To have MD visits lined up with
imaging visits
1.3. Schedule of Activities
(SoA), Laboratory
Assessments
Text regarding calcium and albumin adjusted
calcium was added.
For increased accuracy of lab
assessments
2.1. Study Rationale
11. References
Text was reworded and revised to add that
patient may still benefit from out-of-
specifications drug product.
Seven new references (ECIS 2020, American
Cancer Society 2022, Turesson 2018, Kumar
2020a, Howlader 2021, Marinac 2020, and
Orlowski 2013) have been added to the list of
references to support Multiple myeloma
information and references Kyle 2009, Palumb0
To further clarify the study
rationale.


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
Section Number 
and Name
Description of Change 
Brief Rationale
2011, and Korde 2011 was deleted as text
related to them was deleted.
2.2.1. Multiple myeloma 
Text was replaced and was revised per the 
updated references.
To update with more recent data.
2.3.1. Risks for Study 
Participation, Table 2 and 
Table 3 
Texts related to CRS, other neurotoxicities,
prolonged or recurrent cytopenia, serious
infection were updated in Table 2.
Text related to Hypogammaglobulinemia, TLS,
and Hypersensitivity reactions was updated in
Table 3.
To align with the latest USPI
2.3.3. Benefit-Risk 
Assessment 
Text related to the assumed cilta-cel OOS safety 
and efficacy was updated. 
To clarify risk: benefit of
receiving OOS product
4.3. Justification of dose 
Text in this section was revised 
To align with the latest USPI
4.4. End of Study 
Definition  
The definition of end of study and participant 
study completion definition were reworded 
To better define end of study for
patients
6.1. Study Intervention 
Administered
The text in this section was revised 
To align with the latest USPI
6.1.2. Criteria for 
Lymphodepleting 
Chemotherapy 
(Cyclophosphamide and 
Fludarabine) 
Administration 
Criteria for Lymphodepleting Chemotherapy 
related to clinical laboratory values,
echocardiogram/MUGA scan, Eastern
Cooperative Oncology Group (ECOG), Grade 3
toxicity to any bridging therapy, cumulative
dose of corticosteroids, major surgery, live
attenuated vaccine, supplemental oxygen, new
arrhythmia, new medical conditions, washout
from bridging therapy, which are not as per the
latest USPI were removed.
In addition, text related to presence of 
indwelling catheter to the dose of
lymphodepleting chemotherapy and text related
to dose modification were deleted.
To align with the latest USPI
To align with the latest USPI
To align with the latest USPI
6.1.5.Cilta-cel OOS 
Administration, Table 5 
Description of Cilta-cel 
OOS
6.1.4. Clinical assessment 
Prior to cita-cel OOS 
Infusion  
Text related to Hospitalization requirements or 
administration of Cilta cel OOS was revised as 
per the latest USPI.
Signs of active infection or inflammatory
disorders, wherein inflammatory disorders was 
added and some of the redundant text regarding 
manufacturing and quality testing of cilta-cel
OOS was deleted.
To align the text with latest
USPI
To align the text with latest
USPI
6.1.6.1. Management of 
Cytokine Release 
Syndrome; 6.1.6.2. 
Neurologic toxicities
New text and table regarding “CRS Grading and 
Management Guidance” and CAR-T-cell related 
neurotoxicity was added/modified.
To align the text with latest
USPI
6.1.6.2.2. Other 
Neurotoxicities 
Text regarding Guillain-Barre Syndrome (GBS), 
Peripheral neuropathy, and Cranial Nerve
Palsies was updated.
To align text with latest USPI


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date:  02 September 2022
Section Number
and Name
Description of Change 
Brief Rationale
Text of “movement impairments” was revised to 
Parkinsonism. 
Some points in this section were
added from a specificity
perspective.
6.8. Concomitant Therapy
6.5. Dose Modification
Text related to bridging therapy was deleted and 
text related to prevention and treatment of
COVID-19 and HBV reactivation was added.
Text related to dose modification was updated.
To align text with latest USPI
To align text with latest USPI
6.1.6.4. Prolonged or 
Recurrent Cytopenia; 
6.1.6.5. 
Hypogammaglobulinemia; 
6.1.6.6. Serious infection;
6.1.6.7. Hypersensitivity
reactions
6.1.6.8. Secondary
primary malignancy
Text regarding prolonged cytopenia,
hypogammaglobulinemia, Serious infection,
hypersensitivity reactions, and secondary
primary malignancy was updated.
To align text with latest USPI
Throughout the protocol 
Precaution text regarding COVID-19 was
added.
Consenting phase was revised to “Screening
Phase”
Cilta-cel was used consistently
Randomization was changed to enrollment
Added as new safety signal for
CAR-T and COVID-19
meaning that there is an
increased risk of death from
COVID-19 post cilta-cel
infusion.
As consent is either acquired or
it isn’t and study procedures
cannot occur until consent is
acquired.
To maintain consistency
throughout the document.
There is no randomization as it
is a single arm study.
8. Study assessments and
Procedures, Post infusion,
Post-treatment
The frequency for obtaining  survival status and
subsequent anticancer therapy after disease
progression is documented was changed from
"every 12 weeks until the end of study” to
“every 16 weeks until the end ofstudy”. Also
text regarding hospitalization was updated per
the institutional guidelines.
To decrease the frequency of
follow up once patient is off
study (all patients will be in case
of progressive disease)
8. Study assessments and
Procedures, Overview,
Post-treatment, Screening,
Lymphodepleting
chemotherapy
ECG was replaced with ECOG/MUGA.
Text “Rescreening may occur with sponsor
approval” was inserted in Screening Phase and
overall text regarding all the phases was updated
and revised.
To align with the visit schedule.
To allow for consideration on
individual basis for re-screening
for trial


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date:  02 September 2022
Section Number 
and Name
Description of Change 
Brief Rationale
8.1.2. Bone marrow 
examination  
Text related to bone marrow aspiration or 
biopsy was updated and revised. 
As it was confirmed that bone
marrow examination was
required only if CR or
progressive disease
8.1.3. Minimal Residue 
Disease evaluation 
Text related to fresh bone marrow aspirate was 
updated from screening to “prior to LD 
chemotherapy” 
To give broader time frame with
which BM sample can be
collected
8.2.2. Vital Signs 
Text related to vital signs was updated. 
To give broader time frame with
which BM sample can be
collected
8.3.1. Time period and 
Frequency for Collecting 
adverse event and Serious 
Adverse event 
Information 
Text related to HBV reactivations and COVID- 
19 infections, neurocognitive toxicity, AE
seriousness was updated. Deaths not related to
disease progression was added as a new
criterion.
Also in AESI second primary malignancy was 
added along with prolonged and recurrent
cytopenias.
“Any grade movement and neurocognitive
toxicity [ie, Parkinsonism] was added as SAEs 
to be reported within 24 hours of awareness.
To align with latest USPI
To align with latest USPI
To align with latest USPI
10.2. Appendix 2 Clinical 
laboratory tests 
Urine drug screen test and “fasting” from 
glucose (fasting) were deleted. 
Statement related to testing of calcium and 
albumin was added. 
To remove unnecessary
laboratory test
To align with addition of those
tests in lab section of SoA.
10.6. Appendix 6 Study 
Conduct During a Natural
Disaster/Major
Disruption/ Pandemic
Text in this section was updated 
To align with the latest template
10.16. Appendix 16 
Monitoring for
Participants Receiving
cilta-cel OOS as
Outpatient
Appendix 16 was deleted 
To align with latest USPI
10.15. Appendix 15: 
Cilta-cel OOS Outpatient 
Administration Guidelines
Text in Logistical consideration for qualified 
healthcare facility was updated.
To align with the latest USPI
Throughout the protocol 
Minor grammatical, formatting, or spelling, and 
template related changes were made.
Minor errors were noted


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date:  02 September 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 7
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 10
1. 
PROTOCOL SUMMARY................................................................................................................... 11
Synopsis......................................................................................................................................... 11
Schema.......................................................................................................................................... 14
Schedule of Activities (SoA)........................................................................................................... 16
2. 
INTRODUCTION................................................................................................................................ 24
Study Rationale.............................................................................................................................. 24
Background.................................................................................................................................... 25
2.2.1. 
Multiple Myeloma........................................................................................................................ 25
2.2.2. 
B-cell Maturation Antigen............................................................................................................ 25
2.2.3. 
CAR-T Therapy........................................................................................................................... 26
2.2.4. 
Cilta-cel....................................................................................................................................... 26
2.2.5. 
Nonclinical Studies ..................................................................................................................... 27
2.2.6. 
Clinical Studies ........................................................................................................................... 27
Benefit-Risk Assessment............................................................................................................... 30
2.3.1. 
Risks for Study Participation....................................................................................................... 32
2.3.2. 
Benefits for Study Participation .................................................................................................. 41
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 41
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 42
4. 
STUDY DESIGN ................................................................................................................................ 43
Overall Design................................................................................................................................ 43
Scientific Rationale for Study Design............................................................................................. 45
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 46
Justification for Dose...................................................................................................................... 47
End of Study Definition................................................................................................................... 47
5. 
STUDY POPULATION ...................................................................................................................... 47
Inclusion Criteria............................................................................................................................ 48
Exclusion Criteria........................................................................................................................... 49
Lifestyle Considerations................................................................................................................. 50
Screen Failures.............................................................................................................................. 51
Criteria for Temporarily Delaying Administration of Study Intervention ......................................... 51
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 51
Study Intervention Administered .................................................................................................... 51
6.1.1. 
Pre-infusion Supportive Therapy................................................................................................ 51
6.1.2. 
Criteria for Lymphodepleting Chemotherapy (Cyclophosphamide and Fludarabine)
Administration ............................................................................................................................. 52
6.1.3. 
Lymphodepleting Chemotherapy (Cyclophosphamide and Fludarabine) Administration .......... 52
6.1.4. 
Clinical Assessment Prior to cilta-cel OOS Infusion................................................................... 53
6.1.5. 
Cilta-cel OOS Administration...................................................................................................... 53
6.1.6. 
Management Guidelines for Potential Risks............................................................................... 54
6.1.6.1. 
Management of Cytokine Release Syndrome......................................................................... 54
6.1.6.2. 
Neurologic Toxicities ............................................................................................................... 57
6.1.6.2.1. 
CAR-T Cell-related Neurotoxicity (Immune Effector Cell-Associated Neurotoxicity
Syndrome [ICANS]).............................................................................................................. 57
6.1.6.2.2. 
Other Neurotoxicities............................................................................................................ 60
6.1.6.3. 
Tumor Lysis Syndrome............................................................................................................ 62
6.1.6.4. 
Prolonged or Recurrent Cytopenia.......................................................................................... 62


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date:  02 September 2022
6.1.6.5. 
Hypogammaglobulinemia........................................................................................................ 63
6.1.6.6. 
Serious Infections .................................................................................................................... 63
6.1.6.7. 
Hypersensitivity Reactions ...................................................................................................... 64
6.1.6.8. 
Second Primary Malignancy.................................................................................................... 64
Preparation/Handling/Storage/Accountability ................................................................................ 64
Measures to Minimize Bias: Randomization and Blinding............................................................. 65
Study Intervention Compliance...................................................................................................... 65
Dose Modification........................................................................................................................... 65
Continued Access to Study Intervention After the End of the Study ............................................. 66
Treatment of Overdose .................................................................................................................. 66
Concomitant Therapy..................................................................................................................... 66
6.8.1. 
Permitted Medications ................................................................................................................ 66
6.8.2. 
Prohibited Therapies................................................................................................................... 67
6.8.3. 
Subsequent Anticancer Therapy ................................................................................................ 68
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ............................................................................................... 68
Discontinuation of Study Intervention ............................................................................................ 68
Participant Discontinuation/Withdrawal From the Study................................................................ 68
Lost to Follow-up............................................................................................................................ 69
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 69
Efficacy Assessments .................................................................................................................... 72
8.1.1. 
Myeloma Protein Measurements in Serum and Urine................................................................ 73
8.1.2. 
Bone Marrow Examination.......................................................................................................... 73
8.1.3. 
Minimal Residual Disease Evaluations....................................................................................... 74
8.1.4. 
Documentation of Extramedullary Plasmacytomas.................................................................... 74
8.1.5. 
Skeletal Survey........................................................................................................................... 75
Safety Assessments....................................................................................................................... 75
8.2.1. 
Physical Examinations................................................................................................................ 76
8.2.2. 
Vital Signs................................................................................................................................... 76
8.2.3. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ........................................ 76
8.2.4. 
Neurologic Examination.............................................................................................................. 76
8.2.5. 
Immune-Effector Cell-associated Encephalopathy (ICE) Tool Scores....................................... 77
8.2.6. 
Handwriting Assessment............................................................................................................ 77
8.2.7. 
Clinical Safety Laboratory Assessments .................................................................................... 77
8.2.8. 
Replication Competent Lentivirus (RCL) .................................................................................... 77
8.2.9. 
Pregnancy Testing...................................................................................................................... 78
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 78
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 78
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 81
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 81
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 81
8.3.5. 
Pregnancy................................................................................................................................... 81
8.3.6. 
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events ............................................................................................. 82
Pharmacokinetics........................................................................................................................... 82
Biomarkers..................................................................................................................................... 82
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 83
Statistical Hypotheses.................................................................................................................... 83
Sample Size Determination ........................................................................................................... 83
Populations for Analysis Sets ........................................................................................................ 83
Statistical Analyses ........................................................................................................................ 83
9.4.1. 
General Considerations.............................................................................................................. 84
9.4.1.1. 
Primary Endpoints ................................................................................................................... 84
9.4.1.2. 
Secondary Endpoints .............................................................................................................. 84


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
9.4.1.3. 
Exploratory Endpoints ............................................................................................................. 85
9.4.1.4. 
Biomarker Analyses................................................................................................................. 86
Interim Analysis.............................................................................................................................. 86
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 87
Appendix 1: Abbreviations and Definitions .................................................................................... 87
Appendix 2: Clinical Laboratory Tests ........................................................................................... 89
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 91
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 91
10.3.2. 
Financial Disclosure.................................................................................................................... 94
10.3.3. 
Informed Consent Process ......................................................................................................... 94
10.3.4. 
Data Protection ........................................................................................................................... 95
10.3.5. 
Long-Term Retention of Samples for Additional Future Research ............................................ 95
10.3.6. 
Committees Structure................................................................................................................. 95
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 96
10.3.8. 
Data Quality Assurance.............................................................................................................. 97
10.3.9. 
Case Report Form Completion................................................................................................... 97
10.3.10. Source Documents ..................................................................................................................... 98
10.3.11. Monitoring ................................................................................................................................... 99
10.3.12. On-Site Audits............................................................................................................................. 99
10.3.13. Record Retention...................................................................................................................... 100
10.3.14. Study and Site Start and Closure ............................................................................................. 100
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 102
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 102
10.4.2. 
Attribution Definitions................................................................................................................ 103
10.4.3. 
Severity Criteria........................................................................................................................ 103
10.4.4. 
Special Reporting Situations .................................................................................................... 104
10.4.5. 
Procedures ............................................................................................................................... 104
10.4.6. 
Product Quality Complaint Handling......................................................................................... 106
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 106
Appendix 5: Contraceptive Guidance .......................................................................................... 107
Appendix 6: Study Conduct During a Natural Disaster/Major Disruption/ Pandemic .................. 109
Appendix 7: Cytokine Release Syndrome ASTCT Consensus Grading System ........................ 113
Appendix 8: Immune-Effector Cell-associated Neurotoxicity Syndrome (ICANS) ASTCT
Consensus Grading Systema,b..................................................................................................... 114
Appendix 9: Immune-Effector Cell-associated Encephalopathy (ICE) Tool ................................ 115
Appendix 10: Criteria for Response to Multiple Myeloma Treatment .......................................... 116
Appendix 11: Eastern Cooperative Oncology Group Performance Status Grade....................... 118
Appendix 12: Handwriting Adverse Event Toxicity Grading Criteria............................................ 119
Appendix 13: Anti-microbial Prophylaxis Recommendations ...................................................... 120
Appendix 14: Hepatitis B Virus Screening ................................................................................... 121
Appendix 15: Cilta-cel OOS Outpatient Administration Guidelines ............................................. 122
Appendix 16: Formulas for Estimating Glomerular Filtration Rate .............................................. 124
Appendix 17: Adverse Event Reporting Guidance for 68284528MMY2005 Study ..................... 125
Appendix 18: Protocol Amendment History................................................................................. 126
11. REFERENCES................................................................................................................................. 132
INVESTIGATOR AGREEMENT............................................................................................................... 134


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date:  02 September 2022
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities for Study Procedures/Assessments ...................................................... 16
Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study
Participants (cilta-cel OOS and cilta-cel).................................................................................. 32
Table 3: 
Other Potential Risks and Mitigation Strategies for Study Participants (cilta-cel).................... 39
Table 4: 
Pre-infusion Medications .......................................................................................................... 52
Table 5: 
Description of Cilta-cel OOS..................................................................................................... 53
Table 6: 
CRS Grading and Management Guidance............................................................................... 56
Table 7: 
Guidelines for the Management of CAR-T Cell-related Neurotoxicity (eg, ICANS) ................. 58
Table 8: 
Guidelines for the Management of Raised ICP/Cerebral Edemaa............................................ 60
FIGURES
Figure 1: Schematic Overview of Manufacturing Cilta-Cel OOS Drug Product and Study Flow
Chart ......................................................................................................................................... 14
Figure 2: LCAR-B38M Coding Region..................................................................................................... 26


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved, Date:  02 September 2022
1. 
PROTOCOL SUMMARY
Synopsis
A Safety and Efficacy Study of JNJ‐68284528 (ciltacabtagene autoleucel) Out‐of‐Specification (OOS) for
Commercial Release in Patients with Multiple Myeloma
Insert Short Title: Not Applicable.
JNJ-68284528 (ciltacabtagene autoleucel [cilta-cel]) is an autologous chimeric antigen receptor-T cell
(CAR-T) therapy that targets B-cell maturation antigen (BCMA), a molecule expressed on the surface of
mature B-lymphocytes and malignant plasma cells. Results from Study 68284528MMY2001
(CARTITUDE-1) indicate that cilta-cel has significant anti-myeloma activity and a safety profile consistent
with the known mechanism of action of the product. In this study, participants whose manufactured cilta-
cel does not meet the commercial release specifications (cilta-cel out-of-specifications [OOS]) are eligible
for inclusion.
OBJECTIVES
Primary objective:
 
To evaluate the efficacy of cilta-cel OOS based on overall response of partial response (PR) or better
(overall response rate, ORR).
Secondary objectives:
 
To assess the safety of cilta-cel OOS.
 
To further characterize the efficacy of cilta-cel OOS based on other endpoints.
 
To determine whether replication competent lentivirus is present in participants that receive cilta-cel
OOS.
Hypothesis
The study hypothesis is that cilta-cel OOS will demonstrate similar safety and efficacy to data from study
68284528MMY2001, as assessed by the primary and secondary endpoints.
OVERALL DESIGN
This is an open-label, single-arm multicenter Phase 2 study to evaluate the safety and efficacy of cilta-cel
OOS in adult participants (≥18 years) with multiple myeloma (MM) as described in cilta-cel US prescribing
information ([USPI] or locally approved label, respectively), and whose final manufactured cilta-cel does
not meet the commercial release specifications.
Upon written notification of the cilta-cel being OOS, the treating physician can request the sponsor to
activate an exceptional release process, during which cilta-cel OOS will be assessed individually by the
sponsor for the expected benefit/risk profile. If the benefit/risk profile is deemed favorable, the treating
physician/principal investigator will initiate eligibility and consenting procedures and can formally request
the shipment of the cilta-cel OOS for administration within the study. Exceptional Release of OOS Product
Request Form  must be completed and signed off by treating physician/principal investigator before
releasing cilta-cel OOS to the participant.
The study will be conducted in following 5 phases:
 
Screening Phase,
 
Lymphodepleting Chemotherapy,


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
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Status: Approved, Date:  02 September 2022
 
Cilta-cel OOS Administration,
 
Post infusion, and
 
Post-treatment
Cilta-cel OOS will not be administered to a participant whose medical condition does not meet the criteria
for CAR-T infusion. Non-eligible medical conditions include active uncontrolled infection or condition
where an administration of cilta-cel OOS constitutes serious health risk to the participant.
Eligible participants may continue bridging therapy (ie, anti-plasma cell directed treatment between
apheresis and the first dose of the lymphodepleting chemotherapy) as clinically indicated. Bridging therapy
and lymphodepleting chemotherapy will be considered as part of standard-of-care and are prescribed by the
treating physician, if clinically indicated.
Lymphodepleting chemotherapy consists of IV cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2
daily for 3 days per USPI or locally approved label. Cilta-cel OOS will be administered at a total targeted
dose of 0.75×106 CAR-positive viable T cells/kg (range: 0.5 to 1.0×106 CAR-positive viable T cells/kg) or
per exceptional release criteria determined alternative dose, 5 to 7 days after start of the lymphodepleting
chemotherapy.
Following the infusion of cilta-cel OOS, the participant will be followed for 2 years in this study to assess
response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
All participants who received cilta-cel OOS will continue to be monitored for long-term safety under a
separate long-term follow-up (LTFU) study (68284528MMY4002) for up to 15 years after last dose of
cilta-cel OOS.
A Data Review Committee (DRC) will be commissioned for this study.
NUMBER OF PARTICIPANTS
No formal enrollment target is planned for this study since the number of potential participants with cilta-cel
OOS  is unknown at this time. Based on the current manufacturing experience with study
68284528MMY2001, at least 20 participants are anticipated to enroll in the study.
INTERVENTION GROUP AND DURATION
Prior to administration of cilta-cel OOS, all participants will receive a lymphodepleting chemotherapy
(standard-of-care) of IV cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days per USPI
or locally approved label, respectively. The dose of fludarabine may be reduced to 24 mg/m2 for participants
with an estimated glomerular filtration rate (eGFR) of 30 to 70 mL/min/1.73m2. Cilta-cel OOS (after
approval) will be administered 5 to 7 days after the start of the lymphodepleting chemotherapy. The
anticipated duration of enrollment of participants in this study is 2 years and duration of study is expected
to be 4 years with potential extension.
EFFICACY EVALUATIONS
Efficacy evaluations include myeloma protein measurements and imaging as indicated for enrolled
participants to evaluate response and disease progression. Efficacy evaluations will be measured from
Screening Phase through end of study  by the investigator per International Myeloma Working Group
(IMWG) consensus recommendations for MM treatment response criteria. Blood, serum and bone marrow
samples will be collected for assessment of cilta-cel OOS pharmacokinetics (PK), minimal residual disease
(MRD)-negative rate, and predictive biomarkers of response or resistance to cilta-cel OOS.


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
SAFETY EVALUATIONS
Safety of cilta-cel OOS infusion will be assessed by adverse events, laboratory test results, vital sign
measurements, physical examination findings, handwriting assessments, assessment of Immune-Effector
Cell-associated Encephalopathy (ICE) Tool scores, and assessment of Eastern  Cooperative Oncology
Group (ECOG) performance status grade. The continuing safety profile of the enrolled participants will be
evaluated at the periodic DRC meetings. Follow-up of participants will continue to include all SAEs and
delayed AEs, disease progression, and survival during the Post-treatment Phase.
STATISTICAL METHODS
No formal statistical hypothesis testing will be performed for the study. All participants who received a
cilta-cel OOS infusion will be included in the analysis for efficacy and safety summaries. Descriptive
statistics and time to event analysis as appropriate will be described in detail in the statistical analysis plan.
Initially, data will be reviewed by the DRC after every 10 participants have been treated and followed for
at least 3 months to assess efficacy and safety




JNJ-68284528  (ciltacabtagene autoleucel)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
Abbreviations: IV=intravenous; B/R=benefit/risk; OOS=out-of-specifications.
Footnotes:
a Apheresis is performed to collect peripheral blood mononuclear cells (PBMCs) and is required for manufacturing
of cilta-cel.
b Eligible participants may continue bridging therapy (anti-plasma cell directed treatment between apheresis and the
first dose of the lymphodepleting chemotherapy) as determined by treating physician based on participant’s clinical
status and timing of availability of cilta-cel OOS. Therapy must be stopped within 14 days or at least 5 half-lives,
whichever is earlier, prior to start of lymphodepleting chemotherapy to complete washout (please refer to detailed
guidance for drug classes and radiotherapy to protocol section 6.1.2).
c Exceptional release will be based on release specification criteria and a sponsor medical review process to
determine and document the benefit/risk assessment, which will include the potential OOS safety and efficacy
impact, participant alternative options/medical need, and assessment of potential immediate risk of not receiving
the product. Treating physician then decides whether to request the cilta-cel OOS.
d Lymphodepleting chemotherapy will be prescribed by the site per standard-of-care, as clinically indicated. It
consists of IV cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days, with the first Day-7 to
Day-5 prior to infusion of cilta-cel OOS on Day 1. The dose of fludarabine may be reduced to 24 mg/m2 for
participants with an estimated glomerular filtration rate (eGFR) of 30 to 70 mL/min/1.73m2 (please refer to
Section 10.16, Appendix 16 for eGFR calculation).












JNJ-68284528  (ciltacabtagene autoleucel)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
Table 1: 
Schedule of Activities for Study Procedures/Assessments
Phase 
Screening
Phase (28
days from
time of
consent)
Cyclophosphamide
and fludarabine
lymphodepleting
chemotherapys
(SOC)
Cilta-cel OOS
infusion
Post Infusion (Day 1 to Day 100)
Any participant who received an infusion of cilta-cel OOS should continue all
subsequent assessmentsb
Posttreatment
Day 101 and
up to End of
studyb
Day  
After
cilta-cel
OOS is
approved
for
exceptional
release
Day-5* 
(assessments may 
be conducted 
≤72 hours predose) 
*Window for start
of
lymphodepleting
chemotherapy:
Day-7 to Day-5
Day 1 
(Infusion) 
Day 
3 
Day 
7 
(±1 
day) 
Day 
10 
(±1 
day) 
Day 
14 
(±1 
day) 
Day 
21 
(±2 
days) 
Day 
28 
(±2 
days) 
Day 
35 
(±2 
days) 
Day 42 
(±2 
days) 
Day 
56 
(±2 
days) 
Day 
100 
(±2 
days)b 
(every 84
days after
Day 100)c
(±7 days)
Replication
Competent
Lentivirus (RCL)
(whole blood)
X 
Predose 
At approximately 3, 6 and 12 months, then yearly until EOS or until the post-treatment assays for an
individual participant are negative for RCL during the first year.
Additional event-triggered testing for RCL may be conducted as clinically indicated.
Immunophenotyping
(Whole blood)o
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm
PK CAR transgene
levels (whole
blood)o
Predose 
X 
X 
X 
X 
X 
X 
X 
X 
Xn
Immunogenicityo
Predose 
X 
X 
X 
X 
X (Day 184)
Flow cytometry
(bone marrow
aspirate-central
laboratory)
X (prior to first
dose of
lymphodepleting
chemotherapy
[≤7 days])
X 
At suspected CR and at
progressive disease
(PD) or EOS


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
Table 1: 
Schedule of Activities for Study Procedures/Assessments
Phase 
Screening
Phase (28
days from
time of
consent)
Cyclophosphamide
and fludarabine
lymphodepleting
chemotherapys
(SOC)
Cilta-cel OOS
infusion
Post Infusion (Day 1 to Day 100)
Any participant who received an infusion of cilta-cel OOS should continue all
subsequent assessmentsb
Posttreatment
Day 101 and
up to End of
studyb
Day  
After
cilta-cel
OOS is
approved
for
exceptional
release
Day-5*
(assessments may
be conducted
≤72 hours predose)
*Window for start
of
lymphodepleting
chemotherapy:
Day-7 to Day-5
Day 1
(Infusion)
Day
3
Day
7
(±1
day)
Day
10
(±1
day)
Day
14
(±1
day)
Day
21
(±2
days)
Day
28
(±2
days)
Day
35
(±2
days)
Day 42
(±2
days)
Day
56
(±2
days)
Day
100
(±2
days)b
(every 84
days after
Day 100)c
(±7 days)
Cytokine profiling
(serum)o
X
(≤7 days prior to
first dose)
Predose
2 hours post-
dose (±10 min)
X 
X 
X 
X 
X 
X 
X 
X 
X
MRD (bone marrow 
aspirate) 
(central laboratory) 
X (prior to first 
dose of
lymphodepleting
chemotherapy
[≤7 days])
On Day 56 and at time of suspected CR and disease progression.
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ASTCT=American Society for
Transplantation and Cellular Therapy; BCMA=B-cell maturation antigen; CAR-T=chimeric antigen receptor-T cell; CR=complete response; sCR=stringent complete response;
CRS=cytokine release syndrome; CT=computed tomography; D=Day; ECHO=echocardiography; ECOG=Eastern Cooperative Oncology Group; EOS=End of Study; FISH=fluorescence in
situ hybridization; FLC=free-light chain; HBV=hepatitis B virus; HCV=hepatitis C virus; HTLV=Human T-cell lymphotropic virus; HBsAg=hepatitis B surface antigen; ICANS=Immune-
Effector Cell-associated Neurotoxicity Syndrome; ICE=Immune-Effector Cell-associated Encephalopathy; ICF=informed consent form; Ig=Immunoglobulins; INR=international
normalized ratio; LD=lymphodepleting; LLOQ=lower limit of quantitation; LTFU=long-term follow-up; LVEF=left ventricular ejection fraction; OOS=out-of-specifications;
PD=progressive disease; PI=prescribing information; PK=pharmacokinetics; PT=prothrombin time; RCL=Replication Competent Lentivirus; SAE=serious adverse event; SOC=standard-
of-care; SPEP=serum protein electrophoresis; MM=multiple myeloma; MRD=minimal residual disease; MRI=magnetic resonance imaging; MUGA=multiple-gated acquisition;
UPEP=urine protein electrophoresis; US=United States.
Footnotes:
a. 
ICF must be signed after cilta-cel OOS is approved for exceptional release and before first study related procedures are performed. Evaluations for eligibility determination
performed outside the screening window may need to be repeated.
b. 
For participants who discontinue the study before Day 100, the Day 100 assessments should be performed prior to withdrawal if feasible. Participants who discontinue after Day 100
but before end of study should have urine and serum disease assessments performed prior to withdrawal if feasible at the time of discontinuation, unless performed within 14 days
prior to discontinuation. End of Study (EOS) is defined as 2 years after each participant has received his or her initial dose of cilta-cel OOS. All participants who received cilta-cel
OOS will continue to be monitored under a separate long-term follow-up (LTFU) safety study (68284528MMY4002) for up to 15 years after last dose of cilta-cel OOS.


JNJ-68284528  (ciltacabtagene autoleucel)
Clinical Protocol 68284528MMY2005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  02 September 2022
c. 
Post-treatment assessments to be obtained until progressive disease is documented or the start of subsequent anticancer therapy, with the exception of survival status and subsequent
anticancer therapy, which are to be collected until end of study. Telephone contact will be made to determine survival status and subsequent anticancer therapy every 84 days for up
to EOS, unless the participant has died, is lost to follow-up, or has withdrawn consent.
d. 
Disease characteristics cytogenetics (full karyotyping or FISH as well as molecular genetics [if applicable]), both of which may originate from prior to or during the screening period
within 42 days before, availability of cilta-cel OOS infusion or before the lymphodepleting chemotherapy, as applicable. A pathologist/cytogeneticist should complete the
cytogenetics data collection worksheet.
e. 
Serology results performed as standard-of-care within 28 days prior to written notification for availability of cilta-cel OOS. Hepatitis B: HBsAg, anti-HBc, anti-HBs, HBV DNA
quantification (for participants who are anti-HBs positive without history of vaccination or for participants who are anti-HBs positive and anti-HBc positive); For participants at risk
for HBV reactivation, monitor HBV DNA, AST/ALT every 12 weeks (±7 days) for one year post-dose of cilta-cel OOS (See Section 10.14, Appendix 14). Hepatitis C: HCV
antibody, HCV-RNA (for participants who are anti HCV positive); HIV serology. Human T-cell lymphotropic virus (HTLV), and other infectious diseases as applicable per local
regulations.
f. 
Immediately before the start of infusion, at the end of infusion, and 0.5, 1, 2 hours after end of infusion. Monitor until normalized after a CRS event.
g. 
Temperature will be checked at least twice a day up to Day 28. Participants will be provided with a thermometer and instructed on the use of the thermometer and entering
2 temperatures including their maximum daily temperature in a diary. Diary will be reviewed at each visit, then collected on Day 28 and stored with participant source documents.
h. 
UPEP sample collected as part of the standard-of-care and prior to the participant signing ICF may be used for analysis at the central laboratory. For patients in CR/sCR spot
urine protein showing continued CR/sCR is permitted.
i. 
Bone marrow morphology from an aspirate and core biopsy to be assessed locally at all time points. Additionally, FISH testing needs to be done for bone marrow aspirate or biopsy
samples collected prior to lymphodepleting chemotherapy at a central laboratory.
j. 
Results from skeletal survey performed as routine follow-up within 42 days may be used without these tests being repeated. The skeletal survey is to be performed by either
roentgenography or low dose computed tomography (CT) scans without the use of IV contrast. If a CT scan is used it must be of diagnostic quality. Additional imaging (X-ray, CT,
or magnetic resonance imaging [MRI]) will be performed as clinically indicated (eg, to document response or progression).
k. 
Extramedullary plasmacytomas should be assessed for all participants with a history of plasmacytomas or if clinically indicated prior to the first dose of the lymphodepleting
chemotherapy, by clinical examination or radiologic imaging, including MRI or CT as appropriate, see also Sections 8.1.4 and 2.3.1.
l. 
Pre-infusion ICE test and handwriting sample should be performed before premedication with diphenhydramine.
m. 
Immunophenotyping samples should also be collected at suspected CR, every 12 weeks until 1-year and then every 6 months post-1 year. Samples will not be collected if LLOQ is
reached after 1-year. Additional event-triggered testing immunophenotyping may be conducted as clinically indicated.
n. 
Samples for PK CAR transgene levels should also be collected at suspected CR, every 12 weeks until 1-year and then at least annually until EOS. Samples will not be collected if
LLOQ is reached after 1-year. Additional event-triggered testing for PK CAR transgene may be conducted as clinically indicated.
o. 
Collect additional samples when any of the following are observed or reported: 1) CRS or ICANS/neurotoxicity related to CAR-T therapy (Grade ≥3) (at onset of the event, at any
increase in grade of the CRS and at time of resolution) or additional event-triggered testing for immunophenotyping and PK CAR transgene levels may be conducted as clinically
indicated. If these additional sampling timepoints occur on a day of a regularly scheduled sample collection, only 1 sample collection is required for that day.
p. 
Yearly monitoring of malignancies will be continued until 15 years after the last administration of cilta-cel OOS on a separate long-term-follow-up study. For participants diagnosed
with a new or recurrent malignancy, a tumor sample should be collected, and DNA, RNA, or protein analysis may be performed to investigate the presence oflentiviral elements.
q. 
All participants will be evaluated for IgG, IgA, IgM. Testing for IgD and IgE will only be performed for participants with IgD and IgE-type myeloma. Additional immunoglobulin
samples may be collected as clinically indicated for safety and treated according to institutional guidelines (see Section 6.1.6.5).
r. 
Local laboratory assessments may be used under specified circumstances (See Section 8.1).
s. 
If the time from consent to the start of lymphodepleting (LD) chemotherapy is ≤ 7 days, repeat assessments prior to administration of LD chemotherapy are not required with
exception of weight and vitals.


JNJ-68284528  (ciltacabtagene autoleucel)
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Status: Approved, Date:  02 September 2022
2. 
INTRODUCTION
Cilta-cel (ciltacabtagene autoleucel [cilta-cel]) is a genetically modified autologous T cell
immunotherapy that binds to B-cell maturation antigen (BCMA, also known as CD269 and tumor
necrosis factor receptor superfamily member 17 [TNFRSF17]). Cilta-cel employs chimeric
antigen receptor (CAR) technology to genetically engineer autologous peripheral blood T cells to
identify and kill cells that express BCMA, which is primarily expressed on late-stage B cells,
plasma cells, and malignant B-lineage cells. Cilta-cel is being developed for the treatment of
multiple myeloma.
For the most comprehensive nonclinical and clinical information regarding cilta-cel, refer to the
US prescribing information (USPI) (or locally  approved label) for cilta-cel and Investigator’s
Brochure (IB) (IB JNJ-68284528).
The term “study treatment” throughout the protocol, refers to “study intervention-cilta-cel OOS”
as defined in Section 6.1, Study Intervention Administered.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject" or “patient”.
Study Rationale
Cilta-cel is an autologous BCMA-targeted CAR-T cell therapy that relies on the participant’s
T cells, collected during apheresis, as starting material for the manufacturing process. There exists
a high degree of individual variability of the apheresis material and issues during the
manufacturing process that may cause the finished drug product to not meet all pre-specified
release criteria. As a personalized therapy, unlike off-the-shelf therapies, such as small molecule
or antibody therapies, the drug product cannot be exchanged by another drug product eg, from
another readily manufactured batch fully meeting all specifications. The clinical circumstances of
a participant may also not allow the additional time required to re-apherese or re-manufacture to
produce a drug product that fully meets specifications. Additionally, a patient may still benefit
from out-of-specifications (OOS) drug product.
Participants whose final manufactured cilta-cel batches do not meet the commercial release
specifications are eligible for inclusion. Upon written notification of the cilta-cel being OOS, the
treating physician can request the sponsor to activate an exceptional release process, during which
cilta-cel OOS will be assessed individually by the sponsor for the expected benefit/risk profile. If
the benefit/risk profile is deemed favorable, the treating physician/principal investigator will
initiate eligibility and screening procedures and can formally request the shipment of the cilta-cel
OOS for administration within the study. After providing informed consent the participant is
enrolled into the study to receive cilta-cel OOS and followed for 2 years in this study to assess the
safety and efficacy of cilta-cel OOS. All participants who received cilta-cel OOS will continue to


JNJ-68284528  (ciltacabtagene autoleucel)
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Status: Approved, Date:  02 September 2022
be monitored under a separate long-term follow-up (LTFU) safety study (68284528MMY4002)
for up to 15 years after last dose of cilta-cel OOS.
Background
Cilta-cel is an autologous CAR-T therapy that targets BCMA, a molecule expressed on the surface
of mature B-lymphocytes and malignant plasma cells. Results from study 68284528MMY2001
(CARTITUDE-1) indicate that cilta-cel has significant anti-myeloma activity and a safety profile
consistent with the known mechanism of action of the product.
2.2.1. 
Multiple Myeloma
Multiple myeloma is an incurable, malignant, plasma cell disorder. It is the second most common
hematologic malignancy, with 35,842 cases and approximately 23,275 deaths estimated in the
EU-27 countries in 2020 (ECIS 2020). The current 5-year relative survival rate in Europe for
patients with multiple myeloma is approximately 50%, with the most recent estimate of 51.3%
provided by a study from the Swedish Multiple Myeloma Registry for the period 2011-2015
(Turesson 2018). In the US, multiple myeloma accounts for approximately 18% of hematological
malignancies and 1.8% of all new cancer cases (Kumar 2020a). For 2022, the American Cancer
Society projects about 34,470 new cases of multiple myeloma and 12,640 deaths in the US
(American Cancer Society 2022). The 5-year survival rate in the US for patients with multiple
myeloma diagnosed from 2011 to 2017 was 55.6% (Howlader 2021). By race and ethnicity, the
incidence and death rates are highest in the non-hispanic black population (American Cancer
Society 2022; Marinac 2020).
Multiple myeloma is characterized by the proliferation of neoplastic clones of plasma cells derived
from B-lymphocytes. These neoplastic clones grow in the bone marrow, frequently invade the
adjacent bone, disrupt both bone homeostasis and hematopoiesis, and cause multifocal destructive
lesions throughout the skeleton that result in bone pain and fracture (Chung 2017). Common
clinical presentations of multiple myeloma are hypercalcemia, renal insufficiency, anemia, bony
lesions, bacterial infections, hyperviscosity, and secondary amyloidosis (Orlowski 2013).
Treatment options for multiple myeloma have substantially improved over time and vary
depending on the aggressiveness of the disease, underlying prognostic factors, physical condition
of the patient, and existing co-morbidities (Chung 2017). Therapeutic options include agents such
as proteasome inhibitors, immunomodulatory drugs (IMiDs), monoclonal antibodies, and stem cell
transplantation.
Despite these therapeutic achievements, the disease recurs and remains incurable. Thus, there is a
need for novel therapeutic approaches.
2.2.2. 
B-cell Maturation Antigen
B-cell maturation antigen (BCMA, also known as CD269 and TNFRSF17) is a 20 kilodalton,
type III membrane protein that is part of the tumor necrosis receptor superfamily. BCMA is
predominantly expressed in B-lineage cells and plays a critical role in B-cell maturation and
subsequent differentiation into plasma cells (Tai 2015). BCMA binds 2 ligands that induce B-cell


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Status: Approved, Date:  02 September 2022
proliferation: a proliferation inducing ligand (APRIL; CD256) and B-cell activating factor (BAFF;
CD257) (Avery 2003; Darce 2007; Patel 2004). Upon binding of BCMA monomers to the APRIL
trimer, activation and phosphorylation of p38MAPK, ELK, and NF-κB are triggered through
intracellular tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) molecules leading
to pro-survival gene regulation (Bossen 2006; Hatzoglou 2000; Kimberley 2009).
In multiple myeloma cell lines and patient samples, BCMA is more stably expressed specifically
on the B-cell lineage than CD138, a key plasma cell marker which is also expressed on normal
fibroblasts and epithelial cells (Palaiologou 2014). The expression characteristics of BCMA make
it an ideal therapeutic target in the treatment of multiple myeloma (Frigyesi 2014; Tai 2015).
2.2.3. 
CAR-T Therapy
Chimeric antigen receptor-T (CAR-T) cell therapy uses modified autologous T cells that are
activated in an MHC-independent manner upon binding to their target. This results in lysis of the
targeted cells (Mikkilineni 2020).
2.2.4. 
Cilta-cel
Cilta-cel consists of autologous CAR-T cells that target BCMA. The novel design features two
targeting domains on BCMA, to confer avidity of LCAR-B38M to the BCMA expressing cells.
The LCAR-B38M coding sequence comprises a human CD8 alpha signal peptide (CD8α SP),
BCMA targeting domain consisting of 2 different variable fragments of heavy chain antibodies
(VHH [single domain antibody, clone VHH1 and VHH2]), human CD8 alpha hinge and
transmembrane domain (CD8α hinge+TM), human CD137 cytoplasmic domain  (4-1BB
costimulatory domain), and a human CD3 zeta cytoplasmic domain (CD3ζ (Figure 2). The
expression of LCAR-B38M is driven and controlled by a human elongation factor 1 alpha
promoter (hEF1α promoter).
Figure 2: 
LCAR-B38M Coding Region
Abbreviations: BCMA=B-cell maturation antigen; hCD3ζ=a human CD3 zeta cytoplasmic domain; CD8α SP=CD8 alpha signal
peptide; CD8α hinge+TM=CD8 alpha hinge and transmembrane domain; GGGGS=4 glycines and 1 serine; VHH=variable
fragments of heavy-chain antibodies (clone A37353 as VHH1 and clone A37917 as VHH2).
CD8SP 
BCMA targeting domain 
CD8hinge+ TM  CD137 cytoplasmic 
hCD3 (cytoplasmic)
VHH1 
VHH2 
GGGGS linker


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2.2.5. 
Nonclinical Studies
The nonclinical pharmacology program was designed to characterize the biologic activity and
mechanism of action of cilta-cel. In vitro mechanistic proof-of-principle studies have assessed
target engagement with respect to:
 
On-target binding (ie, binding of VHH to BCMA)
 
Off-tumor target activity (ie, in human non-myeloma cell lines, including lung, liver, breast,
brain, embryonic kidney and kidney expressing hERG)
 
On-tumor target activity (ie, in human multiple myeloma cell lines)
Refer to the latest edition of Investigator’s Brochure (IB JNJ-68284528) for a complete description
of the nonclinical study information.
2.2.6. 
Clinical Studies
Efficacy and Safety Studies
Study Legend-2
Legend-2 is an ongoing Phase 1, single-arm, open-label, multicenter, first-in-human trial to
determine the safety and efficacy of LCAR-B38M CAR-T cells used to treat participants with
relapsed multiple myeloma. Enrollment in this investigator-initiated study completed in November
2017; a total of 74 participants with relapsed or refractory multiple myeloma have been treated
with LCAR-B38M CAR-T cell therapy  (NCT 03090659). Refer to the latest edition of
Investigator’s Brochure (IB JNJ-68284528) for a complete description of the safety and efficacy
outcomes of Legend-2.
Study 68284528MMY2001
A total of 113 participants (Phase 1b: 35; Phase 2: 78) were enrolled (apheresed) between 16 July
2018 and 7 October 2019 across 16 sites in US, out of which 101 participants (Phase 1b: 30; Phase
2: 71) received lymphodepleting chemotherapy and 97 participants (Phase 1b: 29; Phase 2: 68)
received cilta-cel infusion and received it at the targeted recommended Phase 2 dose (RP2D).
These 97 participants constituted the all treated analysis set, which was the basis for all efficacy
and safety analyses presented below. At the clinical data cutoff, 1 September 2020, the median
duration of follow-up for the all treated analysis set was 12.4 months. Four participants received
lymphodepleting chemotherapy but did not receive cilta-cel infusion. Two of them refused future
study treatment, one withdrew due to adverse event and one died.
In the all treated analysis set, the median time since initial diagnosis to enrollment was 5.94 years,
and the median number of lines of prior therapy was 6. Participant’s median age was 61 years. All
participants had received prior treatment with a proteasome inhibitor, IMiD, and anti-CD38
antibody therapy. Ninety-six (99%) participants were refractory to the last line of therapy prior to
study entry, and 85 (87.6%) participants were triple-refractory (refractory to an anti-CD38, a


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proteasome inhibitor, and a IMiD) and 41 (42.3%) participants penta-refractory (refractory to an
anti-CD38, at least 2 PIs, and at least 2 IMiDs), respectively. A total of 87 (89.7%) participants
had one or more prior autologous stem cell transplant(s) and 8 (8.2%) participants had a prior
allogeneic transplant.
Primary efficacy endpoint:
Response was assessed by an Independent Review Committee (IRC) based on International
Myeloma Working Group (IMWG) criteria. The ORR (stringent complete response
[sCR]+complete response [CR]+very good partial response [VGPR]+partial response [PR]) was
97.9% (95% confidence interval [CI]: 92.7%, 99.7%), with 92 participants (94.8%) achieving
VGPR or better and 78 participants (80.4%) achieving an sCR. The median duration of response
(DOR) was 21.8 months (95% CI: 21.8 months, not evaluable [NE]).
Major secondary efficacy endpoints:
 
Time to response (TTR): median time to first response (PR or better) and to best response
were 0.95 and 2.56 months, respectively
 
Fifty-six participants (57.7%) achieved minimal residual disease (MRD) negativity at the 10- 5
threshold of sensitivity with 42 participants (43.3%) achieving MRD-negative CR/sCR.
 
The overall median progression-free survival (PFS) based on the IRC response assessment
was 22.8 months (95% CI: 22.8 months, NE) and the 12-month PFS rate was 76.3% (95% CI:
66.5%, 83.6%).
Exposure:
The median (range) of cilta-cel dose formulated and dose administered were 0.693 (0.52, 0.94)
and 0.709 (0.51, 0.95) × 106 CAR-positive viable T cells/kg, respectively.
 
All 97 participants (100%) experienced at least one treatment emergent adverse event
(TEAE). The most common (at least 20%) TEAEs were: neutropenia, cytokine release
syndrome (CRS), anemia, thrombocytopenia, leukopenia, lymphopenia, fatigue, cough,
hypocalcemia, hypophosphatemia, diarrhea, decreased appetite, aspartate aminotransferase
increased, nausea, hypoalbuminemia, alanine aminotransferase increased, hyponatremia,
constipation, hypokalemia, chills, pyrexia.
 
All but one participant had at least one TEAE considered to be related to JNJ 68284528 cilta-
cel by the investigator.
 
All participants experienced at least one Grade 3 or 4 TEAE.
 
Fifty-three (54.6%) participants experienced treatment-emergent SAEs, among whom 29
(29.9%) had Grade 3 or 4 and 6 (6.2%) participants had Grade 5 treatment-emergent SAEs.
 
Among the 97 participants in the all treated population, 21 deaths (21.6%) were reported, of
which 10 were attributed to progressive disease. The 11 remaining deaths were attributed to
AEs with 6 related to cilta-cel (3 infections, 1 respiratory failure, 1 CRS/ HLH, and
1 neurotoxicity). None of the deaths occurred within 30 days of the initial cilta-cel infusion.
Two deaths (sepsis on Day 45 and CRS/HLH on Day 99) occurred within 100 days of the
initial cilta-cel infusion.


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 
Adverse event of special interest (AESI):
 
CRS: All-grade CRS was reported for 92 (94.8%) participants, with 3, 1, and 1
participants experienced Grades 3, 4, and 5 events, respectively, evaluated by the
American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading
system. Median time from cilta-cel infusion to CRS onset was 7 days (range: 1 to 12),
and the median duration of CRS was 4 days (range: 1 to 14 after excluding one participant
with a 97-day duration complicated by HLH). All events of CRS had recovered, with the
exception of 1 (1.1%) fatal event from the participant with the 97-day durationwith HLH.
 
Neurotoxicity was reported for 20 (20.6%) participants:
o 
Immune Effector Cell-Associated Neurotoxicity (ICANS): All grade ICANS was
reported for 16 (16.5%) participants. Of these, 2 (2.1%) participants had maximum
Grade 3 or 4 events, evaluated by the ASTCT consensus grading system. Median
time from cilta-cel infusion to ICANS onset was 8 days (range: 3 to 12), and the
median duration of ICANS was 4 days (range: 1 to 12). All events had recovered.
Concurrent CRS was noted for 15 out of 16 participants.
o 
Other neurotoxicities (not reported as ICANS [ie, onset after a period of recovery
from CRS and ICANS]): All-grade other neurotoxicities were reported for
12 (12.4%) participants. Of these, 8 participants had maximum Grade 3 or 4 events
and 1 participant had a fatal event. Median time from cilta-cel infusion to first onset
of other neurotoxicities was 26.5 days (range: 11 to 108). Events of other
neurotoxicities was fatal for 1 participant, did not recover for 5 participants, and
recovered for 6 participants. Among those recovered, the median time to recovery
was 74.5 days.
 
Tumor lysis syndrome (TLS): 1 participant reported Grade 4 treatment-emergent TLS,
accompanied by Grade 3 blood creatinine increased.
 
Ten participants (10.3%) experienced aSPM. Eight participants (8.2%) developed second
hematologic malignancies with the most frequently reported being myelodysplastic
syndrome in 6 participants (6.2%). Three participants (3.1%) developed acute myeloid
leukemia, 
all 
of which 
resulted 
in 
death. 
Cutaneous/noninvasive 
and
noncutaneous/invasive malignancies were reported for 3 (3.1%) and 1 (1.0%)
participants, respectively. All SPMs were considered not related to cilta-cel by
investigator assessment.
 Other safety observations:
 
Cytopenic TEAEs were reported for all 97 participants (100.0%). Ninety-six participants
(99.0%) reported 1 or more Grade 3 or 4 cytopenic TEAEs. No participants experienced
Grade 5 cytopenic TEAEs. Three participants (3.1%) experienced serious
thrombocytopenia, 1 participant (1.0%) experienced serious neutropenia, and 4


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participants (4.1%) experienced serious febrile neutropenia. Eight (8.2%), 10 (10.3%),
and 23 (23.7%) participants had their initial Grade 3 or 4 events not recovered to Grade
2 or lower by Day 60 for lymphopenia, neutropenia, and thrombocytopenia, respectively.
The most frequently reported (>40% of participants) TEAEs (by Preferred Term) within
the Blood and lymphatic system disorders System Organ Class included:
o 
anemia: 79 participants (81.4%) (Grade 3 or 4: 66 [68.0%]),
o 
thrombocytopenia: 77 participants (79.4%) (Grade 3 or 4: 58 [59.8%]),
o 
leukopenia: 60 participants (61.9%) (Grade 3 or 4: 59 [60.8%]), and
o 
lymphopenia: 51 participants (52.6%) (Grade 3 or 4: 48 [49.5%]).
 
Infections: 56 (57.7%) participants had infection TEAE, of whom 19 (19.6%) participants
with Grade 3 or 4 events, and 3 (3.1%) participants with fatal events (sepsis, septic shock,
lung abscess).
Conclusion:
Data from study 68284528MMY2001 establishes a positive benefit/risk profile for cilta-cel in the
treatment of patients with heavily pretreated, relapsed and highly refractory multiple myeloma.
Cilta-cel treatment yielded deep and durable responses with VGPR or better in  94.8% of
participants and a median DOR was 21.8 months. The safety profile is generally consistent with
the current understanding of CAR-T therapy. CRS was common (94.8%), but most were low
grade. Neurotoxicity was reported in 20.6% of participants, including ICANS and other events not
defined as ICANS (Grade >3 in 9.2% of participants).
Grade 3 or 4 cytopenias were common in the post-infusion period, and the majority of these events
recovered by Day 60. Infectious AEs Grade >3 were reported for 22.7% of participants. Six
participants died due to cilta-cel related AEs, including 1 each of CRS complicated by secondary
HLH, neurotoxicity, respiratory failure, and 3 due to infection (NCT03548207).
Benefit-Risk Assessment
The potential risks of cilta-cel OOS are identified from the following: 1) results of nonclinical
studies; 2) mechanism of action; and 3) previous clinical experience with cilta-cel and
LCAR-B38M CAR-T cells. Detailed information about the known and expected benefits and risks
of cilta-cel may be found in the latest edition of IB (IB JNJ-68284528).
By stimulating an inflammatory cascade, there is potential for toxicity in other tissues or organs
by non-specific immune cell activation. Therefore, special attention should be given to both
immunological and immunogenicity-related toxicities. Longer post-treatment follow-up and
treatment of additional participants, particularly participants who have received fewer prior
therapies than participants in the Legend-2 and 68284528MMY2001 studies, may reveal
additional risks.


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Status: Approved, Date:  02 September 2022
As part of this study, participants will be treated with drug product that did not meet the pre-defined
release specifications required for commercial product. While a benefit/risk assessment for each
individual study participant will be performed via medical review by the sponsor, there is a risk
that cilta-cel OOS has a different safety and efficacy profile compared to cilta-cel meeting all drug
product specifications. Main risks regarding potential benefit is to receive a drug product with
inferior efficacy compared to historic data from 68284528MMY2001. In terms of safety there may
also be risks for higher rates, more severe or new adverse events (AEs) after receipt of cilta-cel
OOS compared to data from 68284528MMY2001.
Important identified and potential risks with mitigation strategies associated with cilta-cel and
cilta-cel-OOS, respectively, are outlined in Table 2 and other potential risks and mitigation
strategies for cilta-cel are presented in Table 3.


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2.3.1. 
Risks for Study Participation
Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
Potential risks associated with cilta-cel OOS
Lack of efficacy  
 Administration of cilta-cel OOS may be less efficacious compared to 
drug product fully meeting drug product specifications 
 Sponsor medical review process will determine and
document the benefit/risk assessment for each study
participant, which will include the potential OOS safety
and efficacy impact, study participant alternative
options/medical need, and assessment of potential
immediate risk of not receiving the product.
More frequent, more 
severe, new adverse 
events 
 Cilta-cel OOS may exhibit a different safety profile compared to 
drug product fully meeting drug product specifications 
 Sponsor medical review process will determine and
document the benefit/risk assessment for each study
participant, which will include the potential OOS safety
and efficacy impact, study participant alternative
options/medical need, and assessment of potential
immediate risk of not receiving the product.
Risks associated with cilta-cel
It is assumed that all important identified and other potential risks of cilta-cel apply to cilta-cel OOS. Study participants should be closely monitored, and adverse
events managed according to current recommendations for cilta-cel as summarized below
Important Identified Risks associated with cilta-cel
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies


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Status: Approved, Date:  02 September 2022
Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
Cytokine Release 
Syndrome 
 Symptoms indicative of CRS may include, but are not limited to, 
fever (with or without rigors), arthralgia, nausea, vomiting, 
tachypnea, hypoxia, tachycardia, hypotension, headache, confusion, 
tremor, delirium, dyspnea, pulmonary edema, and capillary leak. 
 Potentially life-threatening complications of CRS may include 
cardiac dysfunction, adult respiratory distress syndrome, neurologic 
toxicity, renal failure, hepatic failure, and disseminated intravascular 
coagulation. 
 Rarely, severe CRS can evolve into a presentation consistent with 
hemophagocytic lymphohistiocytosis/macrophage activation 
syndrome (HLH/MAS) that may require additional therapy. Severe 
thrombocytopenia, low fibrinogen, and often disseminated
intravascular coagulation (DIC) may be features of HLH, all of 
which combined may increase the risk of severe bleeding in these
subjects. Section 6.1.5.1 describes measures to be taken if HLH is
suspected.
 Fatal HLH occurred in one patient (1%), 99 days after cilta-cel
infusion. The HLH event was preceded by prolonged CRS lasting 
97 days. The manifestations of HLH/MAS include hypotension, 
hypoxia with diffuse alveolar damage, coagulopathy, cytopenia and 
multi-organ dysfunction, including renal dysfunction. 
 Monitor closely for CRS and follow guidance for
management in protocol.
 Laboratory testing to monitor for disseminated
intravascular coagulation, a manifestation of CRS,
 Daily monitoring of chemistry and hematology
assessments (including ferritin and CRP), when fever or
other signs of potential CRS are present. Body
temperature should be monitored at least twice daily for
28 days post infusion.
 Pulmonary, renal and hepatic function to be monitored
closely
 Resources necessary for resuscitation (ie, agents such as
epinephrine and aerosolized bronchodilator; medical
equipment such as oxygen, tracheostomy equipment, and a
defibrillator) should be readily available.
 At the first sign of CRS (such as fever) participants should
be immediately hospitalized for evaluation. See Table 5
for hospitalization requirements.
 Tocilizumab (at least 2 doses) must be available prior to
administration of cilta-cel OOS. Tocilizumab intervention
may be considered with presenting symptom of fever in
the absence of clear infectious etiology. Early tocilizumab
should be considered in participants at high risk of severe
CRS.
 Vital signs and laboratory parameters must be monitored
at regular intervals until normal.
 Based on institutional practice guidelines, consider
alternate immunosuppressants (eg, other cytokine-
targeting therapies) for participants who develop high
grade CRS with laboratory findings overlapping with
HLH/MAS that remains severe or life-threatening
following administration of tocilizumab and
corticosteroids.


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Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
 The use of myeloid growth factors, particularly
granulocyte colony-stimulating factor (G-CSF), should be
avoided during CRS.
 Notify the sponsor if participant is experiencing Grade 2
or higher CRS. CRS will be captured as an adverse event
of special interest.
Neurotoxicity
Immune-Effector Cell-
Associated
Neurotoxicity Syndrome
(ICANS)
 Symptoms indicative of ICANS may include, but are not limited to
speech disorders, aphasia, convulsions, disturbances in
consciousness, confusion, disorientation, or coordination and
balance disorders
 Early recognition of neurologic adverse events is critical to
management. Participants should be advised to seek medical
evaluation if they notice new onset of headache, convulsions, speech
disorders, visual disorders, disturbances in consciousness, confusion
and disorientation, and coordination, balance disorders, or mental
status changes. Notify the sponsor if participant is experiencing any
grade ICANS
 Monitor closely for neurologic AEs, including CAR-T
cell-related neurotoxicity (eg, ICANS) and raised
intracranial pressure / cerebral edema; follow guidance
for management in protocol.
 Participants should have the Immune-Effector Cell-
associated Encephalopathy (ICE) Assessment Tool
performed at baseline and daily after the first symptoms
of CAR-T cell-related neurotoxicity (eg, ICANS) are
suspected and until resolution.
 Consider performing neuroimaging (eg, magnetic
resonance imaging [MRI]) at screening and/or neurology
consultation if pre-existing disease is suspected.
 Monitor patients for signs or symptoms of neurologic
toxicities for 4 weeks after infusion and treat promptly.
At the first sign of neurotoxicity, neurology consultation
and evaluation should be considered.
 Consider non-sedating, anti-seizure medicines (eg,
levetiracetam) for seizure prophylaxis for any Grade 2 or
higher neurologic toxicities.
 Treatment with tocilizumab should be considered when
concurrent with CRS. Other causes of neurologic
symptoms should be ruled-out. Guidelines for the
management of raised ICP/cerebral edema as per Table 8.


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Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
 Other cytokine-targeting therapies (for example, IL1) may
be used based on institutional practice, especially for
cases of neurotoxicity which does not respond to
tocilizumab or corticosteroids. Therapy directed at
reduction or elimination of CAR-T cells, including
chemotherapy, may be considered in consultation with
the sponsor for participants who develop neurotoxicity
that remains severe or life-threatening following prior
therapies, including tocilizumab and corticosteroids.
 Other
Neurotoxicities
 Other severe or serious neurological toxicities may occur after a
period of recovery from CRS and/or initial ICANS.
 Movement and Neurocognitive Toxicity (ie, Parkinsonism):
A cluster of symptoms with variable onset spanning more than one
symptom domain was observed, including: changes in movement
(eg, micrographia or changes in handwriting, tremors, bradykinesia,
rigidity, shuffling gait, impaired balance and coordination, difficulty
writing, difficulty performing activities of daily living like dressing
or feeding oneself), cognitive impairments (eg, memory loss or
forgetfulness, disturbance in attention, mental slowness or fogginess,
difficulty speaking or slurred speech, difficulty reading or
understanding words), and personality changes (eg, reduced facial
expression, flat affect, reduced ability to express emotion, less
communicative, disinterest in activities).
 This delayed onset of movement and neurocognitive toxicity was
observed at a higher frequency in participants with high burden of
disease and in participants experiencing higher grade CRS (Grade 2
and above) and any grade ICANS. This may be indicative that
≥Grade 2 CRS or any grade ICANS are early indicators for the
development of other neurotoxicity after a period of recovery from
CRS and/or ICANS. Therefore, ≥Grade 2 CRS or any grade ICANS
may represent an opportunity for early intervention and more
aggressive supportive care (including steroids), especially in patients
treated with a high tumor burden, that may mitigate the risk for
 At the first sign of neurotoxicity, neurology consultation
and evaluation should be considered.
Movement and Neurocognitive Toxicity (ie, Parkinsonism):
 If neurologic or psychiatric symptoms consistent with a
cluster of movement and neurocognitive toxicity are
noted, contact the medical monitor and refer the
participant immediately to a neurologist for a full
evaluation.
 Consider early and aggressive supportive care including
steroids in patients presenting with higher grade CRS or
any grade ICANS and handwriting assessments for early
detection of neurotoxicity symptoms, and extended
monitoring and reporting time for neurotoxicity for the
duration of the study.
 Consider reducing baseline burden of disease with
bridging chemotherapy prior to infusion with cilta-cel in
patients with high tumor burden.
 Therapy directed at reduction or elimination of CAR-T
cells, including chemotherapy, may be considered for
patients who develop neurotoxicity that remains
unresponsive to other interventions.
 Greater than or equal to Grade 2 CRS or any grade ICANS
may represent an opportunity for early intervention and
more aggressive supportive care (including steroids)


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Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
developing late, other neurotoxicity. Infection and sepsis were seen 
concurrently in many of these patients. 
 Cranial Nerve Palsies: 
Occurrence of 7th, 3rd, 5th, and 6th cranial nerve palsy, some of 
which were bilateral, worsening of cranial nerve palsy after 
improvement, and occurrence of peripheral neuropathy in patients 
with cranial nerve palsy have been reported in trials of cilta-cel.
Median time of onset of symptoms was 62 days (range: 4 to 136
days), median duration of peripheral neuropathies was 256 days
(range: 2 to 465 days) including those with ongoing neuropathy.
 Peripheral Neuropathy: 
Occurrence of peripheral neuropathy, including sensory, motor, or 
sensorimotor, have been reported in trials of cilta-cel. Median time 
of onset of symptoms was 62 days (range: 4 to 136 days), median
duration of peripheral neuropathies was 256 days (range: 2 to 465
days) including those with ongoing neuropathy
 Guillain-Barré Syndrome: 
A fatal outcome following Guillain-Barré syndrome has been 
reported after treatment with cilta-cel in another ongoing study.
Symptoms reported include those consistent with Miller-Fisher
variant of GBS, motor weakness, speech disturbances, and
polyradiculoneuritis.
especially in patients treated with high tumor burden, may
mitigate the risk of developing neurotoxicity later, after
resolution of CRS.
 Infection and sepsis were seen concurrently in many of
these patients.
Cranial Nerve Palsies:
 Monitor patients for signs and symptoms of cranial nerve
palsies. Consider management with short-course systemic
corticosteroids, depending on the severity and progression
of signs and symptoms.
Peripheral Neuropathy:
 Monitor patients for signs and symptoms of peripheral
neuropathies. Consider management with short-course
systemic corticosteroids, depending on the severity and
progression of signs and symptoms.
Guillain-Barré Syndrome:
 Monitor for signs and symptoms of GBS after cilta-cel
infusion. Consider treatment with IVIG and escalate to
plasmapheresis, depending on toxicity severity per
institutional guidelines.


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Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
Prolonged or Recurrent 
Cytopenia 
Participants may exhibit cytopenias for several weeks following 
lymphodepleting chemotherapy and cilta-cel OOS infusion. In Study 
68284528MMY2001 (N=97), 30% (29/97) of patients experienced 
prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients 
experienced prolonged Grade 3 or 4 thrombocytopenia that had not 
resolved by Day 30 following cilta-cel infusion. In 31% (29/95) of
patients who recovered from Grade 3 or 4 neutropenia after 1 month, the
median time to recovery from cilta-cel infusion was 1.8 months (range:
1.0 to 3.7 months). In 52% (32/61) of patients who recovered from
Grade 3 or 4 thrombocytopenia after 1 month, the median time to
recovery from cilta-cel infusion was 1.9 months (range: 1.1 to 8.5 
months). 
 Blood counts should be monitored after cilta-cel OOS
infusion and provide supportive care (eg, irradiated
packed red blood cells [PRBCs] and platelets,
granulocyte colony-stimulating factor for neutropenia) as
outlined by institutional guidelines.
 The use of myeloid growth factors, particularly
granulocyte-colony stimulating factor (G-CSF), should be
avoided during CRS. Pegylated myeloid growth factors
(ie, pegfilgrastim) are prohibited until Day 100.
 Prolonged neutropenia may increase the risk of infection.
Severe thrombocytopenia may increase the risk of
bleeding. Monitor hematological parameters and provide
supportive care as outlined by institutional guidelines.
 Parvovirus B19 monitoring by PCR should be considered
in participants experiencing prolonged neutropenia or a
decline in neutrophil counts following recovery.
Serious Infection 
 Administration of cilta-cel OOS may increase the risk of infection 
due to cytopenias or hypogammaglobulinemia. 
 HBV reactivation, in some cases resulting in fulminant hepatitis, 
hepatic failure and death, may occur in participants treated with 
drugs directed against B cells. HBV reactivation has occurred in 
participants who appear to have resolved hepatitis B infection. 
 Subjects receiving cilta-cel may be at a higher risk of severe/fatal 
outcomes from COVID-19 infection compared with patients who 
are receiving standard of care therapy. Subjects should be reminded 
of the importance of vaccines and other preventative measures. 
Investigators should consider prophylaxis (eg, Evusheld, if 
available) and antiviral medications (eg, Paxlovid, if available) for 
patients diagnosed with COVID-19 infection, as noted in 
Section 10.6, Appendix 6. 
 Do not administer cilta-cel OOS infusion to participants
with active infection.
 Participants should be monitored frequently for infection
and should have blood cultures obtained, serum
inflammatory markers (CRP), and/ or and empiric
antibiotics administered as appropriate, based on clinical
judgment and per institutional standards.
 Perform screening for hepatitis B virus (HBV), hepatitis C
virus (HCV), and human immunodeficiency virus (HIV)
and monitor as clinically indicated, and initiate treatment
as appropriate. Routinely monitor HBV DNA and
AST/ALT for participants with risk of HBV reactivation.
Prophylaxis for participants at high risk of HBV
reactivation is recommended per institutional guidance.
 Immunocompromised patients are at risk for opportunistic
infections; prophylactic use of antibiotics, antivirals, or
antifungals should be considered.


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Table 2: 
Important Identified and Potential Risks with Mitigation Strategies for Study Participants (cilta-cel OOS and cilta-cel)
Risks of Clinical
Significance 
Risk Characterization and Rationale 
Mitigation Strategies
 
Extended use of anti-microbial therapies for at least 6
month or consistent with post ASCT consensus guidelines
after CAR-T dosing are recommended (Section 10.13,
Appendix 13)
 
The safety of immunization with live viral vaccines has
not been studied. Vaccination with live virus vaccines is
not recommended for at least 6 weeks prior to the start of
lymphodepleting chemotherapy, and until immune
recovery following treatment with cilta-cel.
Abbreviations: ALT=alanine aminotransferase; ASCT=autologous stem cell transplant; AST=aspartate aminotransferase; CAR-T=chimeric antigen receptor-T (cells);
CMV=cytomegalovirus; CRP=C-reactive protein; CRS=cytokine release syndrome; DMSO=dimethyl sulfoxide; G-CSF=granulocyte-colony stimulating factor;
HBV=hepatitis B virus; ICANS=Immune-Effector Cell-Associated Neurotoxicity Syndrome; ICE=Immune-Effector Cell-associated Encephalopathy;
ICP=intracranial pressure; IgG=Immunoglobulin G; IVIG=intravenous immunoglobulin; MRI=magnetic resonance imaging; OOS=out-of-specifications;
PCR=polymerase chain reaction; TLS=tumor lysis syndrome.


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Table 3: 
Other Potential Risks and Mitigation Strategies for Study Participants (cilta-cel)
Risks of Clinical Significance 
Risk Characterization and Rationale 
Mitigation Strategies
Tumor Lysis Syndrome (TLS) 
Although TLS is uncommon in participants with 
multiple myeloma, participants must be monitored 
closely for symptoms of TLS  
 Monitor closely for TLS with frequent monitoring of
chemistry parameters (ie, hyperkalemia,
hyperuricemia, hyperphosphatemia, and
hypocalcemia), and follow guidance for management
in protocol.
 High risk participants, ie, those with a high tumor
burden (60% plasma cell infiltrate on the bone
marrow biopsy or aspirate [whichever is higher] or a
participant with multiple extramedullary disease sites
or plasmacytomas), should be treated prophylactically
in accordance with local standards. (eg, extra
hydration; diuretics; allopurinol; and primary or
secondary uricosuric agents, as indicated).
Hypogammaglobulinemia 
Hypogammaglobulinemia may occur in participants 
receiving cilta-cel OOS. 
Hypogammaglobulinemia was reported as an adverse 
event in 12% of patients; laboratory IgG levels fell 
below 500 mg/dL after infusion in 92% (89/97) of
patients treated with cilta-cel.
Hypogammaglobulinemia either as an adverse
reaction or a laboratory IgG level below 500 mg/dL,
after infusion occurred in 94% (91/97) of patients
treated with cilta-cel. Thirty-eight percent of patients 
received intravenous immunoglobulin (IVIG) post 
cilta-cel for either an adverse reaction or 
prophylaxis.
 Monitor immunoglobulin levels after treatment and
more frequently, if clinically indicated. Treat according
to local guidelines, including administration of Ig
replacement and monitoring for infection.

Participants with IgG <400 mg/dL or recurrent
infections (including HBV reactivation) should be
considered for prophylactic IV or subcutaneous IgG
per institutional guidelines.
 Vaccination with live virus vaccines is not
recommended for at least 6 weeks prior to the start of
lymphodepleting chemotherapy.
Second primary malignancy (SPM) 
Second primary malignancy is a theoretical
possibility due to the risk of lentiviral insertion  
(DNA integration) of the lentiviral vector.
 Second primary malignancies should be managed per
institutional standards.
 Second primary malignancies must be reported during
the duration of the study, irrespective of when they
occur, and subsequently will be collected in a long-
term follow-up study yearly until 15 years post dosing
of cilta-cel OOS.


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Table 3: 
Other Potential Risks and Mitigation Strategies for Study Participants (cilta-cel)
Risks of Clinical Significance 
Risk Characterization and Rationale 
Mitigation Strategies
 A tumor sample should be collected and DNA, RNA or
protein analysis may be performed to investigate the
presence of lentiviral elements.
 SPM is an adverse event of special interest (AESI).
Hypersensitivity reactions 
Allergic reactions may occur with the infusion of
cilta-cel. Hypersensitivity reactions have occurred in
5% of patients following cilta-cel infusion. All
reactions were Grade 1 and symptoms included
flushing (n=4), chest discomfort (n=2), tachycardia
(n=1), wheezing (n=1), term or (n=1), and burning
sensation (n=1).Serious hypersensitivity reactions
including anaphylaxis, may be due to dimethyl
sulfoxide (DMSO), dextran 40, or residual
kanamycin in cilta-cel.
 Participants should be carefully monitored for 2 hours
after infusion for signs and symptoms of severe
reaction
 Participants should be treated urgently per institutional
standards, according to the severity of the
hypersensitivity reaction avoiding corticosteroid use if
possible.
 Participants should receive premedication (ie,
antihistamine, antipyretic) prior to cilta-cel OOS
dosing as noted in Section 6.1.1.
Abbreviations: DMSO=dimethyl sulfoxide; ICANS=Immune-Effector Cell-Associated Neurotoxicity Syndrome; ICE=Immune-Effector cell-associated Encephalopathy;
IgG=Immunoglobulin G; IVIG=intravenous immunoglobulin; TLS=tumor lysis syndrome; MRI=magnetic resonance imaging; OOS=out-of-specifications;
PCR=polymerase chain reaction; SPM=second primary malignancy.


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2.3.2. 
Benefits for Study Participation
Potential benefits for the participant are that the drug product (cilta-cel OOS) may elicit a treatment
effectiveness with a safety profile comparable to the commercial drug product that met the
specification criteria.
2.3.3. 
Benefit-Risk Assessment for Study Participation
The benefit/risk will be determined for each individual participant ahead of enrollment into the
study and must be determined as positive by both, the sponsor’s medical review as well as by the
treating physician/principal investigator. The benefit/risk assessment by medical evaluation
includes assessment of the out-of-specifications’ potential impact on cilta-cel´s safety and efficacy,
the participant’s alternative treatment options, medical need, and assessment of potential
immediate hazards of not receiving the cilta-cel OOS. While clinical information of out-of-
specifications release criteria drug product is limited, the following outcomes have been observed
in participants within the Legend-2 study, where study participants received a dose below the target
dose per USPI or locally approved label.
 
In Legend-2, participants were treated with LCAR-B38M CAR-T cells, which expresses the
identical CAR and provides supporting benefit-risk data.
 
The safety and efficacy summary of Legend-2 is described in the latest edition of the IB (IB
JNJ-68284528). There were 13 participants in Legend-2 study who received a dose in range
of 0.1 × 106 to 0. 5 × 106 cells/kg, out of 13 participants, 9 participants achieved PR or better.
Albeit changes in the methodology of cell-count and manufacturing changes have been
implemented for commercial cilta-cel, these data are seen supportive in the assessment of
benefit/risk of cilta-cel OOS for a dose below the target dose per USPI or locally approved
label.
 
In study 68284528MMY2001, based on release specification criteria, 4 out of 97 participants
received a drug product that was out of specification. Two participants received a cilta-cel
infusion which did not meet the requirement for a single dose of 0.5 × 106 CAR-positive
cells/kg/bag specification and hence these 2 participants were dosed with 2 cilta-cel infusion
bags each to achieve the target dose. Two other participants received a product that was above
the accepted natural killer (NK) cell value range. Of these 4 participants, 2 achieved VGPR
and 2 achieved a sCR. There were no clinically significant AE signals reported for these
participants.
As part of this open-label study, emerging safety and efficacy data will be closely monitored by
the study responsible physician and study team. A Data Review Committee (DRC) will regularly
review aggregated outcomes and can trigger additional safety analysis and reviews as indicated.
Clinically important information with updated guidance on OOS and potential impact on safety
and efficacy will be made available to investigators as appropriate.


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It is assumed that cilta-cel OOS will display similar safety and efficacy as cilta-cel, as of the 1
September 2020 clinical data cut-off, 97 participants had received cilta-cel infusion in Study
68284528MMY2001. The safety profile is in-line with observations from the Legend-2 study.
Refer to the latest edition of Investigator’s Brochure (IB JNJ-68284528) for a complete
description of the safety and efficacy outcomes of Study 68284528MMY2001.
Thus, taking into account the measures taken to minimize risk to participants of this study, the
potential risks identified in association with cilta-cel are justified by the anticipated benefits that
may be afforded to participants with multiple myeloma.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 To evaluate the efficacy of 
cilta-cel OOS  
 Overall Response of partial response or better (ie, ORR),
as defined by the International Myeloma Working Group
(IMWG) response criteria and assessed by the
investigator. Time frame: Screening Phase through End
of Study (EOS) (Month 24 after cilta-cel OOS
infusion)/Early withdrawal
Secondary
 To assess the safety of cilta- 
cel OOS  
 Incidence and severity of treatment emergent adverse
events, serious adverse events, adverse events of special
interest, abnormalities in safety (laboratory assessments),
vital signs, and physical examinations
 To further characterize the 
efficacy of cilta-cel OOS  
 Partial Response (PR)/very good partial response
(VGPR)/complete response (CR)/stringent complete
response (sCR) rate and clinical benefit rate (CBR=ORR
[sCR+CR+VGPR+PR]+MR [minimal response]), as
defined by the IMWG response criteria, duration of
response (DOR), progression-free survival (PFS), overall
survival (OS) and minimal residual disease
(MRD)-negative rate.
 To determine whether 
replication competent
lentivirus is present in
participants that receive
cilta-cel OOS
 Presence of replication competent lentivirus
Exploratory
 To characterize the
pharmacokinetics and
pharmacodynamics of
cilta-cel OOS

Biomarkers including baseline expression of BCMA in
MM cells, depletion of BCMA expressing cells, systemic
cytokine concentrations, and CAR-T PK parameters such
as expansion and persistence via monitoring CAR-T
positive cell counts, and CAR transgene levels
 To assess the
immunogenicity of cilta-cel
OOS

Presence of anti-cilta-cel OOS antibodies.


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Abbreviations: BCMA=B-cell maturation antigen; CAR-T=Chimeric antigen receptor-T cells; CBR=clinical benefit
rate; CR=complete response; DOR=duration of response; EOS=End of Study; IMWG=International Myeloma
Working Group; MM=multiple myeloma; MRD=minimal residue disease; MR=minimal response; OOS=Out-of-
Specifications; 
ORR=overall 
response 
rate; 
OS=overall 
survival; 
PFS=progression-free 
survival;
PK=pharmacokinetics; PR=partial response; sCR=stringent complete response; VGPR=very good partial
response.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The study hypothesis is that cilta-cel OOS will demonstrate similar safety and efficacy to data
from study 68284528MMY2001, as assessed by the primary and secondary endpoints.
4. 
STUDY DESIGN
Overall Design
This is an open-label, single-arm multicenter Phase 2 study to evaluate the safety and efficacy of
cilta-cel OOS in adult participants (≥18 years) with multiple myeloma as described in cilta-cel
USPI (or locally approved label, respectively), and whose final manufactured cilta-cel does not
meet the commercial release specifications.
Upon written notification of the cilta-cel being OOS, the treating physician can request the sponsor
to activate an exceptional release process, during which cilta-cel OOS will be assessed individually
by the sponsor for the expected benefit/risk profile. If the benefit/risk profile is deemed favorable,
the treating physician/principal investigator will initiate screening procedures upon obtaining
informed consent. If eligible, the treating physician/principal investigator can formally request the
shipment of the cilta-cel OOS for administration within the study. Exceptional Release of OOS
Product Request Form must be completed and signed off by the treating physician/principal
investigator before releasing cilta-cel OOS to the participant.
The study will be conducted in following 5 phases:
 
Screening Phase,
 
Lymphodepleting chemotherapy,
 
Cilta-cel OOS Administration,
 
Post infusion, and
 
Post-treatment
Cilta-cel OOS will not be administered to a participant whose medical condition does not meet the
criteria for CAR-T infusion. Non-eligible medical conditions include active uncontrolled infection
or condition where an administration of cilta-cel OOS constitutes serious health risk to the
participant.


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Eligible participants may continue bridging therapy (ie, anti-plasma cell directed treatment
between apheresis and the first dose of the lymphodepleting chemotherapy) as clinically indicated
(ie, to maintain disease stability while waiting for availability of cilta-cel). Bridging therapy and
lymphodepleting chemotherapy will be considered as part of standard-of-care and are prescribed
by the treating physician, if clinically indicated.
Lymphodepleting chemotherapy consists of IV cyclophosphamide 300 mg/m2 and fludarabine 30
mg/m2 daily for 3 days per USPI or locally approved label. Cilta-cel OOS will be administered at
a total targeted dose of 0.75×106 CAR-positive viable T  cells/kg (range: 0.5 to 1.0×106 CAR-
positive viable T cells/kg) or per exceptional release criteria determined alternative dose, 5 to 7
days after start of the lymphodepleting chemotherapy.
Efficacy evaluations include myeloma protein measurements and imaging as indicated for enrolled
participants to evaluate response and disease progression. Efficacy evaluations will be measured
from Screening Phase through end of study by the investigator per IMWG consensus
recommendations for multiple myeloma treatment response criteria (Section 10.10, Appendix 10).
Blood, serum and bone marrow samples will be collected for assessment of cilta-cel OOS PK,
MRD-negative rate, and predictive biomarkers of response or resistance to cilta-cel OOS.
Safety evaluations will be assessed by adverse events, laboratory test results, vital sign
measurements, physical examination findings, handwriting assessments, assessment of Immune-
Effector Cell-associated Encephalopathy (ICE) Tool scores, and assessment of Eastern
Cooperative Oncology Group (ECOG) performance status grade.
The safety profile will be evaluated at DRC meetings during the study. Follow-up of participants
will continue to include all SAEs and delayed AEs, disease progression, and survival during the
Post-treatment Phase. All study evaluations will be conducted according to the SoA, Table 1.
Following the cilta-cel OOS infusion, the participant will be followed for 2 years in this study to
assess response, DOR, PFS, OS, and safety. All the participants who received cilta-cel OOS will
continue to be monitored for long-term safety under a separate LTFU study 68284528MMY4002
for up to 15 years after last dose of cilta-cel OOS.
No formal enrollment target is planned for this study since the number of potential participants
with cilta-cel OOS is unknown at this time. Based on the current manufacturing experience with
the study 68284528MMY2001, at least 20 participants are anticipated to enroll in the study.
In the event the cilta-cel is OOS, the investigator will inform the study participant that the product
did not meet release specifications prior to administration. The investigator will discuss with the
participant the potential risks of receiving or not receiving the product as well as alternative
treatment options, which will be properly documented in the participant's study records and ICF
will be obtained. If required, approval/notification from the relevant health authorities for use of
the cilta-cel OOS will be obtained. The investigator should also inform or obtain approval from
the IEC/IRB as per institutional guidelines, as required.


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A DRC will be commissioned for this study.
Refer to Committees Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and Study
Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema.
Scientific Rationale for Study Design
Pre-specified release specifications are intended to ensure safe and efficacious use of the drug
product, a positive benefit/risk assessment may support the administration of cilta-cel that does
not meet the specifications set forth in the health authority approval.
The sponsor therefore intends to provide access to OOS drug product for participants whose final
manufactured cilta-cel does not meet the commercial release specifications through enrollment in
this study.
The study is planned as an open-label, single-arm multicenter Phase 2 study to evaluate the safety
and efficacy of cilta-cel OOS in adult participants (≥18 years) with multiple myeloma. It is planned
to enroll at least 20 participants. Participation is based on  the formal request from the treating
physician and a written notification of availability of cilta-cel OOS after sponsor’s assessment of
a positive benefit to risk. Participants will be consented for study eligibility after availability of
cilta-cel OOS. Safety criteria that must be met prior to starting of lymphodepleting chemotherapy
and infusion of cilta-cel OOS is presented in Section 6.1.2 and Section 6.1.4, respectively.
Rationale for Pharmacokinetics and Immunogenicity Assessments
Data obtained from the cilta-cel OOS treatment in this study will provide information about the
PK profile of cilta-cel OOS in participants with multiple myeloma. Therefore, samples will be
obtained from all participants for PK assessments. If needed for exploration purposes, data may
also be used for a population PK analysis to estimate additional PK parameters and provide
information about the determinants of inter-participant variability in this population.
Immunogenicity to cilta-cel OOS is possible. Therefore, the presence of anti-cilta-cel antibodies
will be determined from serum samples collected from all participants after the cilta-cel OOS
treatment.
Biomarker Collection
Biomarker samples will be collected to evaluate the mechanism of action of cilta-cel OOS or help
to explain interindividual variability in clinical outcomes or may help to identify population
subgroups that respond differently to an intervention. The goal of the biomarker analyses is to
evaluate the pharmacodynamics of cilta-cel OOS  and aid in evaluating the intervention-clinical
response relationship. Biomarker samples will be collected to evaluate the depth and durability of
clinical response through evaluation of MRD-negative rate, using DNA sequencing of
immunoglobulin genes.


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Biomarker samples may be used to help address emerging issues and to enable the development
of safer, more effective, and ultimately individualized therapies.
4.2.1. 
Study-Specific Ethical Design Considerations
The primary health risk to the study participant is an altered efficacy and/or safety profile of the
drug product due to OOS which could impact the biology and clinical characteristics of cilta-cel
and affect treatment outcomes. Per assessment of the principal investigator the clinical
circumstances of study participants may not allow for alternative therapeutic options for the
treatment of multiple myeloma, including re-apheresis, re-manufacturing cilta-cel, both with the
aim to receive a drug product meeting release specification. Therefore, there is a high unmet
medical need for making cilta-cel OOS available to patients without alternative treatment options
for relapsed/refractory multiple myeloma (RRMM).
Cilta-cel is an approved drug for the treatment of RRMM, as per locally approved label, albeit
with an OOS product. Access to the manufactured cilta-cel OOS, is dependent on a positive
benefit/risk assessment and exceptional release per sponsor’s medical review and principal
investigator’s judgment, as described below:
 
In the event a cilta-cel batch does not meet release specifications, an OOS investigation by the
sponsor will be initiated. The sponsor designated medical representative will contact the
treating physician to inform them of  the OOS product and to retrieve patient information
required for medical assessment, if the treating physician initiates further benefit/risk
assessment. This includes (but is not limited to) basic demographics, relevant medical history
including prior lines of treatment, current clinical status, and minimum clinical data required
to assess patient treatment eligibility for enrollment per USPI per locally approved label,
availability or patient access to alternative treatment options in the market or region.
 
Based on the manufacturing and clinical information received the sponsor will conduct and
document the benefit/risk assessment for each OOS drug product. The benefit/risk medical
evaluation includes assessment of the potential OOS impact on safety and efficacy,
participant’s alternative options, medical need, and assessment of potential immediate hazards
of not receiving the cilta-cel. If the treating physician also deems that the benefit/risk profile
is favorable, and decides to request the OOS product, then the treating physician as principal
investigator for the study will initiate eligibility screening procedures and formally request the
shipment of the cilta-cel OOS for administration within the study by completing and signing
off Exceptional Release of OOS Product Request Form.
 
Exceptional release of cilta-cel OOS that has not met pre-determined release specifications is
understood to be used under exceptional circumstances and only when deemed safe and
appropriate for the participant. For cilta-cel OOS where the sponsor and the treating physician
believe the potential benefits outweigh the potential risks for the participant, the sponsor will
follow local regulations for exceptional release of the cilta-cel OOS batch.


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Potential study participants will be fully informed of the risks and requirements of the study and,
during the study, participants will be given any new information that may affect their decision to
continue participation. They will be told that their consent to participate in the study is voluntary
and may be withdrawn at any time with no reason given and without penalty or loss of benefits to
which they would otherwise be entitled. Only participants who are fully able to understand the
risks, benefits, and potential AEs of the study, and provide their consent voluntarily will be
enrolled. The total blood volume to be collected is considered to be an acceptable amount of blood
to be collected over this time period from the population in this study based upon the standard of
the American Red Cross (Section 8).
Justification for Dose
As per the USPI, the recommended dose range is 0.5‑1.0×106 CAR-positive viable T cells per kg
of body weight, with a maximum dose of 1×108 CAR-positive viable T cells per single infusion.
Based on clinical trials, it is possible that doses below the specified dose ranges per label could
also be efficacious (see also Section 2.3.3). A viable CAR-positive T cell count outside the drug
product specifications may be a cause for OOS drug product for a particular participant and will
be accepted for dosing within this protocol if the respective participant´s benefit-risk assessment
is positive.
End of Study Definition
End of Study Definition
The end of study is defined as 2 years after the last participant has received his or her initial dose
of cilta-cel OOS per Schedule of Activities (SoA). A participant is being followed for 2 years to
assess response, DOR, PFS, OS, and safety. The final data from the study site will be sent to the
sponsor (or designee) after completion of the final participant assessment at that study site, in the
time frame specified in the Clinical Trial Agreement.
Participant Study Completion Definition
A participant will be considered to have completed the study if they have completed follow-up
period of 2 years to assess response, DOR, PFS, OS, and safety after his or her initial dose of cilta-
cel OOS or discontinue prematurely due to death, or has experienced a clinical endpoint that
precludes further continuation in the study.
Participants who prematurely discontinue study treatment for any reason other than those
mentioned above before completion of the study will not be considered to have completed the
study.
5. 
STUDY POPULATION
Screening for eligible participants will be performed based on formal request from the treating
physician and a written notification from the sponsor for availability of cilta-cel OOS. Refer to
Section 5.4, Screen Failures for conditions under which the repeat of any screening procedures is
allowed.


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The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
>18 years of age.
Type of Participant and Disease Characteristic
2. 
Eligible for treatment with cilta-cel per USPI or locally approved label.
3. 
Participant is suffering from serious or life-threatening multiple myeloma per USPI (or
locally approved label, respectively), and re-apheresis, re‑manufacturing, or other anti-
myeloma directed therapies is not considered feasible or adequate per investigator.
4. 
A favorable participant benefit/risk assessment is concluded following the sponsor’s
medical review.
5. 
Has adequate general health status and organ function per investigator assessment and
meets the criteria to receive cilta-cel OOS (see Section 6.1.4).
6 
Meets the criteria to receive lymphodepleting chemotherapy (see Section 6.1.2).
Sex and Contraceptive/Barrier Requirements
7. 
A woman of childbearing potential must have a negative highly sensitive serum (-human
chorionic gonadotropin [-hCG]) pregnancy test during screening and prior to the first
dose of cyclophosphamide and fludarabine.
8. 
A woman using oral contraceptives must use an additional contraceptive method
(Examples of highly effective methods of contraception are located in Section 10.5,
Appendix 5, Contraceptive Guidance).
9. 
A woman must be (as defined in Section 10.5, Appendix 5, Contraceptive Guidance)
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective method of contraception (failure rate of <1% per
year when used consistently and correctly) and agrees to remain on a highly
effective method while receiving study treatment and until 1 year after receiving
a last dose of cilta-cel OOS infusion. The investigator should evaluate the


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potential for contraceptive method failure (eg, noncompliance, recently
initiated) in relationship to the first dose of study treatment. Examples of highly
effective methods of contraception are located in Section 10.5, Appendix  5.
Contraceptive Guidance.
10. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for 1 year after the last dose of study treatment.
(cilta-cel OOS).
11. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum 1 year after receiving the last dose of study treatment
(cilta-cel OOS).
12. 
Male participants must agree to the following during the intervention period and for at
least 1 year after the last dose of study treatment:
 Who is sexually active with a woman of childbearing potential must agree to use a
barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal
foam/gel/film/cream/suppository) from the time of signing the ICF until 1 year after
the last dose of study treatment (cyclophosphamide, fludarabine [standard-of-care] or
cilta-cel OOS, respectively)
 Who is sexually active with a woman who is pregnant must use a condom
Informed Consent
13. 
Must sign an ICF indicating that he or she understands the purpose of, and procedures
required for, the study and is willing to participate in the study.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Medical Conditions
1. 
History of active uncontrolled infection or condition where an administration of cilta-
cel OOS constitutes serious health risk to the participant.
2 
Known allergies, hypersensitivity, or intolerance to the excipients of cilta-cel OOS
including dimethyl sulfoxide (DMSO), dextran 40, or residual kanamycin per USPI
(or local approved label).
3. 
Criterion modified per Amendment 1
3.1. 
Any conditions (listed below), for which, in the opinion of the investigator,
participation would not be in the best interest of the participant (eg, compromise the


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well-being) or that could prevent, limit, or confound the protocol-specified
assessments.
Medical conditions include:
 
Uncontrolled autoimmune disease. Stable disease, controlled with or without
pharmacologic treatment for at least 6 months prior to dosing could be considered.
 
Overt clinical evidence of dementia or altered mental status
 
Any history of Parkinson’s disease or other neurodegenerative disorder
 
Known active, or prior history of central nervous system (CNS) involvement or
exhibits clinical signs of meningeal involvement of multiple myeloma
 
Stroke within 6-months of cilta-cel dosing
4. 
Hepatitis B infection as defined according to Section 10.14, Appendix 14. In the event
the infection status is unclear, quantitative levels are necessary to determine the
infection status at Screening Phase (Hwang 2015).
5. 
Hepatitis C infection defined as (anti-HCV antibody positive or detectable
HCV-RNA) or known to have a history of hepatitis C.
NOTE: For participants with positive hepatitis C antibody due to prior resolved
disease can be enrolled, only if a confirmatory HCV RNA test is undetectable. For
participants with known history of HCV infection, confirmation of sustained virologic
response is required for study eligibility, defined as undetectable HCV-RNA ≥24
weeks after completion of antiviral therapy.
6. 
Seropositive for HIV.
NOTE: Investigators should ensure that all study enrollment criteria have been met after
screening. If a participant's clinical status changes (including any available laboratory results or
receipt of additional medical records) after screening but before the first dose of study treatment
is given such that he or she no longer meets all eligibility criteria, then the participant should be
excluded from participation in the study. The required source documentation to support meeting
the enrollment criteria are noted in  Section 10.3, Appendix 3, Regulatory, Ethical, and Study
Oversight Considerations.
Lifestyle Considerations
Sex and contraceptive/barrier requirements are necessary for the duration of 1 year after the last
dose of study treatment (see Sections 5.1, 8.2.9, and 8.3.5).


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Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not enrolled into
the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the eligibility criteria for participation in this study may be
re-screened and re-consented if deemed of potential benefit to the patient by the treating physician
and upon the sponsor’s written approval. Rescreened participants must be assigned new participant
numbers.
Criteria for Temporarily Delaying Administration of Study Intervention
The criteria for temporary delay in administration of study treatment is based on participant’s
medical condition and the criteria described in Sections 6.1.2 and 6.1.4.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
Study Intervention Administered
For this study, study treatment refers to cilta-cel OOS, cyclophosphamide and fludarabine.
Cyclophosphamide and fludarabine should be prescribedby the treating physician as per the USPI.
Study treatment administration must be captured in the source documents and the case report form
(CRF). All dosing information must be recorded in the Dosage Administration page of the
electronic CRF (eCRF).
Cilta-cel OOS will be provided under the responsibility of the sponsor.
6.1.1. 
Pre-infusion Supportive Therapy
Participants should receive premedication before cilta-cel OOS infusion as noted below (Table 4).
Avoid use of prophylactic systemic corticosteroids as it may interfere with the activity cilta-cel
OOS.


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Table 4: 
Pre-infusion Medications
Medication 
Dose 
Administration
Antihistamine diphenhydramine (50 mg) or 
equivalent 
Oral - administer 1 hour (±15 minutes) prior to cilta-cel
OOS infusion
Or
IV- start infusion 30 minutes (±15 minutes) prior to
cilta-cel OOS infusion
Antipyretics 
acetaminophen (650 mg to 1,000 mg) 
or equivalent 
Oral or IV - administer 30 minutes (±15 minutes) prior
to cilta-cel OOS infusion
Abbreviations: IV=intravenous; OOS=out-of-specifications.
6.1.2. 
Criteria for Lymphodepleting Chemotherapy (Cyclophosphamide and
Fludarabine) Administration
Participants must meet the following criteria (also refer to Section  5.1) to proceed with
cyclophosphamide and fludarabine dosing:
 
Negative pregnancy test for women of childbearing potential up to 72 hours prior to the first
dose of the lymphodepleting chemotherapy.
 
No signs of active infection. For participants requiring systemic anti-microbial treatment or
with temperature ≥38.0°C  within 7 days prior to the first dose of lymphodepleting
chemotherapy, the investigator must receive approval to proceed from the sponsor.
6.1.3. 
Lymphodepleting Chemotherapy (Cyclophosphamide and
Fludarabine) Administration
At the completion of manufacture and quality testing of cilta-cel, written notification will be sent
to the clinical site. Prior to dosing with cyclophosphamide and fludarabine, review of eligibility,
safety assessments and disease characteristics should be completed per Section 6.1.2. The details
regarding safety monitoring and study visits during this phase are included in the SoA (Table 1).
Administer a lymphodepleting regimen of cyclophosphamide 300 mg/m2 intravenously daily and
fludarabine 30 mg/m2 intravenously daily for 3 days. The dose of fludarabine should be reduced
to 24 mg/m2 for participants with an estimated glomerular filtration rate of 30 to
70 mL/min/1.73 m2. For other dose modifications, see corresponding manufacturer’s prescribing
information for additional guidance to account for renal insufficiency and other conditions
appropriately. Administer cilta-cel OOS IV infusion 5 to 7 days after the start of the
lymphodepleting regimen (the first day of conditioning is Day -7 to Day -5, and the day of cilta-
cel infusion is Day 1). Cyclophosphamide and fludarabine should be administered using
administration procedures and supportive care according to the site’s standard of care, if clinically
indicated. Cilta-cel OOS should be administered as described in the USPI or locally approved
label.
If toxicities due to the lymphodepleting regimen results in delays to cilta-cel OOS dosing for more
than 14 days, the lymphodepleting regimen should be re-administered after a minimum of 21 days
following the first dose of the first lymphodepleting regimen.


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6.1.4. 
Clinical Assessment Prior to cilta-cel OOS Infusion
Participants will be evaluated for safety on the day of cilta-cel OOS infusion prior to dosing. If a
significant health status change (eg, clinical deterioration, rapidly progressing disease) occurs
following the start of the lymphodepleting chemotherapy  (see Section  6.1.2), the investigator
should contact the sponsor prior to dosing.
Infusion of cilta-cel OOS should be delayed if any of the following events occur:
 
Signs of active infection  or inflammatory disorders. Do not administer cilta-cel OOS to
participants with active infection. For participants requiring systemic anti-microbial
treatment, or with temperature ≥38.0°C within 48 hours before cilta-cel OOS infusion,
investigator must consult with the sponsor prior to dosing.
 
Grade 3 non-hematologic toxicities of cyclophosphamide and fludarabine conditioning
(except for Grade 3 nausea, vomiting, diarrhea, or constipation). Investigator must consult
with the sponsor prior to cilta-cel OOS dosing and cilta-cel OOS infusion should be delayed
until resolution of these events to Grade ≤1.
If resolution of these events to Grade ≤1 takes more than 14 days, the lymphodepleting
chemotherapy  should be re-administered (cyclophosphamide 300 mg/m2 and fludarabine 30
mg/m2 daily for 3 days) after a minimum of 21 days following the first dose of the first
lymphodepleting chemotherapy (cyclophosphamide and fludarabine).
6.1.5. 
Cilta-cel OOS Administration
Cilta-cel OOS will be administered as summarized in Table 5.
Table 5: 
Description of Cilta-cel OOS
Intervention Name 
Cilta-cel OOS
Type 
Cell suspension of CAR positive viable T cells
Dose Formulation 
The cilta-cel OOS cryopreserved drug product will be placed in a vapor
shipping container along with a data logger and shipped to the site for treatment
according to the clinical protocol. Preparation for administration and product
infusion will be performed according to the clinical protocol and Prescribing
Information.
Dosage Level 
Formulated to a target dose of 0.75×106 CAR positive viable T cells/kg
participant weight (dose range 0.5×106 CAR-positive viable T cells/kg to
1.0×106 CAR-positive viable T cells/kg).
Note: out of range dose may be the reason for the OOS. In which case, the
formulated dose will be the dose to be administered.
Dosage Frequency  
The actual dose for study treatment administration will be based on the
subject’s weight (kg) at apheresis. Single IV infusion on Day 1.
Route/Regimen of 
Administration 
Cilta-cel OOS IV infusion is to be administered under the supervision of site
staff. Refer to the USPI (or locally approved label, respectively) for cilta-cel
infusion instructions.
Hospitalization 
Requirements 
The site of CAR-T infusion is determined per institutional guidance/practices.
However, patients should be instructed to remain within proximity of a certified
healthcare facility for at least four weeks following infusion.


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Table 5: 
Description of Cilta-cel OOS
Intervention Name 
Cilta-cel OOS
Following infusion, monitor patients at least daily for 10 days following cilta-
cel OOS infusion (whether the participant will be dosed outpatient or inpatient
according to institutional guidelines) at a certified healthcare facility for signs or
symptoms of cytokine release syndrome and neurologic toxicities as per USPI.
Monitor periodically for 4 weeks for signs and symptoms of delayed neurologic
toxicity.
Participants are asked to remain within close proximity of a certified healthcare
facility for at least 4 weeks following infusion.
Vital signs and Clinical
Safety Monitoring
Monitor vital signs as indicated in the Section 1.3 SoA (Table 1). 
Use 
Experimental
Investigational Medicinal 
Product (IMP)
Yes
Non-Investigational 
Medicinal Product/Auxiliary
Medicinal Product
(NIMP/AxMP)
No
Sourcing 
Provided centrally by the sponsor
Packaging and Labeling 
Cilta-cel OOS IV infusion is to be administered to individual participants under
the supervision of site staff.
Current/Former Name(s) or 
Alias(es)
ciltacabtagene autoleucel
6.1.6. 
Management Guidelines for Potential Risks
6.1.6.1. 
Management of Cytokine Release Syndrome
At the clinical data cutoff, 1 September 2020, CRS was reported for 92 of 97 participants (94.8%)
who received cilta-cel in the study 68284528MMY2001. Most participants (87 [89.7%]
participants) experienced CRS AEs that were Grade 1 or 2, 3 (3.1%) participants experienced
Grade 3 CRS, 1 participant experienced Grade 4 CRS, and 1 participant experienced Grade 5 CRS
(see Section 2.2.6).
Symptoms indicative of CRS may include, but are not limited to, fever (with or without rigors),
arthralgia, nausea, vomiting, tachypnea, hypoxia, tachycardia, hypotension, headache, confusion,
tremor, delirium, dyspnea, pulmonary edema, and capillary leak (Lee 2019). Potentially life-
threatening complications of CRS may include cardiac dysfunction, adult respiratory distress
syndrome, neurologic toxicity, renal failure, hepatic failure, and disseminated intravascular
coagulation.
Laboratory testing to monitor for disseminated intravascular coagulation, a manifestation of CRS,
should be carried out in addition to daily monitoring of chemistry and hematology assessments
(including ferritin and C-reactive protein [CRP]) when fever or other signs of potential CRS are
present (see Table 1). In addition, pulmonary, renal and hepatic function will be monitored closely
(see Table 1). Cytokine release syndrome will be captured as an AESI (see Section 8.3.1).


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Rarely, severe CRS can evolve into a presentation consistent with HLH/macrophage activation
syndrome (MAS) that may require additional therapy. In these cases, laboratory testing may reveal
high serum levels of ferritin, lactate dehydrogenase, soluble CD25, and cytokines (such as IFNγ
and IL-6), and low serum levels of fibrinogen (Neelapu 2018). Severe thrombocytopenia, low
fibrinogen, and often DIC may be features of HLH, all of which combined may increase the risk
of severe bleeding in these subjects. If HLH is suspected, anticoagulation should be avoided or
modified based on institutional guidelines depending on platelet count and renal function. Subjects
with HLH should have their platelet count and coagulation parameters very closely monitored and
maximal support should be provided to avoid major bleeding complications. For example, consider
platelet transfusion if platelets are less than 50 × 109/L. Under these circumstances, investigators
should consider treating the subject in the ICU, so that maximal monitoring and support can be
carried out during this period.
Trained clinical personnel should be prepared to intervene in the event of CRS. Resources
necessary for resuscitation (ie, agents such as epinephrine and aerosolized bronchodilator; medical
equipment such as oxygen, tracheostomy equipment, and a defibrillator) should be readily
available. Tocilizumab must be available prior to administration ofcilta-cel OOS. Vital signs and
laboratory parameters must be monitored at regular intervals until normal. Additional specimens
for pharmacokinetic and pharmacodynamic testing should be collected as per the schedule outlined
in SoA (Section 1.3).
Infection and CRS may have a similar presentation. Therefore, investigators are strongly
encouraged to evaluate for an infection at the first signs or symptoms of CRS. Cultures and
imaging should be obtained: the clinical signs and symptoms should determine which tests are
appropriate.
Recommendations for the clinical management of CRS are provided in Table 6. At the first sign
of CRS (such as fever) participants should be immediately hospitalized for evaluation. The use of
myeloid growth factors, particularly granulocyte colony-stimulating factor (G-CSF), should be
avoided during CRS. Tocilizumab intervention may be considered with presenting symptom of
fever per investigator discretion when other sources of fever have been eliminated and early
tocilizumab should be considered in participants at high risk of severe CRS (for example, high
baseline tumor burden, early fever onset, or persistent fever after 24 hours of symptomatic
treatment). Other cytokine-targeting therapies (for example, IL1, TNF) may be used based on
institutional practice, especially for cases of CRS which does not respond to tocilizumab or
corticosteroids.


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Table 6: 
CRS Grading and Management Guidance
CRS Gradea 
Tocilizumabb
Corticosteroidsf
Grade 1
Temperature ≥38°Cc 
In patients with:
 Early onset of fever (if onset less
than 72 hours after infusion)
Tocilizumab 8 mg/kg intravenously
(IV) over 1 hour (not to exceed 800 mg)
may be considered
N/A
Grade 2
Symptoms require and respond to
moderate intervention.
Temperature ≥38°Cc with:
Hypotension not requiring
vasopressors,
and/or,
Hypoxia requiring oxygen via canulae
or blow-by,
or,
Grade 2 organ toxicity.g
Administer tocilizumab 8 mg/kg IV
over 1 hour (not to exceed 800 mg). 
Repeat tocilizumab every 8 hours as
needed if not responsive to intravenous
fluids up to 1 liter or increasing
supplemental oxygen.
Consider dexamethasone 10 mg IV
every 12-24 hours.
If no improvement within 24 hours or rapid progression, repeat tocilizumab and
escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).
If no improvement within 24 hours or continued rapid progression, switch to
methylprednisolone 2 mg/kg IV every 12 hours.
After 2 doses of tocilizumab, consider alternative anti-cytokine agents.d
Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.
Grade 3
Symptoms require and respond to
aggressive intervention.
Temperature ≥38°Cc with:
Hypotension requiring one vasopressor
with or without vasopressin,
and/or,
Hypoxia requiring oxygen via high-
flow nasal canulae, facemask, non-
rebreather mask, or Venturi mask,
or,
Grade 3 organ toxicity or Grade 4
transaminitis.
Per Grade 2 
Administer dexamethasone 10 mg IV
every 12 hours.
If no improvement within 24 hours or rapid progression, repeat tocilizumab and
escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).
If no improvement within 24 hours or continued rapid progression, switch to
methylprednisolone 2 mg/kg IV every 12 hours.
After 2 doses of tocilizumab, consider alternative anti-cytokine agents.d
Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.


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CRS Gradea 
Tocilizumabb 
Corticosteroidsf
Grade 4
Life-threatening symptoms. 
Requirements for ventilator support, 
continuous veno-venous hemodialysis 
(CVVHD). 
Temperature ≥38°Cc with: 
Hypotension requiring multiple 
vasopressors (excluding vasopressin),
and/or,
Hypoxia requiring positive pressure
(e.g., CPAP, BiPAP, intubation, and
mechanical ventilation),
or,
Grade 4 organ toxicity (excluding
transaminitis).
Per Grade 2 
Administer dexamethasone 20 mg IV
every 6 hours.
After 2 doses of tocilizumab, consider alternative anti-cytokine agentsd. Do not
exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.
If no improvement within 24 hours, consider methylprednisolone (1-2 g IV, repeat
every 24 hours if needed; taper as clinically indicated) or other
immunosuppressants (e.g. other anti-T cell therapies).
Abbreviations: BiPAP bilevel positive airway pressure; CPAP continuous positive airway pressure, CRS cytokine release syndrome, NA  Not Applicable.
a 
Based on ASTCT 2019 grading system (Lee et.al, 2019), modified to include organ toxicity.
b 
Refer to tocilizumab prescribing information for details.
c 
Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia, as it may be masked by
interventions such as antipyretics or anti-cytokine therapy (eg, tocilizumab or steroids). Absence of fever does not impact
CRS management decision. In this case, CRS management is driven by hypotension and/or hypoxia and by the more
severe symptom not attributable to any other cause.
d 
Monoclonal antibodies targeting cytokines may be considered based on institutional practice for unresponsive CRS.
e 
Low-flow nasal cannula is ≤6 L/min; high-flow nasal cannula is >6 L/min.
f 
Continue corticosteroids use until the event is Grade 1 or less; taper steroids if total corticosteroid exposure is greater than
3 days.
g 
Organ toxicity grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE) version 5.0.
Supportive care for CRS (including but not limited to anti-pyretic agents, IV fluid support,
vasopressors, supplemental oxygen) should be administered according to the clinical
manifestations of the participant’s illness. Similarly, ancillary testing such as B-type natriuretic
peptide (BNP) assessment, echocardiograms, arterial blood gas, assessments of coagulation
laboratory tests, should be performed if clinically indicated.
6.1.6.2. 
Neurologic Toxicities
Based on the specific mode-of-action of cilta-cel, severe or serious neurological toxicities
(including CAR-T cell-related neurotoxicity, eg, ICANS) may occur (Section 6.1.6.2.1).
Participants should be monitored for neurotoxicity for the duration of study (Section 6.1.6.2.2).
6.1.6.2.1. 
CAR-T Cell-related Neurotoxicity (Immune Effector Cell-Associated
Neurotoxicity Syndrome [ICANS])
Participants should have the ICE Assessment Tool (ICE-Tool; Section 10.9, Appendix 9)
performed at baseline (within 24 hours prior to infusion of cilta-cel infusion) and daily after the
first symptoms of CAR-T cell-related neurotoxicity (eg, ICANS) are suspected and until
resolution. Consider performing ICE-Tool more frequently until neurotoxicity symptoms resolve.
Consider performing neuroimaging (eg, magnetic resonance imaging [MRI]) at Screening Phase
and/or neurology consultation if pre-existing disease is suspected; see Section 8.2.


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Early recognition of neurologic adverse events is critical to management. Symptoms indicative of
ICANS may include, but are not limited to, speech disorders, aphasia, convulsions, disturbances
in consciousness, confusion, disorientation, or coordination and balance disorders. Participants
should be monitored for neurologic toxicities and advised to seek medical evaluation if they notice
new onset of symptoms. If these or other neurological toxicities are observed, regardless of
causality, then the sponsor’s medical monitor must be consulted.
At the first sign of neurotoxicity, neurology consultation and evaluation should be considered for
all neurological toxicities. Rule out alternative etiologies including infectious etiologies (eg, viral
origin such as, human herpesvirus [HHV] HHV-6, HHV-7) if clinically indicated. Participants
who have a lumbar puncture as part of their neurologic work up should have a sample of
cerebrospinal fluid (CSF) for additional testing (eg, biomarkers) as clinically indicated. For signs
of seizures or raised intracranial pressure (ICP)/cerebral edema, consider neuroimaging (CT/MRI),
transfer the participant to the intensive care unit (ICU) and treat according to institutional
guidelines or practices.
General management for CAR-T  cell-related neurotoxicity (eg, ICANS) with or without
concurrent CRS is summarized in  Table 7. All neurological adverse events, including CAR-T
related neurotoxicity (eg, ICANS), will be captured as an AESI (see Section 8.3.1).
Table 7: 
Guidelines for the Management of CAR-T Cell-related Neurotoxicity (eg, ICANS)
ICANS Grade 
Presenting Symptomsa
Concurrent CRS  
No Concurrent CRS
Grade 1 
ICE score 7-9b
or depressed level of
consciousnessc:
awakens spontaneously.
Management of CRS as 
appropriate per Table 6. 
Monitoring of neurologic 
symptoms and consider 
neurology consultation and
evaluation, per investigator 
discretion.
Monitor neurologic symptoms
and consider neurology
consultation and evaluation, per
investigator discretion.
Consider dexamethasone.
Consider non-sedating, anti-seizure medicines (eg, levetiracetam)
for seizure prophylaxis.
Grade 2 
ICE score-3-6b
or depressed level of
consciousnessc:
awakens to voice.
Administer tocilizumab per 
Table 6 for management of 
CRS.
If no improvement after starting 
tocilizumab, administer 
dexamethasoned 10 mg
intravenously every 6 hours if
not already taking other
corticosteroids. Continue
dexamethasone use until the
event is Grade 1 or less, then
taper.
Administer dexamethasoned 10
mg intravenously every 6 hours.
Continue dexamethasone use
until the event is Grade 1 or
less, then taper.
Consider non-sedating, anti-seizure medicines (eg, levetiracetam)
for seizure prophylaxis. Consider neurology consultation and other
specialists (ie, intensivists) for further evaluation, as needed.
Grade 3 
ICE score-0-2b
or depressed level of
consciousnessc:
Administer tocilizumab per 
Table 6 for management of 
CRS. 
Administer dexamethasoned
10 mg intravenously every 6
hours.


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awakens only to tactile
stimulus,
or seizuresc, either:
• any clinical seizure,
focal or generalized,
that resolves rapidly,
or
• non-convulsive
seizures on EEG that
resolve with
intervention,
or raised ICP:
focal/local edema on
neuroimagingc.
In addition, administer 
dexamethasoned 10 mg 
intravenously with the first dose 
of tocilizumab and repeat dose
every 6 hours. Continue
dexamethasone use until the
event is Grade 1 or less, then
taper.
Continue dexamethasone use
until the event is Grade 1 or
less, then taper.
Consider non-sedating, anti-seizure medicines (eg, levetiracetam)
for seizure prophylaxis.  Consider neurology consultation and other
specialists (ie, intensivists) for further evaluation, as needed.
Grade 4 
ICE score-0b
or depressed level of
consciousnessc either:
• participant is
unarousable or
requires vigorous or
repetitive tactile
stimuli to arouse, or
• stupor or coma,
or seizuresc, either:
• life-threatening
prolonged seizure (>5
min), or
• repetitive clinical or
electrical seizures
without return to
baseline in between,
or motor findingsc:
• deep focal motor
weakness such as
hemiparesis or
paraparesis,
or raised ICP / cerebral
edemac, with
signs/symptoms such
as:
• diffuse cerebral
edema on
neuroimaging, or
• decerebrate or
decorticate posturing,
or
• cranial nerve VI
palsy, or
• papilledema, or
• Cushing's triad.
Administer tocilizumab per 
Table 6 for management of 
CRS. 
As above, or consider 
administration of 
methylprednisolone 1,000 mg
intravenously per day with first
dose of tocilizumab and
continue methylprednisolone
1,000 mg intravenously per day
for 2 or more days, per
investigator discretion.
As above, or consider
administration of
methylprednisolone 1000 mg
intravenously per day for 3
days; if improves, then manage
as above.
Consider non-sedating, anti-seizure medicines (eg, levetiracetam)
for seizure prophylaxis.
Consider neurology consultation and other specialists (ie,
intensivists) for further evaluation, as needed.
In case of raised ICP/cerebral edema, refer to Table 8 for additional
management guidelines.
Abbreviations: ICANS=Immune Effector Cell-associated Neurotoxicity Syndrome, ICE=Immune Effector Cell-associated
Encephalopathy; ICP=intracranial pressure; CRS=cytokine release syndrome; EEG=electroencephalogram


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a Management is determined by the most severe event, not attributable to any other cause.
b If participant is arousable and able to perform Mental Status assessment, the following domains should be tested:
orientation, naming, following commands, writing, and attention (see Section 10.9, Appendix 9; ICE-Tool).
c Attributable to no other cause.
d All references to dexamethasone administration are dexamethasone or equivalent.
Table 8: 
Guidelines for the Management of Raised ICP/Cerebral Edemaa
 Elevate head of participant's bed to an angle of 30 degrees.
 If participant has ommaya reservoir, drain CSF to target opening pressure of <20 mmHg.
 Hyperventilation to achieve target partial pressure of arterial carbon dioxide (PaCO2) of 28–30 mmHg but
maintained for no longer than 24 hours.
 Consider neurology and/or neurosurgery consultation.
 Use high-dose corticosteroids with methylprednisolone IV 1 g/day, as recommended above.
 Hyperosmolar therapy with either mannitol (20 g/dL solution) or hypertonic saline (3% or 23.4%, as
detailed below):
o 
Mannitol: initial dose 0.5–1 g/kg; maintenance at 0.25–1 g/kg every 6 hours while monitoring
metabolic profile and serum osmolality every 6 hours, and withhold mannitol if serum
osmolality is ≥320 mOsm/kg, or the osmolality gap is ≥40,
o 
Hypertonic saline: initial 250 mL of 3% hypertonic saline; maintenance at 50–75 mL/hour
while monitoring electrolytes every 4 hours, and withhold infusion if serum Na levels reach
≥155 mEq/L,
o 
For participants with imminent herniation: initial 30 mL of 23.4% hypertonic saline; repeat
after 15 min, if needed.
 Consider IV anesthetics for burst-suppression pattern on electroencephalography.
a In addition to toxicity management guidelines provided in Table 7: Guidelines for the Management of CAR-T
Cell-Related Neurotoxicity (ie, ICANS)
Abbreviations: CAR-T=chimeric antigen receptor-T; CSF=cerebrospinal fluid; ICANS=Immune-Effector Cell-associated
Neurotoxicity Syndrome; ICP=intracranial pressure; IV=intravenous.
6.1.6.2.2. 
Other Neurotoxicities
Neurologic toxicity with several signs and symptoms of Parkinsonism  (ie, movement and
neurocognitive toxicity) distinct from ICANS  have been reported in trials with cilta-cel. The
median onset of Parkinsonism was 27 days (range: 14 to 108 days) from infusion of ciltacabtagene
autoleucel. The median duration of Parkinsonism symptoms was 234 days (range: 62 to 482) days)
including those subjects who died from MNT or had ongoing MNT at the time of death due to
other cause, or with ongoing parkinsonism.
 
Symptoms to watch for include:
 
movement impairments (eg, micrographia or changes in handwriting, tremors,
bradykinesia, rigidity, shuffling gait, impaired balance and coordination, difficulty
writing, difficulty performing activities of daily living like dressing or feeding oneself),
 
cognitive impairments (eg, memory loss or forgetfulness, disturbances in attention,
mental slowness or fogginess, difficulty speaking or slurred speech, difficulty reading or
understanding words),
 
personality change (eg, reduced facial expression, flat affect, reduced ability to express
emotions, less communicative, disinterest in activities)
 
Guillain-Barre Syndrome (GBS): Symptoms of GBS have been reported in other
CARTITUDE studies and  include those consistent with Miller-Fisher variant of GBS,


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encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis. Monitor for
signs and symptoms of GBS after cilta-cel infusion. Consider treatment with IVIG and
escalate to plasmapheresis, depending on toxicity severity.
 
Peripheral neuropathy: Occurrence of peripheral neuropathy, including sensory, motor, or
sensorimotor, have been reported in trials of cilta-cel. Median time of onset of symptoms was
62 days (range: 4 to 136 days), median duration of peripheral neuropathies was 256 days
(range: 2 to 465 days) including those with ongoing neuropathy. Monitor patients for signs
and symptoms of peripheral neuropathies. Consider management with short-course systemic
corticosteroids, depending on the severity and progression of signs and symptoms.
 
Cranial nerve palsies: Occurrence of 7th, 3rd, 5th, and 6th cranial nerve palsy, some of which
were bilateral, worsening of cranial nerve palsy after improvement, and occurrence of
peripheral neuropathy in patients with cranial nerve palsy have been reported in trials of cilta-
cel. Median time of onset of symptoms was 26 days (range:21 to 101 days) following infusion
of cilta-cel. Median time to resolution was 70 days (range: 1 to 79 days) following onset of
symptoms.
Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with
short-course systemic corticosteroids, depending on the severity and progression of signs and
symptoms.
Of note, the delayed onset of parkinsonism was observed at a higher frequency in participants with
high burden of disease and in participants experiencing higher grade CRS (Grade 2 and above)
and any grade ICANS. This may be indicative that ≥Grade 2 CRS or any grade ICANS are early
indicators for the development of other neurotoxicity after a period of recovery from CRS and/or
ICANS. Therefore, ≥Grade 2 CRS or any grade ICANS may represent an opportunity for early
intervention and more aggressive supportive care (including steroids), especially in patients treated
with a high tumor burden, that may mitigate the risk for developing late, other neurotoxicity.
Infection and sepsis were seen concurrently in many of these patients.
Additional monitoring and mitigation strategies include enhanced bridging therapy to reduce
baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments
for early detection of neurotoxicity symptoms, and extended monitoring and reporting time for
neurotoxicity for the duration of study.
Early detection, workup and intervention, may be important to prevent neurologic toxicity from
worsening. The following is a list of potential diagnostics that should be considered in participants
with new neurologic symptoms:
 
Positron emission tomography/computed tomography (PET/CT) of the brain and/or brain
MRI with perfusion and an electroencephalogram (EEG).
 
Lumbar puncture to rule out infection (in particular John Cunningham virus [JCV], herpes
zoster virus [HZV], herpes simplex virus [HSV]-1/2, HHV-6, HHV-7, Epstein-Barr virus
[EBV], cytomegalovirus [CMV]).
 
Serologic testing for HHV-6 and HHV-7 by polymerase chain reaction (PCR) for viremia.
 
Cerebrospinal fluid flow cytometry and cytology should be considered to rule out
leptomeningeal disease.


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 
Cerebrospinal fluid analysis to rule out paraneoplastic syndromes.
 
Thiamine level (consider empiric thiamine replacement while awaiting results)
(MD Anderson 2019)
Other cytokine-targeting therapies (for example, IL1) may be used based on institutional practice,
especially for cases of neurotoxicity which does not respond to tocilizumab or corticosteroids.
Therapy directed at reduction or elimination of CAR-T cells, including chemotherapy, may be
considered in consultation with the sponsor for participants who develop neurotoxicity that
remains unresponsive to other interventions.
Per Section 8.5 of the protocol, if CSF or other relevant biological sample analysis is clinically
indicated, a sample of CSF will be requested for additional analysis by the sponsor.
6.1.6.3. 
Tumor Lysis Syndrome
Although TLS is uncommon in participants with multiple myeloma, it has been reported after cilta-
cel infusion. Participants should be monitored closely for symptoms of TLS. Management of TLS,
including hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia, is highly
recommended. It is also required that high-risk participants, ie, those with a high tumor burden
(60% plasma cell infiltrate on the bone marrow biopsy or aspirate [whichever is higher] or a
participant with multiple extramedullary disease sites or plasmacytomas), be treated
prophylactically in accordance with local standards (eg, extra hydration; diuretics; allopurinol
300 mg daily and primary or secondary uricosuric agents, as indicated).
6.1.6.4. 
Prolonged or Recurrent Cytopenia
Participants may exhibit cytopenias for several weeks following lymphodepleting chemotherapy
and cilta-cel infusion.
In study CARTITUDE-1 (N=97), 30% (29/97) of patients experienced prolonged Grade 3 or 4
thrombocytopenia that had not resolved by Day 30 following cilta-cel infusion. In 31% (29/95) of
patients who recovered from Grade 3 or 4 neutropenia after 1 month, the median time to recovery
from cilta-cel infusion was 1.8 mnths (range: 1.0-3.7 mos). In 52%  (32/61) of patients who
recovered from Grade 3 or 4 thrombocytopenia after one month, the median time to recovery from
cilta-cel infusion was 1.9 months (range: 1.1 to 8.5 months). One patient underwent autologous
stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.
Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were seen in
63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4
cytopenia following cilta-cel infusion. After Day 60 following cilta-cel, 31%, 12%, and 6% of
patients 
had 
a 
recurrence 
of 
Grade 
3 
or 
higher 
lymphopenia,
neutropenia, and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4
cytopenia [see Adverse Reactions (6.1) of USPI]. Eighty-seven percent (84/97) of patients had
one, 
two 
or
three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4


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cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia respectively at
the time of death.
Parvovirus B19 monitoring by PCR should be considered in participants experiencing prolonged
neutropenia or a decline in neutrophil counts following recovery.
6.1.6.5. 
Hypogammaglobulinemia
Hypogammaglobulinemia can occur in patients receiving treatment with cilta-cel.
Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory
IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients treated with cilta-cel.
Hypogammaglobulinemia either as an adverse reaction or a laboratory
IgG level below 500 mg/dL, after infusion occurred in 94% (91/97) of patients treated with cilta-
cel. Thirty-eight percent of patients received intravenous immunoglobulin (IVIG) post cilta-cel for
either an adverse reaction or prophylaxis. Monitor immunoglobulin levels after treatment with
cilta-cel and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines,
including infection precautions and antibiotic or antiviral prophylaxis.
6.1.6.6. 
Serious Infections
Do not administer cilta-cel OOS infusion to participants with active infection. Administration of
cilta-cel may increase the risk of infection due to cytopenias or hypogammaglobulinemia.
Participants should be monitored frequently for infection and should have blood cultures obtained
serum inflammatory markers (CRP), and/or empiric antibiotics administered per institutional
standards. Immunocompromised participants are at risk for opportunistic infections. Prophylactic
use of antibiotics, antivirals, and antifungals should be considered. Extended use of anti-microbial
therapies for at least 6 month (or longer as per institutional guidelines) or consistent with post
ASCT consensus guidelines after CAR-T dosing are recommended (see Section 10.13,
Appendix 13). Perform screening for HBV, HCV, and HIV and monitor as clinically indicated
(see HBV monitoring recommendations in Section 8.2 and Section 10.14, Appendix 14 and initiate
treatment as appropriate. HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic
failure and death, may occur in participants treated with drugs directed against B cells such as
cilta-cel. HBV reactivation has occurred in participants who appear to have resolved hepatitis B
infection. Routinely monitor HBV DNA and AST/ALT for participants with risk of HBV
reactivation.
Subjects receiving cilta-cel are may be at a higher risk of severe/fatal outcomes from COVID-19
infection compared with patients who are receiving standard of care therapy. Subjects should be
reminded of the importance of vaccines and other preventative measures. Investigators should
consider prophylaxis (eg, Evusheld, if available) and antiviral medications (eg, Paxlovid, if
available) for patients diagnosed with COVID-19 infection, as noted in Appendix 10.6. The safety
of immunization with live viral vaccines has not been studied. Vaccination with live virus vaccines
is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, and
until immune recovery following treatment cilta-cel infusion.


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6.1.6.7. 
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of cilta-cel. Hypersensitivity reactions have
occurred in 5% of patients following cilta-cel infusion. All reactions were Grade 1 and symptoms
included flushing (n=4), chest discomfort (n=2), tachycardia (n=1), wheezing (n=1), term or (n=1),
and burning sensation (n=1)..Serious hypersensitivity reactions including anaphylaxis, may be due
to dimethyl sulfoxide (DMSO), dextran 40, or residual kanamycin in cilta-cel. Serious
hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO),
dextran 40, or residual kanamycin in cilta-cel. Participants should be carefully monitored for 2
hours after infusion for signs and symptoms of severe reaction. Participants should be treated
urgently per institutional standards, avoiding corticosteroid use if possible. Participants should
receive premedication (ie, antihistamine, antipyretic) prior to cilta-cel dosing as noted in
Section 6.1.1.
6.1.6.8. 
Second Primary Malignancy
Second primary malignancy (SPM) is a theoretical possibility due to the risk of lentiviral insertion
(DNA integration) of the lentiviral vector. SPMs should be managed per institutional standards.
SPMs must be reported during the duration of the study, irrespective of when they occur, and
subsequently will be collected in a long-term follow-up study yearly until 15 years post dosing of
cilta-cel OOS  (68284528MMY4002). A tumor sample should be collected, and DNA, RNA or
protein analysis may be performed to investigate the presence of lentiviral elements. Second
primary malignancy is an adverse event of special interest (AESI).
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Cilta-cel OOS is provided in a single-dose unit containing CAR-positive viable T cells based on
the participant’s weight at apheresis reported at the time oforiginal commercial order of cilta-cel
OOS. The cryopreserved drug product is stored at ≤-120C, in the vapor phase of liquid nitrogen.
Cilta-cel OOS therapy contains human cells genetically modified with a lentiviral vector. Follow
local biosafety guidelines applicable for handling and disposal of such products. The product is
prepared from autologous blood collected by apheresis. Cilta-cel OOS may carry a risk of
transmitting infectious viruses to healthcare professionals handling the product. Accordingly,
healthcare professionals should employ universal precautions to avoid potential transmission of
infectious diseases when handling the product.
Detailed instructions for storage conditions and handling will accompany clinical drug supplies to
the clinical study sites. The storage conditions and expiry dates are indicated on the label. Refer to
the USPI for additional guidance on study treatment preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study treatment received at the site is
inventoried and accounted for throughout the study. The study treatment administered to the
participant must be documented on the intervention accountability form. All study treatment will


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be stored and disposed of according to the sponsor's instructions. Study site personnel must not
combine contents of the study treatment containers.
Study treatment must be handled in strict accordance with the protocol and the container label, and
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study treatment must be available for verification by the
sponsor's study site monitor during on-site monitoring visits. The return to the sponsor of unused
study treatment will be documented on the intervention return form. When the study site is an
authorized destruction unit and study treatment supplies are destroyed on-site, this must also be
documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles,
syringes and vials, should be disposed of immediately in a safe manner and therefore will not be
retained for intervention accountability purposes.
Study treatment should be dispensed under the supervision of the investigator or a qualified
member of the study site personnel, or by a hospital/clinic pharmacist. Study treatment will be
supplied only to participants participating in the study. The investigator agrees neither to dispense
the study treatment from, nor store it at, any site other than the study sites agreed upon with the
sponsor. Further guidance and information for the final disposition of unused study treatments are
provided in the prescribing information.
Measures to Minimize Bias: Randomization and Blinding
Randomization is not applicable as this single arm study. Participants will be enrolled if all
inclusion/exclusion criteria are met.
Blinding
As this is an open study, blinding procedures are not applicable.
Study Intervention Compliance
Infusion of cilta-cel OOS will be done in the controlled environment of a qualified clinical site,
under the direct observation of qualified study site personnel and the details of each administration
will be recorded in the eCRF (including date, start and stop times of the IV infusion, volume
infused, and weight of IV infusion bag, including the infusion line, before and after the completion
of the IV infusion) Precautions associated with the use of the study treatment and concomitant
medications will be reviewed by the sponsor.
Refer to the prescribing information for a description of the chain of identity and chain of custody
procedures associated with cilta-cel OOS.
Dose Modification
Target dose of cilta-cel is 0.75×106 cells/kg with the allowed dose in the range of 0.5×106 cells/kg
to 1.0×06 cells/kg. For this study, a lower dose of CAR-T cells may be the reason for OOS. Upon
positive benefit/risk assessment and exceptional release participants may receive modified doses


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below the target dose range. The sponsor will evaluate the safety of the dose to be administered to
each participant in the current study.
Continued Access to Study Intervention After the End of the Study
Cilta-cel is a one-time treatment. Therefore, continued access study treatment after end of the study
is not applicable.
Treatment of Overdose
Cilta-cel will be manufactured, formulated and provided by the sponsor for each individual
participant. The maximum total dose of cells to be administered to any participant is 1.0 x 10 8
CAR-positive viable T cells (ie, the maximum weight adjusted dose calculated for a 100-kg
participant). The dose and administration schedule may be altered for safety purposes based on
emerging data. Thus, there is no risk for overdose of cilta-cel.
Concomitant Therapy
Bridging therapy (between apheresis and cilta-cel OOS administration) can be given to prevent
progression of the multiple myeloma.
Concomitant therapies or treatments (except for those listed in Section 6.8.2) are those deemed
necessary to provide adequate supportive care. All medications must be recorded throughout the
study beginning with start of the first dose of study treatment to Day 100 after the last dose of
study treatment. Concomitant therapies should also be recorded beyond Day 100 in conjunction
with delayed adverse events outlined in Delayed Adverse Events in Section 8.3.1. Time Period
and Frequency for Collecting Adverse Event and Serious Adverse Event Information.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study treatment
must be recorded in the CRF. Recorded information will include a description of the type of
therapy, duration of use, dosing regimen, route of administration, and indication. Exceptions
include medications used to prevent (including vaccines) and treat COVID-19 and HBV
reactivation, which should be reported until 1 year after cilta-cel infusion, regardless of severity or
causality (Section 10.6 Appendix 6).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.8.1. 
Permitted Medications
The following are examples of supportive therapies that may be used during the study:
 
Standard supportive care therapies (antiemetics, antidiarrheals, anticholinergics,
antispasmodics, antipyretics, antihistamines, analgesics, antibiotics and other antimicrobials,
histamine receptor [H2] antagonists or proton pump inhibitors, and other medications intended
to treat symptoms or signs of disease) and therapies intended to treat CAR-T cell-related


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toxicity (ie, CRS) as clinically indicated, according to institutional standards and as deemed
necessary by the investigator.
 
Bisphosphonates may be initiated (if not already being administered) unless contraindicated
within 1 week prior to the first dose of study treatment and continued until disease progression
is established. In the case of severe adverse events such as hypercalcemia, bisphosphonates
may be administrated as clinically indicated, according to institutional standards and as
deemed necessary by the investigator.
 
Hematopoietic growth factor support and transfusions (irradiated blood products) are
permitted to treat symptoms or signs of neutropenia, anemia or thrombocytopenia according
to local standards of care. Non-pegylated myeloid growth factors are permitted up to 1 day
prior to the start of the lymphodepleting chemotherapy (Section 6.1.2).
 
Documented infectious complications should be treated with oral or IV antibiotics or other
anti-infective agents as considered appropriate by the treating investigator, according to
standard institutional practice.
 
Chemotherapy agents used to treat CAR-T cell-related toxicities are permitted upon
consultation with the sponsor (see Section 2.3.1).
6.8.2. 
Prohibited Therapies
There are no prohibited medications for this study; however, the following medications should be
avoided when medically feasible during the study:
 
Systemic corticosteroid use should be avoided, except for the treatment of CRS or CAR-T
cell-related neurotoxicity (eg, ICANS), as described in Table 6 and Table 7, respectively.
Alternative therapies, if feasible, should be given instead of corticosteroids.
 
Any chemotherapy, anticancer immunotherapy (other than cilta-cel), or experimental therapy,
except as described in Section 4.1 (bridging therapy), or protocol-specific therapies which
may be used in conjunction with cilta-cel OOS.
 
While in follow-up, emergency orthopedic surgery or radiotherapy is generally prohibited, but
may be allowed in the absence of disease progression. Cases must be discussed and approved
by the sponsor. Such emergency radiotherapy may consist of localized radiotherapy for pain
control or for stabilization of an extensive bone lesion at high risk of pathologic fracture or
damage to surrounding tissues.
 
Nonsteroidal anti-inflammatory agents should be avoided to minimize the risk of exacerbation
of potential sub-clinical myeloma-related kidney disease. Based on the investigator’s clinical
judgment, low dose aspirin may be continued for thromboprophylaxis.


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 
Other immunosuppressant agents unless used as protocol-specified pre- or post-treatment
medications to treat an adverse event (eg, CRS) or medical condition (eg, autoimmune
disease).
 
Vaccination with live, attenuated vaccine after signing consent and in the 6 weeks prior to
the infusion of cilta-cel OOS, and for 100 days after cilta-cel infusion OOS.
 
The use of IV contrast infusions should be avoided to prevent myeloma-related kidney
disease. If administration of IV contrast is necessary, then adequate precautions including
hydration are indicated.
 
The use of receptor activator of nuclear factor kappa-Β(RANK) ligand inhibitors such as
denosumab is discouraged due to their potential impact on immune function.
 
Pegylated myeloid growth factors (ie, pegfilgrastim) are discouraged within the first 100 days
after cilta-cel infusion OOS (Section 6.1.4).
6.8.3. 
Subsequent Anticancer Therapy
Subsequent anticancer therapy administered after cilta-cel OOS should be only administered after
confirmed disease progression per IMWG criteria (see Section 10.10, Appendix 10) and recorded
in the eCRF. The start and end date and best response should be documented in the eCRF, if
available.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
Discontinuation of Study Intervention
Discontinuation of study treatment is not applicable to this study as cilta-cel OOS is administered
as single-dose to participants after favorable benefit-risk assessment.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Not being able to receive cilta-cel OOS per the decision of the sponsor or principal investigator
as described in Section 4.4.
When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent following dosing with cilta-cel OOS, study assessments for the last visit
in the Post-infusion Phase (Table 1: Day 100;) should be completed prior to withdrawal of consent,
if feasible.


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Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply as local regulations permit.
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to enrollment attempts
should be made to obtain contact information from each participant, eg, home, work, and mobile
telephone numbers and email addresses for both the participant as well as appropriate family
members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods. These contact attempts should be documented in the participant’s
medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
 
Site personnel, or an independent third party, will attempt to collect the vital status of the
participant within legal and ethical boundaries for all participants enrolled, including those
who did not get study treatment. Public sources may be searched for vital status information.
If vital status is determined as deceased, this will be documented, and the participant will not
be considered lost to follow-up. Sponsor personnel will not be involved in any attempts to
collect vital status information.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA summarizes the frequency and timing of safety and efficacy measurements, and ongoing
participant review applicable to this study.


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If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: Echocardiogram/MUGA, vital signs, blood draw,
infusion. Urine and blood collections for assessments should be kept as close to the specified time
as possible. Other measurements may be done earlier than specified timepoints if needed. Actual
dates and times of assessments will be recorded in the source documentation and CRF.
Assessments are to be performed per the SoA (Table 1) and include safety and disease assessments
every 84 days after Day 100. Disease evaluations should continue to be performed until confirmed
disease progression, death, start of a new anticancer treatment, withdrawal of consent for study
participation, or end of the study, whichever occurs first. Once disease progression is confirmed,
subsequent disease assessment is not required.
The volume of blood drawn from each participant in this study is approximately 360 mL up to
Day 100 and approximately 20 to 40 mL at each post-treatment visit. Repeat or unscheduled
samples may be taken for safety reasons or for technical issues with the samples.
Screening Phase
If an assessment was performed as part of the participant’s routine clinical evaluation and not
specifically for this study, it does not need to be repeated after signed informed consent has been
obtained provided the assessments fulfill the study requirements and are performed within the
specified timeframe prior to the first dose of study treatment. Retesting of abnormal clinical
laboratory values that do not meet the eligibility criteria are allowed only once during the
Screening Phase (to reassess eligibility). Rescreening may occur with sponsor approval.
All participants must sign an ICF prior to the conduct of any study-related procedures. The
Screening Phase begins when the cilta-cel OOS is approved for exceptional release.
Lymphodepleting Chemotherapy
At the completion of manufacture and quality testing of cilta-cel, written notification will be sent
to the clinical site. Prior to dosing with cyclophosphamide and fludarabine, review of eligibility,
safety assessments and disease characteristics should be completed per Section 6.1.2. The details
regarding safety monitoring and study visits during this phase are included in the SoA (Table 1).
Cilta-cel OOS Administration
Administration of cilta-cel OOS is fully described in Table 5.
Post-infusion
The post-infusion period starts after the completion of cilta-cel OOS infusion on Day 1 and lasts
until Day 100. Any participant who receives a cilta-cel OOS should continue all subsequent post-
infusion assessments per the SoA (Table 1).


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During this period, participants will be monitored closely with  safety and disease assessments.
Participants will be asked to check their temperature at least twice daily (entering 2 temperatures
including their maximum daily temperature in the provided diary) during the first 28 days (ie, upto
Day 28) after cilta-cel OOS infusion and will be instructed to report any fever (≥38°C) to the study
doctor immediately to initiate monitoring for development of CRS.
Hospitalization is per institutional practices/guidelines (Table 5). Participants will be provided a
"wallet (study) card" with pertinent information about the study and be asked to carry this card
with them for the duration of the post-infusion and post-treatment period.
Post-treatment
The post-treatment period starts on Day 101 and lasts until study completion, defined as 2 years
after each participant has received the initial dose of cilta-cel OOS. Assessments are to be
performed per the SoA (Table 1) and include safety and disease assessments every 84 days. Refer
to Section 8.3 for additional AE collection. Disease evaluation should continue to be performed
until confirmed disease progression, death, start of a new anticancer treatment, withdrawal of
consent for study participation, or end of the study, whichever occurs first. Once disease
progression is confirmed, subsequent disease assessment is not required.
After disease progression is documented, survival status and subsequent anticancer therapy will
be obtained every 16 weeks until the end of study, unless the participant has died, is lost to follow-
up, or has withdrawn consent. If the information is obtained via telephone contact, written
documentation of the communication must be available for review in the source documents. If the
participant has died, the date and cause of death will be collected and documented on the eCRF, if
or when available. Where allowed by local law, public records may be used to document death or
to obtain survival status.
After end of study, participants are offered to enroll into the long-term-follow-up study
(68284528MMY4002) to assess the long-term safety of cilta-cel OOS for up to 15 years.
Following completion of this study, assessment for replication competent lentivirus (RCL) will be
collected yearly until 15 years after dosing with cilta-cel OOS on a follow-up study. In case of a
second primary malignancy a tumor sample should be collected, and DNA, RNA or protein
analysis may be performed to investigate the presence of lentiviral elements.
At the investigator discretion and with sponsor approval, study visits in the post-treatment part of
the study, starting after Day 100, may be performed remotely via telemedicine technology that
connects study participants to their research coordinators and investigators or mobile study
personnel per standard of care. Similarly, blood sample collection may be performed at the
participant’s home by mobile study personnel (ie, nurses and mobile phlebotomist) per standard-
of-care, in the post-treatment period.
Monitor patients at least daily for 10 days following cilta-cel OOS infusion (whether the
participant will be dosed outpatient or inpatient) at a certified healthcare facility for signs of


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symptoms of cytokine release syndrome and neurologic toxicities as per USPI. Monitor
periodically for 4 weeks for signs and symptoms of delayed neurologic toxicity.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form.
Within 24 hours of study treatment infusion, if the study treatment is infused peripherally, blood
samples must be drawn from a vein contralateral to the arm into which cilta-cel OOS is infused. If
the study treatment is infused via a central vein line, blood samples over the subsequent 24 hours
must be drawn from a vein in either arm.
Refer to the SoA (Table 1) for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
Study Protocol and USPI (or locally approved label)
 
Laboratory manual
 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
(version 5.0)
 
Electronic data capture (eDC) Manual
 
Sample ICF
 
Participant diaries and instructions/educational materials
Efficacy Assessments
Disease evaluations must be performed as specified in the SoA Table 1. Disease evaluations until
confirmed disease progression, death, start of a new anticancer treatment, withdrawal of consent
for study participation, or end of study, whichever occurs first. This study will use the IMWG-
based response criteria (Section 10.10 Appendix 10). If it is determined that the study treatment
interferes with the immunofixation assay, CR will be defined as the disappearance of the original
M-protein associated with multiple myeloma on immunofixation, and the determination of CR will
not be affected by unrelated M-proteins secondary to the study treatment (Durie 2006).
Quantitation of M-protein, 24-hour urine protein, serum and urine immunofixation, and free-light
chain (FLC) measurements in serum and urine will be carried out per standard-of-care. Disease
progression must be consistently documented across clinical study sites using the criteria in
Section 10.9, Appendix 9.


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All efforts should be made to collect efficacy data per standard-of-care procedures. Local
laboratory data maybe collected if central laboratory data is not available at a particular timepoint,
however this does not include screening assessments. Documentation of the local laboratory data
should be sent to the principal investigator and filed in the medical record. It is the principal
investigator’s responsibility to ascertain that these results are reviewed and entered into the
participant’s medical record and the eCRF.
8.1.1. 
Myeloma Protein Measurements in Serum and Urine
Assessments will be performed as specified in the SoA (Table 1):
 
Serum protein electrophoresis (SPEP)
 
Serum immunofixation electrophoresis
 
Serum FLC assay (for participant in suspected CR/sCR and every disease assessment for
participants with serum FLC only disease)
 
24-hour urine M-protein quantitation by electrophoresis (UPEP)
 
Urine immunofixation electrophoresis
 
Serum quantitative Immunoglobulins
Blood and 24-hour urine samples will be collected as specified in the SoA Table 1 until the
development of confirmed disease progression. Disease progression based on one of the laboratory
tests alone must be confirmed by at least 1 repeat investigation. Disease evaluations will continue
beyond relapse from CR until disease progression is confirmed. Serum and urine immunofixation
and serum FLC assays will be performed at screening and thereafter when a CR is suspected (when
serum or 24-hour urine M-protein electrophoresis [by SPEP or UPEP] are 0 or non-quantifiable).
For participants with light-chain multiple myeloma, serum and urine immunofixation tests will be
performed routinely per the SoA (Table 1).
8.1.2. 
Bone Marrow Examination
Bone marrow aspirate or biopsy (biopsy alone is acceptable if aspirate is not possible) will be
performed for clinical assessments and biomarker evaluations. Clinical staging (morphology and
immunohistochemistry or immunofluorescence or flow cytometry) should be done by a local
laboratory; cytogenetics will be done at a central laboratory. Ifcytogenetic results are not available
by central laboratory, local laboratory data, if available, may be entered into the eCRF. Bone
marrow aspirate and biopsy will also be performed to confirm CR and sCR and at PD. A portion
of the bone marrow aspirate at each bone marrow aspiration should be sent to the central laboratory
for flow cytometryand to monitor BCMAin CD138-positive MM cells, and checkpoint expression
on T cells. Additionally, bone marrow aspirate (at central laboratory) will be performed at Day 56
post-cilta-cel infusion if not performed within the past 3 months. In the event FISH analysis does
not yield diagnostic results (either centrally or locally), archived bone marrow aspirate or bone
marrow clot sample may be collected for FISH analysis. In addition, MRD-negative rate will be
evaluated as specified in Section 8.1.3 and in the SoA (Table 1).


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8.1.3. 
Minimal Residual Disease Evaluations
Bone marrow aspirates will be collected to monitor MRD-negative rate to define the myeloma
clones as specified in the SoA (Table 1). MRD negativity is being evaluated in the field as a
potential surrogate for PFS and OS. MRD-negative rate will be evaluated using next generation
sequencing (NGS) on bone marrow aspirate DNA. In the event fresh bone marrow aspirate will
not be collected at prior to LD chemotherapy, or if the fresh aspirate does not yield a usable clone,
non-decalcified diagnostic tissue (bone marrow aspirate slides or formalin-fixed paraffin
embedded tissue) should be collected for calibration of myeloma cells to facilitate the assessment
of the secondary  MRD-negative rate endpoints by next generation sequencing (NGS). Bone
marrow aspirate should be sent to central laboratory for MRD-negative rate evaluation as specified
in the Schedule of Activities (SoA).
8.1.4. 
Documentation of Extramedullary Plasmacytomas
Sites of known extramedullary plasmacytomas must be documented ≤14 days prior to the first
dose of the lymphodepleting chemotherapy. Clinical examination or MRI may be used to
document extramedullary sites of disease. CT scan evaluations are an acceptable alternative if
there is no contraindication to the use of IV contrast. Positron emission tomography (PET) scan or
ultrasound tests are not acceptable to document the size of extramedullary plasmacytomas.
However, PET/CT fusion scans can be used to document extramedullary plasmacytomas if the CT
component of the PET/CT fusion scan is of sufficient diagnostic quality.
Extramedullary plasmacytomas should be assessed for all participants with a history of
plasmacytomas or if clinically indicated at ≤14 days prior to the first dose of the lymphodepleting
chemotherapy, by clinical examination or radiologic imaging. Assessment of measurable sites of
extramedullary disease will be performed, measured, and evaluated locally every 4 weeks (for
physical examination) for participants with a history of plasmacytomas or as clinically indicated
during treatment for other participants until development of confirmed CR or confirmed disease
progression. If assessment can only be performed radiologically, then evaluation of extramedullary
plasmacytomas may be done every 12 weeks. The methodology used for evaluation of each disease
site should be consistent across all visits. Irradiated or excised lesions will be considered not
measurable, and will be monitored only for disease progression.
To qualify for VGPR or PR minimal response (MR), the sum of products of the perpendicular
diameters of the existing extramedullary plasmacytomas must have decreased by over 90% or at
least 50%, respectively, and new plasmacytomas must not have developed (see the disease
response criteria in Section 10.9, Appendix 9). To qualify for disease progression, either the sum
of products of the perpendicular diameters of the existing extramedullary plasmacytomas must
have increased by at least 50%, or the longest diameter of previous lesion >1 cm in short axis must
have increased at least 50%, or a new plasmacytoma must have developed. When not all existing
extramedullary plasmacytomas are reported, but the sum of products of the perpendicular
diameters of the reported plasmacytomas have increased by at least 50%, then the criterion for
disease progression is met.


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8.1.5. 
Skeletal Survey
A skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, femora, and any
other bones for which the investigator suspects involvement by disease) is to be performed during
the screening phase (or in the time interval between completion of bridging therapy and start of
lymphodepleting chemotherapy, if bridging therapy is given) and evaluated by the local laboratory
by either roentgenography (“X-rays”) or low dose computed tomography (CT) scans without the
use of IV contrast. If a CT scan is used it must be of diagnostic quality. Following cilta-cel OOS
infusion, and before disease progression is confirmed, X-rays or CT scans should be performed
locally, whenever clinically indicated based on symptoms, to document response or progression.
Magnetic resonance imaging (MRI) is an acceptable method for evaluation of bone disease, and
may be included at the discretion of the investigator; however, it does not replace the skeletal
survey (see the disease response criteria in Section 10.10, Appendix 10). If a radionuclide bone
scan is used at consenting, in addition to the complete skeletal survey, then both methods must be
used to document disease status. These tests must be performed at the same time. Note: a
radionuclide bone scan does not replace a complete skeletal survey.
If a participant presents with disease progression manifested by symptoms of pain due to bone
changes, then disease progression may be documented by skeletal survey or other radiographs,
depending on the symptoms that the participant experiences. If the diagnosis of disease progression
is obvious by radiographic investigations, then no repeat confirmatory X-rays are necessary. If
changes are equivocal, then a repeat X-ray is needed in 1 to 3 weeks.
Safety Assessments
Safety will be measured by adverse events, laboratory test results, vital signs including oxygen
saturation measurements, physical examination findings (including neurological examination),
assessment of ICE-Tool scores, handwriting assessments, and assessment of ECOG performance
status grade. Clinically relevant changes occurring during the study must be recorded on the
adverse event section of the eCRF. Clinically significant abnormalities persisting at the end of the
study/early withdrawal will be followed by the investigator until resolution or until a clinically
stable endpoint is reached. Safety monitoring assessments may be performed more frequently, if
clinically indicated.
The study will include the following evaluations of safety according to the time points provided in
the SoA (Table 1).
Details regarding the Data Review Committee is provided in Committees Structure in
Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Section 10.4,
Appendix 4 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and
Reporting.


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Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the SoA (Table 1).
8.2.1. 
Physical Examinations
The screening physical examination will include, at a minimum, participant’s height, general
appearance, examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities,
musculoskeletal system, and lymphatic system. Thereafter, a symptom-directed physical
examination will be conducted as clinically indicated at subsequent timepoints. Abnormalities will
be recorded in the appropriate section of the eCRF. Body weight will be measured prior to cilta-cel
OOS infusion of (SoA, Table 1). Clinically significant post-baseline abnormalities should be
recorded as adverse events.
8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, blood pressure and oxygen saturation monitoring
will be performed as specified in the SoA (Table 1).
Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic
and diastolic) will be monitored and clinically relevant changes occurring during the study will be
recorded on the adverse event section of the eCRF.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG performance status scale will be used to grade changes in the participant’s daily living
activities (Section 10.11, Appendix 11) and will be assessed as noted in the SoA, Table 1.
8.2.4. 
Neurologic Examination
Magnetic resonance imaging (MRI) at Screening Phase or neurology consultation should be
considered if pre-existing disease is suspected. For participants with prior pertinent neurologic
disease (eg, stroke, encephalitis) consider baseline MRI of brain and an EEG. At the first sign of
neurotoxicity, neurology consultation and evaluation should be considered. CAR-T  cell-related
neurotoxicity (eg, ICANS) should be graded using American Society for Transplantation and
Cellular Therapy (ASTCT) consensus grading. Other neurological adverse events not associated
with ICANS should be graded based on NCI-CTCAE (version 5.0) throughout both phases of the
study. Findings from neurological testing that support CAR-T cell-related neurotoxicity
(eg, ICANS) should be reported in the CRF.


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8.2.5. 
Immune-Effector Cell-associated Encephalopathy (ICE) Tool Scores
The ICE test was developed to provide objectivity for the grading of multiple overlapping
encephalopathy terms currently included on the approved CAR-T products (Lee 2019)
(Section 10.9, Appendix 9). The ICE Tool will be collected as noted in the SoA (Table 1) to guide
management throughout both phases of the study. It will also be used to grade the severity of
ICANS (Section 10.8, Appendix 8). All ICE Tool scores, must be reported in the eCRF.
8.2.6. 
Handwriting Assessment
Qualitative changes in handwriting since baseline are being explored by the sponsor as a potential
early clinical predictive marker for neurotoxicity. Currently no standardized CTCAE toxicity
gradings are available in the NCI-CTCAE (version 5.0). for these type of changes in handwriting.
Therefore, the sponsor has developed a handwriting assessment criterion to assess participants for
occurrence of the following types of changes in handwriting: micrographia, dysgraphia, or
agraphia, as potential early indicators for neurotoxicity (Section 10.12, Appendix 12).
Handwriting assessments will be collected on a writing log according to the SoA, Table 1 and as
instructed by the sponsor. Participants unable to write at baseline are excused from this assessment
during study. The sponsor’s medical monitor should immediately be notified when changes in
handwriting are detected. This will prompt discussion about additional assessments to further
evaluate for other neurotoxicity symptoms, further workup, as well as the potential initiation of
interventions. All cases of handwriting abnormalities (ie, micrographia, dysgraphia, or agraphia)
must be reported as an adverse event in the eCRF. Should a participant experience a serious CAR-
T associated neurotoxicity (either ICANS or other neurotoxicity), then a copy of the handwriting
assessment log should be submitted with the serious adverse event report.
8.2.7. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry, hematology, infectious diseases testing, and a routine urine
sample for urinalysis will be collected as noted in Section 10.2, Appendix 2, Clinical Laboratory
Tests. The investigator must review the laboratory results, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. The laboratory
reports must be filed with the source documents. Participants with Grade 3 or higher toxicity or
unresolved AEs will continue to be assessed until recovery to Grade 1 or baseline, the event is
deemed irreversible, the end of the study, or a maximum of 6 months, whichever occurs first.
8.2.8. 
Replication Competent Lentivirus (RCL)
According to Mohanlal 2016, persistence of replication competent lentivirus (RCL) or delayed
adverse events related to RCL have not been reported in patients who have received lentivirus-
based gene therapies. However, the potential pathogenicity of RCL requires vigilant testing to
exclude the presence of RCL in peripheral blood samples of participants infused with  cilta-cel
OOS.
In accordance with the FDA guidance for industry on Testing of Retroviral Vector-Based Human
Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and


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Patient Follow-up, peripheral blood mononuclear cells for all participants in the study will be
monitored for RCL-specific DNA sequences by a validated PCR method. Monitoring schedule
will include analysis of participant samples at the following time points: pre-treatment, followed
by testing at 3, 6, and 12 months after treatment, and yearly until end of study; participants in
follow-up at the end of study will be enrolled in the separate long-term follow-up study, Protocol
68284528MMY4002, to continue monitoring for up to 15 years. If samples are negative for RCL
during the first year after treatment, RCL assessments may be terminated (See Section 8.5), and
yearly review of medical history will generally be sufficient for the participant. If any post-
treatment samples are positive, further analysis of the RCL, and more extensive patient follow-up
should be undertaken. Additional event-triggered testing for RCL may be conducted as clinically
indicated as specified in Schedule of Activities (SoA).
8.2.9. 
Pregnancy Testing
Additional serum pregnancy tests may be performed, as determined necessary by the investigator
or required by local regulation, to establish the absence of pregnancy at any time during the
participation in the study.
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and product quality complaint (PQC), from clinical studies are crucial for the protection of
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.
The sponsor has established Standard Operating Procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQC can be found in Section 10.4, Appendix 4 Adverse Events,
Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs (with the exception of HBV reactivation and delayed AEs described below) and special
reporting situations, whether serious or non-serious, will be reported from the time a signed and
dated ICF is obtained until 100 days after cilta-cel OOS infusion  or until completion of the
participant's last study-related procedure (whichever is later), which  may include contact for
follow-up of safety. Beyond this AE reporting period, only SAEs regardless of causality and non-
serious AEs that are considered related to a study drug need to be reported until the end of the
study except as defined for delayed AEs below. Events of HBV reactivations and COVID-19


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infections, regardless of severity or relatedness, will be collected during the first-year post-dosing
of cilta-cel OOS. See Section 10.17, Appendix 17 for additional adverse event reporting guidance.
All adverse events, regardless of seriousness, severity, or presumed relationship to study treatment,
must be recorded using medical terminology in the source document and the CRF. Whenever
possible, diagnoses should be given when signs and symptoms are due to a common etiology (eg,
cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper
respiratory infection"). The exceptions are CRS and CAR-T cell-related neurotoxicity, for which
all symptoms associated with these events will be collected in the eCRF. Investigators must record
in the CRF their opinion concerning the relationship of the adverse event to study therapy. All
measures required for adverse event management must be recorded in the source document and
reported according to the sponsor instructions.
An assessment of severity grade will be made by the investigator according to the NCI-CTCAE
version 5.0, except for CRS and CAR-T cell-related neurotoxicity (eg, ICANS). Cytokine release
syndrome should be evaluated according to the ASTCT consensus grading (Section 10.7,
Appendix 7) (Lee 2019). CAR-T cell‑related neurotoxicity (eg, ICANS) should be graded using
the ASTCT consensus grading (Section 10.8, Appendix 8). In addition to capturing ICANS and
CRS AEs (graded by ASTCT consensus grading), all individual symptoms of CRS (eg, fever,
hypotension) and CAR‑T cell-related neurotoxicity (eg, depressed level of consciousness,
seizures) must be captured as individual AEs and graded by CTCAE criteria. Neurotoxicity that is
not temporarily associated with CRS, or any other neurologic AEs that do not qualify as ICANS,
will be graded by CTCAE criteria. Events of neurotoxicity or exacerbation of existing neurologic
AEs will be reported until the end of study.
Changes in handwriting (ie, micrographia, dysgraphia, or agraphia) should be graded using the
criteria outlined in Section 10.12 (Appendix 12) and reported as an AE in the eCRF. Should a
participant experience a serious CAR-T associated neurotoxicity (either ICANS or other
neurotoxicity), then a copy of the handwriting assessment log should be submitted with the serious
AE report.
Delayed Adverse Events
The following delayed AEs need to be reported regardless of seriousness or causality until the end
of study. These will continue to be collected after this study in a subsequent LTFU study
(68284528MMY4002) for up to 15 years after last dose of cilta-cel.
 
New primary malignancies or recurrence of pre-existing malignancy (all grades), with the
exception of multiple myeloma (which should be reported as progressive disease), must be
reported to the sponsor within 24 hours of awareness of the event for the duration of the study,
irrespective of seriousness or causality. In the event of malignancy, a tumor sample should be
collected, and vector integration site analysis may be performed for possible insertional
mutagenesis.


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 
New incidence or exacerbation of a pre-existing neurologic disorder (all grades). Grade 3 or
higher neurotoxicity and any grade movement and neurocognitive toxicity (ie, Parkinsonism)
must be reported to the sponsor within 24 hours of awareness of the event for the duration of
the study, irrespective of seriousness or causality.
 
New incidence or exacerbation of a pre-existing rheumatologic or other autoimmune disorder
(all grades)
 
New incidence of Grade ≥3 hematologic disorder
 
New incidence of Grade ≥3 infection
Serious Adverse Events
All serious adverse events (SAEs), as well as PQC, occurring during the study must be reported to
the appropriate sponsor contact person by study site personnel within 24 hours of their knowledge
of the event.
Serious adverse events (regardless of causality), including those spontaneously reported to the
investigator must be reported throughout the study and subsequently will be collected yearly in a
the long-term follow-up study (68284528MMY4002) for up to 15 years post-infusion of cilta-cel.
The sponsor will evaluate any safety information that is spontaneously reported by an investigator
beyond the time frame specified in the protocol. All events that meet the definition of a SAE will
be reported as SAEs, regardless of whether they are considered related to study drug or protocol-
specific assessments.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form, which must be completed and signed by a physician from the study site, and transmitted to
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
Adverse Events of Special Interest
Cytokine release syndrome, neurotoxicity (including CAR-T cell-related neurotoxicity
[eg, ICANS] and other neurotoxicities), prolonged and recurrent cytopenias, and second primary
malignancies are adverse events of special interest and will be followed as part of standard safety
monitoring activities by the sponsor, regardless of severity or causality. These events will require
enhanced data collection in the eCRF, be reported to the sponsor in a timely manner, irrespective
of seriousness, and followed until recovery or until there is no further improvement. For the
purpose of reporting, SPMs include both new primary malignancies and recurrence of pre‑existing
malignancies with the exception of multiple myeloma (which should be reported as disease
progression).
In addition, the following events must be reported to the sponsor using the Serious Adverse Event
Form within 24 hours of awareness of the event for the duration of the study, irrespective of
seriousness (eg, serious and nonserious adverse events) or causality:


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 
≥Grade 3 CRS
 
≥Grade 3 neurotoxicity
 
Any grade movement and neurocognitive toxicity (ie, Parkinsonism)
 
Any grade second primary malignancy
 
All deaths not related to disease progression occurring any time during study after receiving
cilta-cel should be reported to the sponsor following expedited reporting procedures.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned in the
participant diary.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.4 (Appendix 4) Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate Independent Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise.
8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must discontinue further study treatment.


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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Disease-Related Events and Disease-Related Outcomes Not
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition ofan SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
Pharmacokinetics
Venous blood samples will be used to evaluate the PK of cilta-cel OOS. Samples collected for PK
may additionally be used to evaluate safety or efficacy aspects that address concerns arising during
or after the study period. Genetic analyses will not be performed on these serum samples.
Participant confidentiality will be maintained.
Venous blood samples will be collected for measurement of ciltacel-positive cellular concentration
and transgene levels as specified in the SoA (Table 1). Samples will also be collected at the time
of onset of suspected CRS or cilta-cell-related neurotoxicity (ie, ICANS) regardless of causality
(as specified in Table 1).
The exact dates and times of sampling must be recorded on the laboratory requisition form. Refer
to the laboratory manual for sample collection requirements. Collected samples must be stored
under specified controlled conditions for the temperatures indicated in the laboratory manual.
Biomarkers
Biomarker assessments will focus on several objectives aligned with the objectives of the study:
1) characterization of peripheral CAR-T cell expansion and persistence as well as their memory
and activation phenotypes through assessment of markers including, but not limited to, CD4 +,
CD8+, CD25+, CD45RO and CCL7; 2) determine the ability of cilta-cel OOS to induce MRD
negativity in participants with  relapse/refractory multiple myeloma who have achieved CR;
3) immunophenotyping of other immune CAR negative cell subsets such as CD4+ and CD8+
T cells, regulatory B and T cells or natural killer cells; 4) assessment of serum or plasma proteins
over time including, but not limited to cytokines (such as IL-6, IFN-γ, and IL-10). 5) determine
the clinical benefit (ORR, DOR, PFS, and OS) of cilta-cel OOS in participants with cytogenetic
modifications (del17p, t(4;14), t(14;16), or other high  risk molecular subtypes). Additional
biomarker samples may be collected when clinically indicated and as specified in the Schedule of
Activities (SoA) to help understand unexplained adverse events including but not limited to serum
or peripheral blood mononuclear cells (PBMCs).
The potential presence of Replication Competent Lentivirus (RCL) will be evaluated from whole
blood samples of participants treated with cilta-cel OOS. RCL will be evaluated using a qPCR
assay against the lentiviral vesicular stomatitis virus-G gene. If samples are negative for RCL
during the first year after treatment RCL assessments may be terminated.


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Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may
be deferred or not performed if during or at the end of the study it becomes clear that the analysis
will have no scientific value, or if there are not enough samples or not enough responders to allow
for adequate biomarker evaluation. In the event the study is terminated early or shows poor clinical
efficacy, completion of biomarker assessments is based on the intended utility of the data.
Based on emerging scientific evidence, the sponsor may request additional material from,
including but not limited to, previously collected bone marrow samples, whole blood, bone
marrow aspirate or biopsy, or CSF, or other tissue sample during or after study completion for a
retrospective analysis. For participants diagnosed with a SPM, a tumor sample should be collected.
Additionally, the sponsor will receive a sample of plasmacytoma if patient relapse is suspected.
Participants who have a lumbar puncture as part of their neurologic work up should have CSF sent
for additional tests by the sponsor. In all cases, such analyses would be specific to research related
to the study treatment(s) or diseases being investigated. If a participant dies and an autopsy is
performed, specimens may be requested by the sponsor for analysis.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan. No formal statistical
hypothesis testing will be performed for the study. All participants who received an infusion of
cilta-cel OOS will be included in the analysis for efficacy and safety summaries. Descriptive
statistics and time to event analysis as appropriate will be detailed in the statistical analysis plan.
Initially, data will be reviewed by DRC after every 10 participants have been treated and followed
for at least 3 months to assess efficacy and safety.
Statistical Hypotheses
No formal statistical hypothesis is planned for this study.
Sample Size Determination
Sample size is not based on statistical consideration. Based on the current manufacturing
experience with the study 68284528MMY2001, at least 20 participants are anticipated to enroll in
the study.
Populations for Analysis Sets
The analysis population for this study is defined as:
All treated analysis set, which consists all participants who received a cilta-cel OOS infusion,
will be used for both efficacy and safety analyses.
Statistical Analyses
The statistical analysis plan will be finalized prior to database lock (DBL) and it will include a
more technical and detailed description of the statistical analyses described in this section.


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9.4.1. 
General Considerations
Continuous variables will be summarized using the number of observations, mean, standard
deviation, coefficient of variation, median, and range as appropriate. Categorical values will be
summarized using the number of observations and percentages as appropriate. For time to event
data, the distribution (median and Kaplan-Meier curves) will be provided using Kaplan-Meier
estimates.
9.4.1.1. 
Primary Endpoints
Primary Endpoint: Overall response rate is defined as the proportion of participants who achieve
a PR or better (ORR) according to the IMWG response criteria (Durie 2006, 2015; Rajkumar 2011)
assessed by the investigator.
9.4.1.2. 
Secondary Endpoints
Duration of response (DOR) will be calculated among responders (with a PR or better response)
from the date of initial documentation of a response (PR or better) to the date of first documented
evidence of progressive disease, as defined in the IMWG response criteria assessed by the
investigator. Relapse from CR by positive immunofixation or trace amount of M-protein is not
considered as disease progression. Disease evaluations will continue beyond relapse from CR until
disease progression is confirmed. For participants who have not progressed, data will be censored
at the last disease evaluation before the start of any subsequent anti-myeloma therapy.
Progression-free survival (PFS) defined as the time from the date of the initial infusion of
cilta-cel OOS  to the date of first documented disease progression, as defined in the IMWG
response criteria, or death due to any cause, whichever occurs first. For participants who have not
progressed and are alive, data will be censored at the last disease evaluation before the start of any
subsequent anti-myeloma therapy.
Overall survival (OS) is measured from the date of the initial infusion of cilta-cel OOS to the date
of the participant’s death. If the participant is alive or the vital status is unknown, then the
participant’s data will be censored at the date the participant was last known to be alive.
All safety analyses will be made on the Safety Population.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Section 8.3 provides information on
AEs that are to be reported following initial administration ofstudy treatment. Any AE reported
at or after the initial administration ofstudy treatment is considered to be treatment-emergent. All
reported treatment-emergent AEs will be included in the analysis. For each AE, the percentage of
participants who experience at least 1 occurrence of the given event will be summarized.


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Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or an
SAE.
Parameters with predefined NCI-CTCAE (version 5.0) toxicity grades will be summarized for
TEAEs. Change from baseline to the worst AE grade experienced by the participant during the
study will be provided as shift tables.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for selected laboratory analyte at baseline
and for observed values and changes from baseline at each scheduled time point. Changes from
baseline will be presented in pre-versus post-intervention cross-tabulations (with classes for below,
within, and above normal ranges). Frequency tabulations of the laboratory abnormalities will be
made. A listing of participants with any laboratory results outside the reference ranges will be
provided. A listing of participants with any markedly abnormal laboratory results will also be
provided.
Vital Signs
Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic
and diastolic) will be summarized over time, using descriptive statistics. The percentage of
participants with values beyond clinically important limits will be summarized.
Physical Examinations
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive
statistics will be calculated at baseline and for observed values and changes from baseline at each
scheduled time point. Frequency tabulations of the abnormalities will be made.
9.4.1.3. 
Exploratory Endpoints
Pharmacokinetics
Pharmacokinetic parameters will be estimated for individuals, and descriptive statistics will be
calculated. Correlation of maximum peripheral blood concentration (Cmax) and area under the
peripheral blood concentration-time curve (AUC) with dose may also be explored.
Pharmacokinetic parameters include, but are not limited to, AUC from time 0 to infinity (AUCinf),
AUC from time 0 to t (AUC[0-t]), Cmax, half-life, and time to reach maximum peripheral blood
concentration (Tmax) parameters will be calculated if sufficient data are available for estimation.


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Immunogenicity Assessment
Antibodies to cilta-cel OOS  will be evaluated in serum samples collected from all participants
according to the SoA (Table 1). Samples will also be collected at the time onset of suspected CRS
or CAR-T cell-related neurotoxicity (ie, ICANS) regardless of causality.
Additionally, serum samples should also be collected at the final visit from participants who
discontinued due to progressive disease or were withdrawn from the study. These samples will be
tested by the sponsor or sponsor’s designee. The exact dates and times of blood sampling must be
recorded on the laboratory requisition form. Refer to the laboratory manual for sample collection
requirements. Collected samples must be stored under specified controlled conditions at the
temperatures indicated in the Laboratory Manual.
Cilta-cel transgene concentration will also be determined to aid in the interpretation of
immunogenicity data. These samples will be stored and evaluated if deemed necessary.
Serum samples will be screened for antibodies binding to cilta-cel OOS and the titer of confirmed
positive samples will be reported. Other analyses may be performed to further characterize the
immunogenicity of cilta-cel OOS. Genetic analyses will not be performed on these samples.
Participant confidentiality will be maintained.
9.4.1.4. 
Biomarker Analyses
Descriptive analysis will be performed for each biomarker at baseline and for observed values and
changes from baseline at each scheduled time point. These include but are not limited to CAR-
positive T cell concentrations as well as cytokine levels. Descriptive associations with safety and
efficacy may also be evaluated.
Interim Analysis
No formal interim analysis is planned. Initially, data will be reviewed after every 10 participants
have been treated and followed for at least 3 months to assess efficacy and safety.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
Appendix 1: Abbreviations and Definitions
AE 
adverse event
AESI 
adverse event of special interest
ALT  
alanine aminotransferase
ASCT  
autologous stem cell transplant
AST  
aspartate transaminase
AxMP  
Auxiliary Medicinal Product (also known as NIMP)
BCMA  
B-cell maturation antigen
CAR  
chimeric antigen receptor
CBR  
clinical benefit rate
COVID-19 
Coronavirus Disease-2019
CR  
complete response
CRF  
case report form
CRS  
cytokine release syndrome
CSF  
cerebrospinal fluid
CT  
computed tomography
CTCAE 
Common Terminology Criteria for Adverse Events
DOR  
duration of response
DRC  
Data Review Committee
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EEG  
electroencephalogram
EOS  
end of study
FISH  
fluorescence in situ hybridization
FLC  
free-light chain
FOIA  
Freedom of Information Act
GCP  
Good Clinical Practice
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCV  
hepatitis C virus
HHV  
human herpesvirus
HLH  
hemophagocytic lymphohistiocytosis
HIV  
human immunodeficiency virus
HTLV  
Human T cell lymphotropic virus
IB  
Investigator’s Brochure
ICANS  
Immune-Effector Cell-associated Neurotoxicity Syndrome
ICE 
Immune-Effector Cell-associated Encephalopathy
ICF  
informed consent form
ICH  
International Council for Harmonisation
IEC  
Independent Ethics Committee
Ig 
Immunoglobulin
IMiD  
Immunomodulatory drug
IMP  
Investigational Medicinal Product
IND  
Investigational New Drug
IMWG  
International Myeloma Working Group
IRB  
Institutional Review Board
IRC  
Independent Review Committee
LTFU  
LD  
long-term follow-up
lymphodepleting
MAS  
macrophage activation syndrome
MR  
minimal Response
MRD  
minimal residue disease
MRI 
magnetic resonance imaging
NIMP  
Non-Investigational Medicinal Product


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NCI 
National Cancer Institute
PCR  
polymerase chain reaction
PET  
positron emission tomography
OS  
overall survival
ORR  
overall response rate
OOS  
out-of-specifications
PFS  
progression-free survival
PQC  
Product Quality Complaint
PK 
pharmacokinetics
PR 
partial response
RCL 
Replication Competent Lentivirus
RRMM  
relapsed/refractory multiple myeloma
SAE 
serious adverse events
SoA  
schedule of activities
SPEP  
serum protein electrophoresis
SPM  
second primary malignancy
ULN  
upper limit of normal
UPEP  
urine protein electrophoresis
US  
United States
VGPR  
very good partial response
VHH  
variable fragments of heavy chain antibodies
TEAE  
treatment-emergent adverse event
TLS  
tumor lysis syndrome
USPI 
United States Prescribing Information
Definitions of Terms
Electronic source
system
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.




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Routine 
Urinalysis 
Dipstick  
Specific gravity  
pH  
Glucose 
Protein  
Blood 
Ketones 
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
Sediment (if dipstick result is abnormal)
Red blood cells
White blood cells
Epithelial cells
Crystals
Casts
Bacteria
If dipstick result is abnormal, microscopy will be used to measure sediment.
Infectious 
diseases testing 
Human immunodeficiency virus (HIV), Hepatitis B, Hepatitis C, Human T-cell
lymphotropic virus (HTLV) and other infectious diseases will be performed within 60
days of apheresis (or sooner according to local regulations)
Other Tests 
 
Serum Pregnancy Testing (-human chorionic gonadotropin [β-hCG]) for
women of childbearing potential only.
 
Serology: Hepatitis B: Hepatitis B surface antigen [HBsAg], anti-HBc, anti-HBs,
HBV DNA quantification [for participants who are anti-HBs positive without
history of vaccination or for participants who are anti-HBs positive and anti-HBc
positive]; Monitor HBV DNA, AST/ALT every 3 months for one year post-dose
of cilta-cel out-of-specification [OOS]; Hepatitis C: HCV antibody, HCV-RNA
[for participants who are anti HCV positive]; HIV serology) (Refer Section 10.14,
Appendix 14).
 
Coagulation (Prothrombin time/International normalized ratio, Fibrinogen,
Activated partial thromboplastin time, D-dimer).
a Calculated using modified diet in renal disease (MDRD) formula (Section 10.16, Appendix 16).


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Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the CRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study treatment to
the study site:


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 
Protocol and amendment(s), if any, signed and dated by the principal investigator.
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form Food and Drug Administration [FDA]
1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials


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 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly  identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study treatment
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators 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 regulatory 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.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Informed consent may be obtained remotely. Refer to the Monitoring Guideline.
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants the aims, methods, reasonably anticipated benefits, and
potential hazards of the study, and any discomfort participation in the study may entail. Participants
will be informed that their participation is voluntary and that they may withdraw consent to
participate at any time. They will be informed that choosing not to participate will not affect the
care the participant will receive Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow-up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access It also denotes that the participant
agrees to allow his or her study physician to recontact the participant for the purpose of obtaining
consent for additional safety evaluations and subsequent disease-related treatments, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded by
means of the participant's personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.


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If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
10.3.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand cilta-cel OOS or to understand
multiple myeloma, to understand differential intervention responders, and to develop tests/assays
related to cilta-cel OOS and multiple myeloma. The research may begin at any time during the
study or the post-study storage period.
10.3.6. 
Committees Structure
Data Review Committee
A Data Review Committee (DRC) will be established to monitor data on an ongoing basis to ensure
the continuing safety of the participants enrolled in this study. The committee will meet
periodically to review accumulating data. After the review, DRC will make recommendations
regarding the continuation of the study. Initially, data will be reviewed by DRC after every 10
participants have been treated and followed for at least 3 months to assess efficacy and safety. This
committee will consist ofsponsor personnel independent of the study team and include at least one


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medical expert in the relevant therapeutic area and at least one statistician; committee membership
responsibilities, authorities, and procedures will be documented in its charter.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding cilta-cel OOS or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including biomarker research data, generated as a result of this
study, are considered confidential and remain the sole property of the sponsor. The investigator
agrees to maintain this information in confidence and use this information only to accomplish this
study and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by  the
sponsor in connection with the continued development of cilta-cel OOS, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of biomarker
analyses performed after the Clinical Study Report has been issued will be reported in a separate
report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived


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from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the International Committee
of Medical Journal Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing and
Publication of Scholarly Work in Medical Journals, which state that the named authors must have
made a significant contribution to the conception or design of the work; or the acquisition, analysis,
or interpretation of the data for the work; and drafted the work or revised it critically for important
intellectual content; and given final approval of the version to be published; and agreed to be
accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity
of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study to ensure
the statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central into the sponsor's data base. Written
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and
alterations must be made by the investigator or authorized study site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
eCRF, if applicable.  Study-specific data will be transmitted in a secure manner to the sponsor.


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Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
CRF in English. The CRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements will be completed by the same individual who made the initial
baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after
the initial entry into the CRF, this can be done in either of the following ways:
 Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study treatment administration information; and date of study
completion and reason for early discontinuation of study treatment or withdrawal from the study,
if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data:
 Race
 History of smoking
 Height and weight
 Details of physical examination
 Investigator-completed scales and assessments
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or


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 Complete history of medical notes at the site
 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. These data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site monitoring
to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary (refer to
Section 10.6, Appendix 6 for monitoring during Coronavirus Disease-2019 [COVID-19]). The
monitor will record dates of the visits in a study site visit log that will be kept at the study site. The
nature and location of all source documents will be identified to ensure that all sources of original
data required to complete the CRF are known  to the sponsor and study site personnel and are
accessible for verification by the sponsor study site contact. If electronic records are maintained at
the study site, the method of verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.12. 
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be


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respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first subject screened is considered the first act of recruitment and it becomes the study start
date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A


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study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study treatment development


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Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Council on
Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening (the participant was at risk of death at the time of the event. It does not refer
to an event that hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.


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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study treatment and the event (eg, death from anaphylaxis), the event must be reported
as a serious and unexpected suspected adverse reaction even if it is a component of the study
endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For cilta-cel OOS, the expectedness of an AE will be determined by
whether or not it is listed in the prescribing information.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention  is determined by the investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made by the investigator according to the NCI-CTCAE
(version 5.0), except for CRS and CAR-T cell-related neurotoxicity (ie, ICANS). Cytokine release
syndrome should be evaluated according to the ASTCT consensus grading (Section 10.7,
Appendix 7). CAR-T cell-related neurotoxicity (eg, ICANS) should be graded using the ASTCT
consensus grading (Section  10.8, Appendix 8). Changes in handwriting (ie, micrographia,
dysgraphia, or agraphia) should be graded using the criteria outlined in Section 10.12,
Appendix 12). Other neurotoxicities will be graded by CTCAE criteria. using the following
categorical descriptors:
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate
instrumental activities of daily living (ADL).*
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADL.**
Grade 4 
Life-threatening consequences; urgent intervention indicated.
Grade 5 
Death related to adverse event.
Activities of Daily Living (ADL):
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone,
managing money, etc.


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** 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study treatment in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study treatment
 
Suspected abuse/misuse of a sponsor study treatment
 
Accidental or occupational exposure to a sponsor study treatment
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study treatment from breastfeeding
 
Reporting of participant pregnancy or participant partner(s) pregnancy
Special reporting situations must be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE must be recorded on the SAE page of the CRF.
Since cilta-cel will be individually manufactured and provided by the sponsor for complete
administration in a one-time infusion, overdose with cilta-cel is not applicable for this study. Any
special reporting situation that meets the criteria of an AE, including SAE, should be recorded on
the AE/SAE page of the eCRF. Serious AEs should follow the 24-hour SAE reporting process.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, must be
recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). The exceptions are CRS and CAR-T cell-related neurotoxicity (eg, ICANS and other
neurotoxicity), for which all symptoms associated with these events will be collected in the eCRF.
Investigators must record in the CRF their opinion concerning the relationship of the AE to study
therapy. All measures required for AE management must be recorded in the source document and
reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study (post-infusion and post-treatment period) indicating the following:


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 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study treatment or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
 
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period.
Expected progression of disease should not be considered an AE (or SAE). However, if determined
by the investigator to be more likely related to the study treatment than the underlying disease, the
clinical signs or symptoms of progression and the possibility that the study treatment is enhancing
disease progression, should be reported per the usual reporting requirements.
Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms
of clinical sequelae resulting from disease progression/lack of efficacy will be reported if they
fulfill the SAE definition (refer to Adverse Event Definitions and Classifications in Appendix 4:


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Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting). All
deaths not related to disease progression occurring any time during study after receiving cilta-cel
should be reported to the sponsor following expedited reporting procedures.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form, which
must be completed and signed by a physician from the study site, and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
prepa6ation, storage or distribution of the product or the drug delivery system. The sponsor has
established procedures in conformity with regulatory requirements worldwide to ensure
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.


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Appendix 5: Contraceptive Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Section 10.4, Appendix 4 Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months of amenorrhea, a single follicle stimulating hormone (FSH) measurement is
insufficient.
 
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.


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 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 oral
 injectable
 Sexual abstinence
(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 treatment. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and
the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study treatment.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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Appendix 6: Study Conduct During a Natural Disaster/Major Disruption/
Pandemic
GUIDANCE ON STUDY CONDUCT DURING COVID-19PANDEMIC/NATURAL
DISASTER/MAJOR DISRUPTION
It is recognized that the Coronavirus Disease-2019 (COVID-19)/major disruption may have an
impact on the conduct of this clinical study due to, for example, self-isolation/quarantine by
participants and study site personnel; travel restrictions/limited-access to public places, including
hospitals; study site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgment of the
investigator to protect the health and well-being of participants and site staff. If, at any time, a
participant’s safety is considered to be at risk, study treatment will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
treatment, including follow-up. Modifications to protocol required assessments may be permitted
via COVID-19 Appendix after consultation with the participant, investigator, and the sponsor.
Missed assessments/visits will be captured in the clinical trial management system for protocol
deviations. Discontinuations of study treatments and withdrawal from the study should be
documented with the prefix “COVID-19-related” in the CRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study treatment andfollow-up. Modifications made
to the study conduct as a result of the COVID-19 pandemic should be summarized in the clinical
study report.
Testing for COVID-19 should be performed according to local guidance. If a participant has tested
positive for COVID-19, the following should be reported in the eDC tool:
 
all cases of COVID-19, regardless of severity or causality (including asymptomatic
COVID- 19) up to 1 year after cilta-cel infusion
 
all medications given to prevent (including vaccines) or treat COVID-19 up to 1 year after
cilta-cel infusion


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GUIDANCE SPECIFIC TO THIS PROTOCOL
These emergency provisions are meant to ensure participant safety on study while site capabilities
are compromised by COVID-19-related restrictions. As restrictions are lifted and the acute phase
of the COVID-19 pandemic resolves, sites should revert to original protocol conduct as soon as
feasible.
 
Missed assessments will be captured in the clinical trial management system for protocol
deviations, with the actual visit date documented or reason for withdrawals specified;
discontinuations of study treatments and withdrawal from the study will be captured with the
prefix “COVID-19-related” in the CRF.
 
Any changes in cilta-cel OOS treatment (eg, dose) due to COVID-19 reasons will be recorded.
 
Protocol required laboratory tests and assessments may be performed at a nearby hospital
when they cannot be done at the site. Verification of information outside of the study site may
be obtained by the site and entered into the eCRF, as appropriate. Any biomarker specimen
may be obtained whenever the participant is able to return to the site.
 
When on-site monitoring visits are not feasible (eg, due to local regulations, restrictions, and
guidance), the Site Manager may  arrange to conduct site monitoring visits and activities
remotely. Additional on-site monitoring visits may be needed in the future to catch up on
source data verification.
 
Investigator judgment is required to assess:
 
Information necessary to collect protocol required assessments to assess Response and
Disease Progression according to IMWG criteria, if necessary.
 
Telemedicine visits with or without local laboratory/local Oncologists that would be
sufficient to cover the planned visits, as long as, Telemedicine platform complies to
privacy standards for local Telemedicine process.
RECOMMENDATIONS FOR COVID-19 VACCINATION FOR CILTA-CEL
RECIPIENTS
It is recommended that participants can receive prophylactic COVID-19 vaccination when locally
available, at the discretion of investigator judgment or institutional practice, and in compliance
with the cilta-cel study protocol and local labels for the vaccine.
General guidance for consideration is as follows:
 
Many vaccines against COVID-19 are being developed with different technologies and
platforms, and may have safety and efficacy profiles that are not fully characterized even after
preliminary health authority approval. However, the benefit-risk ratio of receiving a
COVID-19 vaccine among patients with multiple myeloma participating in cilta-cel studies is
considered to be positive, and should be considered for administration while in compliance
with the study protocol and when not otherwise contraindicated for use in the vaccine label.
 
Per protocol, live attenuated vaccines must be completed at least 6 weeks prior to
lymphodepletion therapy or initiated at least 100 days after cilta-cel infusion. There are no
specific timing restrictions for inactivated vaccines, which include vaccines that use


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alternative technology like mRNA or replication-incompetent viral vectors, per protocol.
Enrollment into an interventional clinical trial for an experimental vaccine is prohibited during
study. Any vaccination, including COVID-19 vaccinations, must be recorded on the
concomitant medication page of the eCRF.
 
While not specifically required per protocol, it is encouraged to complete the COVID-19
vaccine series at least 2 weeks prior to lymphodepletion, and to delay vaccination for at least
3 months after cilta-cel infusion, to maximize immune response.
 
No data is currently available to suggest that COVID-19 vaccines pose specific or additional
safety risk beyond other vaccines for cancer patients undergoing treatment. Theoretically, a
diminished immune response may occur in immunocompromised patients, and therefore these
patients may have reduced vaccine effectiveness.
For additional information for reference or guidance, several organizations and journals have
published recommendations for COVID-19 vaccine administration in cancer patients, including:
 
European 
Society 
for 
Blood 
and 
Marrow 
Transplantation 
(EBMT):
https://www.ebmt.org/covid-19-and-bmt
 
ASTCT: https://www.hematology.org/covid-19/ash-astct-covid-19-vaccination-for-hct-and-
car-t-cell-recipients
 
National 
Comprehensive 
Cancer 
Network 
(NCCN): 
https://www.nccn.org/covid-
19/pdf/COVID-19_Vaccination_Guidance_V2.0.pdf
 
Centers for Disease Control and Prevention (CDC): https://www.cdc.gov/vaccines/covid-
19/info-by-product/clinical-considerations.html
 
Nature Reviews Clinical Oncology: COVID-19 vaccine guidance for patients with cancer
participating in oncology clinical trials. Desai A, Gainor JF, Hegde A. et al. (March 15, 2021).
DOI: 10.1038/s41571-021-00487-z: https://www.nature.com/articles/s41571-021-00487-z
 
Investigators should inform patients that emerging data show that patients receiving cilta-cel
are possibly at higher risk of severe/fatal outcomes from COVID-19 infection compared with
patients receiving standard of care therapy (Section 6.1.5.8).
 
Based on guidance from the organizations listed above, the following measures should be
implemented to minimize subjects’ risk of severe COVID-19 infection:
 
Subjects, particularly those who are less than 6 to 9 months from cilta-cel infusion, should be
reminded that the ongoing pandemic is still putting them at risk of contracting COVID-19.
Investigators should ask subjects to continue to limit their risk of exposure to infected
individuals as much as possible and strictly adhere to prevention measures such as proper
masking, hand hygiene, social distancing, and avoiding travel and public transportation to the
extent possible.
 
Investigators should discuss with subjects the importance of COVID-19 vaccines in the
prevention of severe illness, hospitalization, and death from COVID-19. Subjects should
assume that any vaccination administered prior to lymphodepletion and cilta-cel infusion no
longer provides protection. For this reason, it is strongly recommended that all subjects
receive a full COVID-19 vaccination series (eg, a primary series of 3 vaccines and a 4th
booster dose for mRNA vaccines; note: mRNA vaccines are recommended), no sooner than


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3 months after cilta-cel infusion, regardless of vaccination status prior to cilta-cel. In addition,
if not already vaccinated, caregivers, family, and household contacts should be advised to
receive COVID 19 vaccination as well.
 
Investigators should consider prophylaxis (eg, Evusheld, if available in the region) to reduce
subjects’ risk of severe/fatal COVID during the first 6 to 9 months after cilta-cel. It is critical
that subjects understand that multiple myeloma patients (even those who have not received
CAR-T therapy) may not seroconvert until after the 3rd vaccine dose and as a result they may
remain at a very high risk of severe COVID-19 for at least 2 to 3 months after starting
vaccination.
 
Investigators should instruct subjects to notify them or study site staff immediately if they are
diagnosed with COVID 19, even if they are asymptomatic, so that appropriate treatment
measures can be determined.
 
If available in the region, antivirals (eg, Paxlovid or other available agents) should be
considered early after COVID-19 diagnosis. Subjects may remain asymptomatic or have
minimal symptoms for a period of time prior to deteriorating. Investigators should make
subjects aware that these drugs may potentially significantly lower their risk of severe
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Appendix 8: Immune-Effector Cell-associated Neurotoxicity Syndrome
(ICANS) ASTCT Consensus Grading Systema,b
Neurotoxicity 
Domain
Grade 1 
Grade 2 
Grade 3 
Grade 4
ICE Score 
7-9 
3-6 
0-2 
0 (participant is
unarousable and
unable to perform
ICE).
Depressed Level of 
Consciousness 
Awakens 
spontaneously. 
Awakens to 
voice. 
Awakens only to tactile 
stimulus. 
Participant is
unarousable or
requires vigorous or
repetitive tactile
stimuli
to arouse. Stupor or
coma.
Seizure 
N/A  
N/A  
Any clinical seizure, 
focal or generalized, that 
resolves rapidly; or 
Non-convulsive 
seizures on EEG that 
resolve with  
intervention. 
Life-threatening
prolonged seizure
(>5 min); or
Repetitive clinical
or electrical seizures
without return to
baseline in between.
Motor Findings 
N/A  
N/A  
N/A  
Deep focal motor
weakness such as
hemiparesis or
paraparesis.
Raised 
Intracranial 
Pressure / 
Cerebral Edema  
N/A  
N/A  
Focal/local edema on 
neuroimaging. 
Diffuse cerebral
edema on
neuroimaging; or
Decerebrate or
decorticate
posturing; or
Cranial nerve VI
palsy; or
Papilledema; or
Cushing's triad.
Abbreviations: EEG=electroencephalogram; ICANS=Immune-Effector Cell-associated Neurotoxicity Syndrome
ICE=Immune-Effector Cell-associated encephalopathy; ICP=intracranial pressure; N/A=not applicable;
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
a Toxicity grading according to Lee 2019.
b ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings,
raised ICP/cerebral edema) not attributable to any other cause.
Note: all other neurological adverse events (not associated with ICANS) should continue to be graded with
NCI CTCAE version 5.0 during the study.


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Appendix 9: Immune-Effector Cell-associated Encephalopathy (ICE) Tool
Immune-Effector Cell-Associated Encephalopathy (ICE) Toola
Orientation: Orientation to year, month, city, hospital:
 
4 points
Naming: Name 3 objects (eg, point to clock, pen, button):
 
3 points
Following commands: (eg, Show me 2 fingers or Close your eyes and stick out your tongue):
 
1 point
Writing: Ability to write a standard sentence (eg, Our national bird is the bald eagle):
 
1 point
Attention: Count backwards from 100 by 10:
 
1 point
a: ICE-Tool Scoring:
 
Score 10: No impairment
 
Score 7-9: Grade 1 ICANS
 
Score 3-6: Grade 2 ICANS
 
Score 0-2: Grade 3 ICANS
 
Score 0 due to participant unarousable and unable to perform ICE assessment: Grade 4 ICANS
Abbreviations: ICANS=Immune-Effector Cell-associated Neurotoxicity Syndrome ICE=  Immune-Effector Cell-
associated encephalopathy.




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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 as 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 participant has IgA lambda myeloma, then to qualify as 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.).
c Clarifications to the criteria for coding progressive disease: bone marrow criteria for progressive disease are to be
used only in participants without measurable disease by M-protein and by FLC levels; “25% increase” refers to
M-protein, and FLC, and does not refer to bone lesions, or soft tissue plasmacytomas and the “lowest response
value” does not need to be a confirmed value.
Notes: All response categories (CR, sCR, VGPR, PR, MR, and progressive disease) require 2 consecutive assessments
made at any time before the institution of any new therapy; CR, sCR, VGPR, PR, MR, and stable disease categories
also require no known evidence of progressive or new bone lesions if radiographic studies were performed. VGPR
and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on
serum, urine, both, or neither.
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be
confirmed. For progressive disease, serum M-component increases of ≥1 g/dL are sufficient to define relapse if
lowest M-component is ≥5 g/dL.
Source: Adapted from Durie 2015; Rajkumar 2011; Kumar 2016.










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Appendix 15: Cilta-cel OOS Outpatient Administration Guidelines
When evaluating the suitability for outpatient administration, if allowed by local regulations and
institutional guidance among other considerations, investigators should assess the participant’s clinical
status and the health care facility capability to safely manage outpatient logistics. General recommendations
for each of these considerations are provided below:
1. 
Clinical consideration
General guidance for clinical considerations for a participant that is suitable for outpatient administration
and follow-up includes the following:
 
Not requiring packed red blood cell or platelet transfusions more frequently than every 2 days
 
No presence of an indwelling central line (with the exception of a peripherally inserted central
catheter [PICC] line) given risk of infection in the setting of cytopenia
 
No fever or active infection (bacterial, fungal, viral) since study enrollment
 
No Grade 3 or higher non-hematologic toxicities of cyclophosphamide and fludarabine including
nausea, vomiting, and diarrhea
 
No clinically significant coagulopathy that would increase the risk of bleeding in the setting of
cytopenia
 
No high tumor burden defined as at least 60% plasma cell infiltration of the marrow and/or the
presence of extramedullary disease
 
No risk factors for developing clinically significant tumor lysis syndrome and requiring
management with increased hydration, allopurinol, or rasburicase. Patients who are receiving
prophylactic treatment for TLS are eligible for outpatient infusion, if deemed stable by the
investigator
 
No rapidly progressing disease
 
No deterioration in neurologic status, including mental status changes such as confusion or
increased somnolence. The only exception is confusion or somnolence that has resolved and must
be attributed to diphenhydramine premedication for cilta-cel OOS.
 
The following laboratory parameters:
o 
eGFR of ≥40 mL/min/1.73 m2
o 
AST and ALT≤3 times the upper limit of normal
2. 
Logistical consideration for qualified healthcare facility
The following should be considered for outpatient administration and follow-up:
 
Site must discuss with participants how to the presenting signs and symptoms of recognize signs
ofCAR-T associated toxicities (including but not limited to CRS, neurotoxicities, infections, etc.)
as presented in the participant wallet card
 
Site must provide participants with educational material including but not limited to emergency
contact information
 
Participant is required to stay within 30 minutes of transportation to the hospital and remain in
the company of a competent adult at all times until Day 14.


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 
Participant must comply with all the protocol requirement procedures, including measuring and
recording of body temperature twice per day, and coming to the site for safety assessments
according to the SoA (Table 1).
 
Admission to the hospital is required at any time in the event of any presenting signs and
symptoms of CRS and/or neurotoxicity.
 
Participants who experience CRS and/or neurotoxicity, can be discharged from the hospital when
they are afebrile for 24 hours and signs and symptoms of CRS and/or neurotoxicity or other
clinically significant adverse event have resolved.
 
If a patient is admitted for CRS and/or ICANs, upon discharge from the hospital, the participant
must stay locally within 1 hour of transportation to the hospital and remain in the company of a
competent adult at all times for 1 additional week, or up to study Day 21, whichever is sooner.


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Appendix 16: Formulas for Estimating Glomerular Filtration Rate
Modified Diet in Renal Disease (MDRD) Formula
For serum creatinine in mg/dL, the estimated glomerular filtration rate (eGFR) for the MDRD formula is:
eGFR (MDRD) mL/min per 1.73m2= 175 x [serum creatinine (mg⁄dL)]-1.154 x [age]-0.203 x [1.212 if
black] x [0.742 if female]
For serum creatinine in µmol/L, the eGFR for the MDRD formula is:
eGFR (MDRD) mL/min per 1.73m2= 175 x [serum creatinine (mol/L)/88.4]-1.154 x [age]-0.203 x [1.212
if black] x [0.742 if female]
Source: Levey (2006)




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Appendix 18: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 1 (26 May 2021)
Overall Rationale for the Amendment:  The overall reasons for this amendment are to include
recommendations from Safety Management Team (SMT) for Coronavirus Disease-2019 (COVID-19)
vaccinations for cilta-cel recipients, to align reporting of adverse events (AEs), which includes any
non-serious AEs related to study treatment, serious AEs (SAEs) regardless of causality, and delayed AEs.
Tumor lysis syndrome (TLS) is no longer required to be monitored as an adverse event of special interest
(AESI). Potential risks associated with cilta-cel and its management guidelines are updated to align with
latest edition of investigator brochure and other cilta-cel study protocols. The end of study (EOS) definition
is updated to align with other cilta-cel study protocols. The definition of treatment emergent adverse events
(TEAEs) is updated to include any AE reported at or after the initial administration ofstudy treatment.
A Protocol Amendment Summary of Changes Table for current amendment is provided below. The updates
are indicated in bold text and strike-through for the deleted text, wherever applicable.
Section number 
and Name
Description of Change 
Brief Rationale
10.6. Appendix 6: Study
Conduct During a Natural
Disaster
Appendix was updated to include
‘Recommendations for COVID-19 vaccination
for cilta-cel recipients’.
To align with recommendations
from Safety Management Team.
Synopsis-Safety
Evaluations; 4.1. Overall
Design
Text updated to include that participants
follow-up will continue to include all SAEs and
delayed AEs during Post-treatment Phase.
To align with adverse event
reporting guidance.
1.3. Schedule of Activities
(SoA)-Adverse events
(AEs);
8.3.1. Time Period and
Frequency for Collecting
Adverse Event and
Serious Adverse Event
Information-Delayed AEs,
Serious AEs
Adverse event text modified to include the
reporting of following:
 All SAEs regardless of causality, and any
nonserious adverse events considered
related to study treatment until end of study
(EOS).
 For participants who progress before Day
100 post cilta-cel, AEs/SAEs should still be
reported until 100 days post cilta-cel or until
resolution, whichever is later.
 Delayed AEs (regardless of causality) will be
collected from the time of cilta-cel infusion
and for the duration of the study, and
subsequently in a separate long-term follow-
up study for up to 15 years after last
administration of cilta-cel
 Events of hepatitis B virus [HBV]
reactivations should be reported during the
first year post dosing of cilta-cel.
 A note on second primary malignancies
(SPM) was deleted and corresponding
footnote ‘q’ was revised to include ‘a new or
recurrent malignancy’.
 A new appendix added for AE reporting and
guidance. (Appendix 18)
To ensure continuous data
collection of non-serious AEs
(related to study treatment) from
signing of ICF until EOS and
requirement of reporting of
AEs/SAEs data for participants
showing disease progression
before Day 100.
To define reporting duration for
HBV reactivations and long-
term collection of delayed AEs,
for consistency with other
cilta-cel study protocols.


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Section number
and Name
Description of Change 
Brief Rationale
8.3.1. Time Period and
Frequency for Collecting
Adverse Event and
Serious Adverse Event
Information-Adverse
Events of Special Interest
Grade 3 tumor lysis syndrome (TLS) was
deleted as adverse event of special interest
(AESI) and text updated to include that AESIs
will require enhanced data collection in the
electronic CRF (eCRF).
Reporting of SPM updated as: ‘For the
purpose of reporting, second primary
malignancies include both new primary
malignancies and recurrence of pre‑existing
malignancies with the exception of multiple
myeloma (which should be reported as
disease progression)’.
To align with recent IB update
for TLS and adverse event
reporting guidance for SPM.
8.3.1. Time Period and
Frequency for Collecting
Adverse Event and
Serious Adverse Event
Information-All adverse
events; 10.4.5.
Procedures-All adverse
events
Overall, the text of ‘All adverse events’ was
aligned to include details to be recorded in
eCRF.
Additionally, the new text added ‘The
exceptions are cytokine release syndrome
(CRS) and chimeric antigen receptor-T
(CAR-T) cell-related neurotoxicity (eg,
Immune Effector Cell-Associated
Neurotoxicity [ICANS] and other
neurotoxicity), for which all symptoms
associated with these events will be collected
in the eCRF.’
To ensure early detection,
characterizing, monitoring, and
reporting of CRS and CAR-T
cell-related neurotoxicity.
1.3. Schedule of Activities
(SoA); 4.4. End of Study
Definition; 8. Study
Assessments and
Procedures-
Post-treatment;
10.4.3. Severity Criteria;
10.4.4. Special Reporting
Situations
 The end of study (EOS) definition was
updated as ‘2 years after each participant
has received his or her initial dose of cilta-
cel OOS’. The term ‘last participant’ from
EOS definition was deleted.
 The footnote ‘b’ of SoA was revised for
EOS definition.
 Text updated to include severity grading for
CRS, CAR-T cell related cell neurotoxicity,
and handwriting assessments.
 New text added that ‘overdose’ is not
applicable as cilta-cel infusion administered
as a one-time infusion.
 Text related to AE reporting as follows:
‘Any special reporting situation that
meets the criteria of an AE, including
SAE, should be recorded on the AE/SAE
page of the eCRF. Serious AEs should
follow the 24-hour SAE reporting
process’.
To clarify EOS definition and to
align the text of severity criteria
and special reporting situations
with other cilta-cel study
protocols.
3. Objectives and
Endpoints-Secondary
Secondary endpoint revised to include ‘severity’
of treatment-emergent adverse events.
To be consistent with definition
of treatment-emergent adverse
events.
9.4.1.2. Secondary
Endpoints-Adverse Events
The subsection of AEs was updated as below:
“The verbatim terms used in the CRF by
investigators to identify AEs will be coded
using the Medical Dictionary for Regulatory
Activities (MedDRA). Section 8.3 provides
information on AEs that are to be reported
To update treatment emergent
AEs and to include severity
criteria for assessment of
TEAEs.


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Description of Change 
Brief Rationale
following initial administration of study
treatment. Any AE reported at or after the
initial administration of study treatment is
considered to be treatment-emergent. Any
AE occurring at or after the initial
administration of study treatment through the
day of last dose plus 30 days is considered to be
treatment emergent. All reported treatment-
emergent AEs will be included in the analysis.
For each AE, the percentage of participants who
experience at least 1 occurrence of the given
event will be summarized”.
Severity criteria was clarified as ‘Parameters
with predefined National Cancer Institute
Common Terminology Criteria for Adverse
Event (NCI-CTCAE) (version 5.0) toxicity
grades will be summarized for treatment
emergent adverse events (TEAEs)’.
5.2. Exclusion Criteria;
6.1.2. Criteria for
Conditioning Regimen
(Cyclophosphamide and
Fludarabine)
 Exclusion criterion 3 was updated to include 
medical conditions that may result in 
exclusion from the study. 
 New exclusion criteria (4, 5, and 6) were
added to include viral infections (HBV,
hepatitis 
C 
[HCV], 
and 
human
immunodeficiency 
virus 
[HIV]),
respectively.
 Criteria for lymphodepleting chemotherapy
was updated for medical conditions to align
with modified exclusion criterion 3.
Criterion 3 modified to align
with other cilta-cel study
protocols.
As CAR-T therapy may increase
risks of viral infections, new
exclusion criteria are added.
2.3.1. Risks for Study
Participation-Table 2,
Table 3;
6.1.5.1. Management of
Cytokine Release
Syndrome;
6.1.5.4. Other
Neurotoxicities;
6.1.5.5. Tumor Lysis
Syndrome
6.1.5.6. Cytopenia;
6.1.5.7.
Hypogammaglobulinemia;
6.1.5.8. Infections;
6.1.5.9. Hypersensitivity
Reactions
6.1.5.10. Second Primary
Malignancy;
Text of Table 2 and Table 3 were aligned to 
management guidelines for potential risks and 
included new guidelines to risk characterization 
and mitigation strategies, wherever applicable. 
The key updates are listed below:
 To notify the sponsor if participant is
experiencing Grade 2 or higher CRS.
 Recommendation to use cytokine targeting
therapies for CRS and for other
neurotoxicities, which do not respond to
tocilizumab or corticosteroids.
 Language of ‘Other neurotoxicities’ aligned
to include movement impairments,
cognitive impairments, and personality
changes.
 Table (Other neurotoxicities) updated to
include: Infection and sepsis were seen
concurrently in many of these patients.
 Additional monitoring and mitigation
strategies added to ensure early detection
of neurotoxicity and extended monitoring
and reporting time for the study duration.
 TLS is no longer to be reported as an AESI.
To make text consistent with
latest management guidance for
potential risks associated with
cilta-cel.


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Section number
and Name
Description of Change 
Brief Rationale
 Titles of subsections (6.1.5.6. and 6.1.5.8.)
updated to ‘Prolonged Cytopenia’ and
‘Serious Infections’, respectively.
 A subsection (Cytopenia) was updated to
include the risk of bleeding in case of
severe thrombocytopenia and its
monitoring per institutional guideline.
 
Table 3 (Prolonged cytopenia) mitigation
strategy updated to include supportive care
to be provided along with monitoring of
blood counts.
 
A subsection (Hypogammaglobulinemia)
updated to include ‘HBV reactivation’ as
one of the recurrent infection and
administration of subcutaneous
immunoglobulin (IgG) to be considered.
 A subsection (Infections) updated to include
following: ‘Immunocompromised
participants are at risk for opportunistic
infections. Prophylactic use of
antibiotics, antivirals, and antifungals
should be considered’.
 Table 3 (Serious Infection) text aligned to
Appendix 14 for HBV infections.
 A subsection (Hypersensitivity Reactions)
updated to specify the names of
premedication prior to cilta-cel dosing.
 A subsection (SPM) clarified lentiviral
insertion as (DNA integration) of the
lentiviral vector.
6.8.2. Prohibited
Therapies;
6.1.2. Criteria for
Conditioning Regimen
(Cyclophosphamide and
Fludarabine)
 Text updated to include prohibition of
receptor activator of nuclear factor kappa-Β
(RANK) ligand inhibitors and medical
condition such as autoimmune disease.
 Vaccination with live, attenuated vaccine to
be delayed for atleast 6 weeks instead of 4
weeks 
prior 
to 
lymphodepleting
chemotherapy.
 Section 6.1.2. title revised to include
‘lymphodepleting chemotherapy’ instead of
‘conditioning regimen’.
To avoid potential impact to
immune function prior to
cilta-cel infusion.
To align terminology with other
cilta-cel study protocols.
2.3.1. Risks for Study
Participation-Table 3;
5.2. Exclusion Criteria;
6.1.5.9. Hypersensitivity
Reactions
The drug ‘ampicillin’ was deleted. 
Ampicillin is no longer used in
manufacturing process.
2.2.6. Clinical Studies-
Exposure, Conclusion;
6.1.5.1. Management of
Cytokine Release
Syndrome
 Text updated to include latest safety and
efficacy data from the clinical study report
and recent edition of IB update for the study
68284528MMY2001.
To align with recent IB updates.


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Section number
and Name
Description of Change 
Brief Rationale
 An AESI-CRS was updated to clarify that an
excluded participant with 97-day CRS event
was due to complication of hemophagocytic
lymphohistiocytosis (HLH).
1.3. Schedule of Activities
(SoA)
8.1.2. Bone Marrow
Examination
The SoA was updated for following:
 Assessment of ‘Immunophenotyping and
Pharmacokinetics [PK] (Whole blood)’ was
revised to ‘Immunophenotyping’ testing
and to be performed at Day 1 infusion.
 A note added to assessment of bone marrow
aspirate and core biopsy: ‘Fluorescence in
situ hybridization (FISH) testing required to
be performed at central laboratory.’
 ‘Baseline’ assessment was deleted from
minimal residual disease (MRD) bone
marrow aspirate testing.
 The PK sampling was deleted from the
footnotes ‘n’ and ‘p’.
 The footnote ‘o’ was updated to include that
PK-CAR transgene samples would be
collected at least annually until EOS
instead of ‘every 6 months post 1-year’.
Additional event-triggered testing for PK
CAR transgene may be conducted as
clinically indicated.
 The footnote ‘i’ was updated to include
requirement of FISH testing prior to
lymphodepleting chemotherapy.
 A note added to serology testing and
corresponding footnote ‘e’ updated as ‘For
participants at risk of HBV reactivation,
monitor HBV DNA, aspartate
aminotransferase (AST)/alanine
aminotransferase (ALT) every 12 weeks
(±7 days)…’and text cross-referred to
Appendix 14.
 A note added to infectious disease testing
that it should be performed as indicated
clinically.
 A footnote ‘r’ updated to include testing of
an additional Ig samples may be required.
To delete ‘PK’ sampling from
immunophenotyping testing as it
is redundant.
To accurately reflect required
assessments (ie, FISH testing)
and timepoints for MRD (bone
marrow aspirate) testing.
To perform PK CAR transgene
testing per request received from
health authority and to align with
other cilta-cel study protocols.
6.1.5.3. CAR-T Cell-
related Neurotoxicity
(Immune Effector Cell-
Associated Neurotoxicity
Syndrome [ICANS])
PK sampling was deleted from cerebrospinal
fluid (CSF) testing.
To remove the PK testing as it is
not required and will not be done
on CSF samples.
8. Study Assessments and
Procedures-Study-Specific
Materials
Interactive web response system (IWRS)
manual was deleted from the list of study-
specific materials.
IWRS will not be used in this
study.
8.2.7. Clinical Safety
Laboratory Assessments
Text updated to include: ‘Participants with
Grade 3 or higher toxicity or unresolved AEs
To align with AE reporting
guidance.


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Description of Change 
Brief Rationale
will continue to be assessed until recovery to
Grade 1 or baseline, the event is deemed
irreversible, the end of the study, or a
maximum of 6 months, whichever occurs
first’
10.4.6. Product Quality
Complaint Handling-
Definition
Definition updated to include: ‘The sponsor 
has established procedures in conformity 
with regulatory requirements worldwide to
ensure appropriate reporting of product
quality complaint (PQC) information; all
studies conducted by the sponsor or its
affiliates will be conducted in accordance
with those procedures.’
To align with Janssen global
practices
10.2. Appendix 2: Clinical
Laboratory Tests
An assessment updated to include cluster of 
differentiation (CD)-CD4/CD8 Lymphocyte 
Panel.
To align with laboratory
requirements.
10.13. Appendix 13: Anti-
microbial Prophylaxis
Recommendations
 Antimicrobial prophylaxis should be started 
by Day-1 of CAR-T infusion. 
 A following note added: ‘Consider
cytomegalovirus (CMV) serology at
baseline, monitor with PCR testing as
clinically indicated per institution
guidance’.
 For pneumocystis pneumonia:
 
pentamidine should be administered by
Day -1 of CAR-T infusion, or as an
alternative treatment.
 Drug and dosage regimen added for
Day 28.
To align with antimicrobial
prophylaxis guidelines.
10.14. Appendix 14:
Hepatitis B Virus
Screening
A note added: ‘To minimize the number of times
a participant would need to visit the clinic, the
post-treatment follow-up visit (every 28 days post
Day 112 [±7 days]) can be coordinated with the
AST/ALT assessment every 12 weeks (±7 days).’
To align with HBV guidelines.
Throughout the protocol;
10.1. Appendix 1:
Abbreviations and
definitions;
11. References
The term ‘conditioning regimen’ updated to
‘Lymphodepleting chemotherapy’.
The abbreviation list was updated.
Added a new publication on HBV screening.
Minor grammatical, formatting, and spelling
changes were made.
Minor errors were noted.


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11. 
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Status: Approved, Date:  02 September 2022
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
 
02-Sep-2022
12:10:41
(GMT)
Document Approval
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 21 February 2024
Janssen Research & Development
Statistical Analysis Plan
A Safety and Efficacy Study of JNJ-68284528, (ciltacabtagene autoleucel) Out-of-
Specification (OOS) for Commercial Release in Patients with Multiple Myeloma
Protocol 68284528MMY2005; Phase 2
JNJ-68284528  (ciltacabtagene autoleucel)
Status:
Approved
Date:
21 February 2024
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-RIM-1263806
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT05347485


JNJ-68284528  (ciltacabtagene autoleucel)
Statistical Analysis Plan 68284528MMY2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 21 February 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives and Endpoints ................................................................................................................ 6
1.2.
Study Design.................................................................................................................................... 7
2.
STATISTICAL HYPOTHESES............................................................................................................ 8
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 8
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 8
5.
STATISTICAL ANALYSES................................................................................................................. 8
5.1.
General Considerations ................................................................................................................... 8
5.1.1.
Visit Windows ............................................................................................................................... 8
5.1.2.
Pooling Algorithm for Analysis Centers ........................................................................................ 9
5.1.3.
Study Intervention......................................................................................................................... 9
5.1.4.
Study Day and Relative Day......................................................................................................... 9
5.1.5.
Baseline ........................................................................................................................................ 9
5.1.6.
Unique Efficacy Laboratory Values .............................................................................................. 9
5.1.7.
Imputation Rules for Missing Date/Time of Onset/Resolution.................................................... 10
5.1.7.1.
Adverse Event Start/End Date................................................................................................. 10
5.1.7.2.
Concomitant Medication Start/End Date ................................................................................. 10
5.1.7.3.
Multiple Myeloma Diagnosis Date ........................................................................................... 11
5.1.7.4.
Prior Multiple Myeloma Therapy Start/End Date..................................................................... 12
5.1.7.5.
Progressive Disease Date on Prior Multiple Myeloma Therapy.............................................. 12
5.1.7.6.
Subsequent Antimyeloma Therapy Start Date........................................................................ 12
5.1.7.7.
Death Date............................................................................................................................... 13
5.1.8.
Other General Definition............................................................................................................. 13
5.1.8.1.
Measurable Disease of Multiple Myeloma and Measurable Type........................................... 13
5.1.8.2.
Type of Multiple Myeloma at Baseline..................................................................................... 14
5.1.8.3.
End of Follow-up and Duration of Follow-up ........................................................................... 14
5.1.9.
Data Handling Rules for Efficacy Analyses ................................................................................ 14
5.1.10.
Level of Significance................................................................................................................... 14
5.2.
Participant Dispositions.................................................................................................................. 14
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 15
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 15
5.3.2.
Estimand..................................................................................................................................... 15
5.3.3.
Analysis Methods........................................................................................................................ 15
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 16
5.4.1.
Other Categories of Best Responses......................................................................................... 16
5.4.1.1.
Definition.................................................................................................................................. 16
5.4.1.2.
Analysis Methods .................................................................................................................... 16
5.4.2.
Minimal Residual Disease (MRD)-Negative Rate ...................................................................... 16
5.4.2.1.
Definition.................................................................................................................................. 16
5.4.2.2.
Analysis Methods .................................................................................................................... 17
5.4.3.
Duration of Response................................................................................................................. 17
5.4.3.1.
Definition.................................................................................................................................. 17
5.4.3.2.
Analysis Methods .................................................................................................................... 17
5.4.4.
Progression-free Survival ........................................................................................................... 17
5.4.4.1.
Definition.................................................................................................................................. 17
5.4.4.2.
Analysis Methods .................................................................................................................... 18
5.4.5.
Overall Survival........................................................................................................................... 18


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5.4.5.1.
Definition.................................................................................................................................. 18
5.4.5.2.
Analysis Methods .................................................................................................................... 18
5.5.
Tertiary/Exploratory Endpoint(s) Analysis...................................................................................... 18
5.6.
Safety Analyses ............................................................................................................................. 18
5.6.1.
Extent of Exposure ..................................................................................................................... 19
5.6.2.
Adverse Events........................................................................................................................... 19
5.6.3.
Adverse Events of Special Interest............................................................................................. 21
5.6.3.1.
Cytokine Release Syndrome (CRS)........................................................................................ 21
5.6.3.2.
Neurological Adverse Events .................................................................................................. 21
5.6.3.3.
Prolonged and Recurrent Cytopenias ..................................................................................... 22
5.6.3.4.
Secondary Primary Malignancies............................................................................................ 22
5.6.4.
Other Adverse Events................................................................................................................. 23
5.6.5.
Additional Safety Assessments .................................................................................................. 24
5.6.5.1.
Clinical Laboratory Tests......................................................................................................... 24
5.6.5.2.
Vital Signs and Physical Examination Findings....................................................................... 25
5.6.5.3.
Cardiac Function Assessments............................................................................................... 25
5.6.5.4.
ECOG Performance Score...................................................................................................... 25
5.7.
Other Analyses............................................................................................................................... 26
5.7.1.
Pharmacokinetics ....................................................................................................................... 26
5.7.2.
Immunogenicity........................................................................................................................... 26
5.7.2.1.
Immunogenicity Analysis ......................................................................................................... 26
5.7.3.
Pharmacodynamics .................................................................................................................... 26
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 26
5.7.5.
Biomarkers.................................................................................................................................. 26
5.7.5.1.
Minimal Residual Disease (MRD) ........................................................................................... 26
5.7.5.1.1.
Analysis Methods ................................................................................................................. 26
5.7.5.2.
Replication competent lentivirus (RCL) ................................................................................... 26
5.7.5.2.1.
Analysis Methods ................................................................................................................. 26
5.7.5.3.
Molecular Subtyping ................................................................................................................ 26
5.7.5.3.1.
Molecular Subtypes.............................................................................................................. 26
5.7.5.3.2.
Molecular Risk Subgroup Analysis ...................................................................................... 27
5.7.5.4.
Cytokine profiling ..................................................................................................................... 27
5.7.5.5.
Immunophenotyping ................................................................................................................ 27
5.7.6.
Analyses for COVID-19 .............................................................................................................. 27
5.7.7.
Subgroup Analyses..................................................................................................................... 28
5.7.7.1.
Definition of Subgroups ........................................................................................................... 28
5.7.7.2.
Analyses .................................................................................................................................. 28
5.8.
Interim Analyses............................................................................................................................. 29
5.8.1.
Data Review Committee (DRC).................................................................................................. 29
6.
SUPPORTING DOCUMENTATION .................................................................................................. 31
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 31
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 33
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 34
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 36
6.5.
Appendix 5 Prior, Concomitant and Follow-Up Medications.......................................................... 37
6.5.1.
Prior Exposure to Multiple Myeloma Therapies.......................................................................... 37
6.5.2.
Refractory Disease ..................................................................................................................... 37
6.5.3.
Concomitant Medications ........................................................................................................... 38
6.5.4.
Subsequent Antimyeloma Therapy ............................................................................................ 38
6.6.
Appendix 6 Medical History ........................................................................................................... 39
6.7.
Appendix 7 Treatment Compliance................................................................................................ 40
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 41
6.9.
Appendix 9 Medications of Special Interest................................................................................... 42
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 43
6.11.
Appendix 11 Progressive Disease and Response Algorithm based on IMWG Criteria for 
Multiple Myeloma ........................................................................................................................... 49


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7.
REFERENCES................................................................................................................................... 50


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VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
Not Applicable
Initial release


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1.
INTRODUCTION
1.1.
Objectives and Endpoints 
Objectives
Endpoints
Primary

To evaluate the efficacy of 
cilta-cel OOS

Overall Response of partial response or better (i.e., ORR), 
as defined by the International Myeloma Working Group 
(IMWG) response criteria and assessed by the 
investigator. Time frame: Screening Phase through End 
of Study (EOS) (Month 24 after cilta-cel OOS 
infusion/Early withdrawal).
Secondary

To assess the safety of cilta-
cel OOS

Incidence and severity of treatment-emergent adverse 
events, serious adverse events, abnormalities in safety 
(laboratory assessments), vital signs, and physical 
examinations

To further characterize the 
efficacy of cilta-cel OOS

Partial Response (PR)/very good partial response 
(VGPR)/complete response (CR)/stringent complete 
response (sCR) rate and clinical benefit rate (CBR=ORR 
[sCR+CR+VGPR+PR]+MR [minimal response]), as 
defined by the IMWG response criteria, duration of 
response (DOR), progression-free survival (PFS), overall 
survival (OS) and minimal residual disease
(MRD)-negative rate.

To determine whether 
replication competent 
lentivirus is present in 
participants that receive 
cilta-cel OOS

Presence of replication competent lentivirus
Exploratory

To characterize the 
pharmacokinetics and 
pharmacodynamics of 
cilta-cel OOS

Biomarkers including baseline expression of BCMA in 
MM cells, depletion of BCMA expressing cells, systemic 
cytokine concentrations, and CAR-T PK parameters such 
as expansion and persistence via monitoring CAR-T 
positive cell counts, and CAR transgene levels

To assess the 
immunogenicity of cilta-cel 
OOS

Presence of anti-cilta-cel OOS antibodies.
Abbreviations: BCMA=B-cell maturation antigen; CAR-T=Chimeric antigen receptor-T cells; CBR=clinical benefit 
rate; CR=complete response; DOR=duration of response; EOS=End of Study; IMWG=International Myeloma 
Working Group; MM=multiple myeloma; MRD=minimal residue disease; MR=minimal response; OOS=Out-of-
Specifications;
ORR=overall 
response
rate; 
OS=overall 
survival; 
PFS=progression-free 
survival; 
PK=pharmacokinetics; PR=partial response; sCR=stringent complete response; VGPR=very good partial response.


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1.2.
Study Design
This is a Phase 2, open-label, single-arm, multicenter study of cilta-cel OOS administered to adult 
participants (≥ 18 years) with multiple myeloma whose final manufactured cilta-cel does not meet 
the commercial release specifications (cilta-cel OOS) and whose expected benefit/risk profiles for 
cilta-cel OOS are assessed as favorable by the sponsor. The aim of the study is to evaluate the 
safety and efficacy of cilta-cel OOS. It was planned to enroll at least 20 participants. An overview 
of the trial design can be found in Figure 1 of the Protocol. 
Safety and efficacy of participants who received cilta-cel OOS will be evaluated at the periodic 
Data Review Committee (DRC) meetings. Initially, data will be reviewed by a commissioned DRC 
after every 10 participants have been treated and followed for at least 3 months. 
Eligible participants will be administered a lymphodepleting chemotherapy of IV 
cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days per United States 
prescribing information (USPI) or locally approved label. Cilta-cel OOS will be administered at a 
total target dose of 0.75x106 CAR-positive viable T cells/kg (range: 0.5 to 1.0x106 CAR-positive 
viable T cells/kg) or per exceptional release criteria determined alternative dose, 5 to 7 days after 
the start of the lymphodepleting chemotherapy (Section 4.1 of Protocol). 
Efficacy evaluations include myeloma protein measurements and imaging as indicated for enrolled 
participants to evaluate response and disease progression.  Disease status will be evaluated by the 
investigator according to clinical judgement guided by the International Myeloma Working Group 
(IMWG) consensus recommendations4 for multiple myeloma treatment response criteria (Section 
10.10, Appendix 10 of Protocol). 
Safety of cilta-cel OOS infusion will be assessed by adverse events, laboratory test results, vital 
sign measurements, physical examination findings, handwriting assessments, assessment of 
Immune-Effector Cell-associated Encephalopathy (ICE) Tool scores, and assessment of Eastern 
Cooperative Oncology Group (ECOG) performance status grade. 
Following the cilta-cel OOS infusion, participants were to be followed for 2 years in this study to 
assess response, DOR, PFS, OS and safety. All participants who received citla-cel OOS will 
continue to be monitored for long-term safety under a separate long-term follow-up study 
(68284528MMY4002) for up to 15 years after the infusion of cilta-cel OOS.
It was decided by Janssen to prematurely discontinue the study. This decision was made on 19
April 2023. Participants will remain in this study until a minimum of Day 184 visit. Participants
treated with cilta-cel OOS will be offered participation in the long term follow-up study, 
68284528MMY4002. Sites were instructed to ensure all participants were offered participation in 
68284528MMY4002 by the time the last patient infused with cilta-cel OOS in the study reaches 
Day 184.  


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2.
STATISTICAL HYPOTHESES
Since there is no statistical hypothesis for this study, no formal statistical hypothesis testing is 
planned.
3.
SAMPLE SIZE DETERMINATION
Sample size for this study is not based on statistical consideration. Based on the manufacturing 
experience with the study 68284528MMY2001, at least 20 participants were anticipated to enroll 
in the study.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
All Consented Analysis Set
The all consented analysis set includes all participants 
who signed the informed consent for the study
All Treated Analysis Set
The all treated analysis set includes all participants who 
received study intervention (cilta-cel OOS).
Response-evaluable Analysis Set
The response-evaluable analysis set includes all 
participants who received cilta-cel OOS, had measurable 
disease at baseline, and had at least one post-baseline 
efficacy assessment
Pharmacokinetics Analysis Set
The PK analysis set is defined as all participants who 
received a cilta-cel OOS infusion and have at least 1
post-dose pharmacokinetic sample evaluation available.
Immunogenicity Analysis Set
The immunogenicity analysis set is defined as all 
participants who received a cilta-cel OOS infusion and 
have at least 1 post-dose immunogenicity sample
evaluation available.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Visit Windows
Unless otherwise specified, data to be analyzed or listed over time will be presented by scheduled 
visit and time point (as appropriate) that are recorded in the electronic case report form (eCRF).
For safety laboratory (chemistry, hematology, coagulation) and vital sign parameters besides 
temperature, the following visit window rule will be applied for summaries of parameter values 
by visit/time point: for each scheduled visit/timepoint and parameter, if there are multiple non-
missing records per participant, the record with latest date/time will be selected for summary. For 
temperature, if a participant has multiple non-missing records per scheduled visit/timepoint, 
following this selection order to choose a unique record: (1) choose a unique record for summary 
by selecting value from clinic visit over diary entries, and (2) choose the record with the latest 
date/time. For RCL, the following visit window will be used:

Pre-dose of cilta-cel OOS infusion (target study day = 1): study day=1

3 months after cilta-cel OOS infusion (target study day = 91): 2 ≤ study day ≤137


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
6 months after cilta-cel OOS infusion (target study day = 183): 138 ≤ study day ≤ 274

12 months after cilta-cel OOS infusion (target study day = 365): 275 ≤ study day ≤ 457
If there are multiple RCL results within a visit window per participant, choose the result closes to 
the target day and if there are still multiple results after this step, choose the record with the last 
date.
5.1.2.
Pooling Algorithm for Analysis Centers
Data from all study centers will be pooled for analysis purpose.
5.1.3.
Study Intervention
Study intervention refers to cilta-cel OOS.
5.1.4.
Study Day and Relative Day
Study Day 1 refers to the start date of the first infusion of cilta-cel OOS.  
Study day or relative day for a visit or assessment/event is defined as:
•
visit date - date of Study Day 1 +1, if visit date ≥ date of Study Day 1 (i.e., on or after cilta-
cel OOS infusion)
•
visit date - date of Study Day 1, if visit date < date of Study Day 1 (i.e., prior to cilta-cel 
OOS infusion)
5.1.5.
Baseline
The baseline value is defined as the closest non-missing value before the first infusion of cilta-cel 
OOS (including time if time is available), with exception of parameters associated with disease-
related efficacy assessment (such as SPEP, UPEP, SIFE, UIFE, kappa, lambda, kappa/lambda 
ratio) for which the baseline value is defined as the latest non-missing value on and before cilta-
cel OOS infusion (excluding time). For parameters that are not associated with disease-related 
efficacy assessment, if the assessment date is the same as the first infusion date of cilta-cel OOS 
but the time is missing, the assessment will be considered baseline if the Schedule of Activities 
(Table 1 of Protocol) states that the corresponding test is to be conducted pre-dose. 
5.1.6.
Unique Efficacy Laboratory Values
In general, in instances when there are multiple records at a given visit date for laboratory
parameters associated with disease assessment, the following rules will be applied to select the 
unique laboratory values for analysis: 

For SPEP, UPEP, FLC, serum and urine immunofixation, immunoglobulin (IgA, IgD, IgE, 
IgG, IgM, etc.): (a) if multiple records from both central and local laboratory are available, 
central laboratory value always takes precedence over local laboratory values; b) if 
multiple records selected after step (a), select records with specimen condition by priority 
of frozen over refrigerated over ambient/room temperature ; c) if multiple records selected 


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after step (b), select the scheduled visit record; d) if multiple records selected after step (c), 
select the record with the largest visit number/sequence number.

For percent plasma cells (by biopsy/aspirate), choose the largest value of percent plasma 
cells
5.1.7.
Imputation Rules for Missing Date/Time of Onset/Resolution
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations. For analysis and reporting purposes, missing or partial dates in AE (AE onset date,
AE end date), concomitant therapies (start date, end date), multiple myeloma diagnosis date, prior 
multiple myeloma therapies (start date, end date), progressive disease date on prior multiple 
myeloma therapy, and start date of subsequent antimyeloma therapy will be imputed as specified 
below.
5.1.7.1.
Adverse Event Start/End Date
If the start date of an AE is missing completely or partially, the following imputation rules will be 
used: 

When month and year are present and the day is missing: if the AE onset month and year are 
the same as the month and year of first dosing date of study intervention (cilta-cel OOS), the 
day of the AE start date is imputed to the day of first dosing or the day-component of the AE 
end date (possibly imputed), whichever is earlier; if the onset month and year are not the same 
as the month and year of the initial dose of study intervention, the day of the AE start date is 
imputed to the first day of the month.

When only onset year is present: if AE end date is available and is prior to first dosing date of 
study intervention, the day and month of AE end date are used for imputation; otherwise, if 
the onset year is the same as the year of first dosing date of study intervention, impute to the 
date of first dosing of study intervention. If the onset year is different from the year of first 
dosing of study intervention, the 1st of January is imputed. 

If the onset date is completely missing, the earlier one of the initial dosing date of the study 
intervention and the AE end date is imputed as the onset date.
If the end date of an AE is missing completely or partially, the following imputation rules will be 
used: 

If month and year are present and the day of the month is missing, the last day of the month 
is used for imputation. 

If only a year is present, the 31st of December is used for imputation.

If the imputed date is later than the date of death (if available) after imputation, the date of 
death will be used as the imputed date.

If the year of AE end date is missing, no imputation will be applied.
5.1.7.2.
Concomitant Medication Start/End Date
In case of partially missing dates, the imputation will be done as follows:


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
If the date is completely missing or year is missing, no imputation will be performed.

Otherwise, the following rules will be applied to impute partially missing dates (start date, 
end date). If only the day is missing, the 15th day of the month will be used. If both the day 
and month are missing, the 30th of June will be used.
If the imputed start date is after end date, then re-impute the start date to equal to end date. If the 
imputed end date is before the start date, then re-impute the end date to equal the start date. If the 
medication was taken prior to study start, and the imputed start date is after initial dosing date of 
study intervention, further adjust the imputed start date as one day prior to initial dosing date; if 
the medication was taken after study start, and the imputed start date is prior to initial dosing date
of study intervention, further adjust the imputed start date as initial dosing date. 
Also, further adjust the imputed medication end date so that it is on or after initial dosing date (as 
long as it is in line with the partial date information).
5.1.7.3.
Multiple Myeloma Diagnosis Date
For partial date of initial multiple myeloma diagnosis, the following imputation rules will be 
applied:

If only day is missing,
o
if the month and year of the start of the 1st line of prior multiple myeloma therapy 
are the same as the year and month of diagnosis, and the day of the start of the 1st
line of prior multiple myeloma therapy is available, impute day to the day of the start 
of the 1st line of prior multiple myeloma therapy
o
otherwise, impute day to 15
o
if the imputed diagnosis date is on or after the date the informed consent is signed, 
further adjust the imputed diagnosis date to one day prior to the date the informed 
consent is signed

If both month and day are missing,
o
if the year of diagnosis is the same as the year of the start of the 1st line of prior 
multiple myeloma therapy, and month information is available for the start of the 1st
line of prior multiple myeloma therapy

impute month with the month of start of 1st line of prior multiple myeloma 
therapy

if the day of start of 1st line of prior multiple myeloma therapy is available, 
impute diagnosis day with the day of start of 1st line of prior multiple myeloma 
therapy; otherwise, impute diagnosis day with 15
o
otherwise, impute with June 30
o
if the imputed diagnosis date is on or after the date the informed consent is signed, 
further adjust the imputed diagnosis date to one day prior to the date the informed 
consent is signed

If year is missing, no imputation will be applied.


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5.1.7.4.
Prior Multiple Myeloma Therapy Start/End Date 
For partially missing prior multiple myeloma therapy start/end dates, the following imputation 
rules will be applied. If the date is completely missing or year is missing, no imputation will be 
performed. 

If only the day is missing, the 15th day of the month will be used. 

If both the day and month are missing, the 30th of June will be used. 
If the imputed start/end date is after initial dosing date of study intervention, further adjust the 
imputed start/end date as the day prior to initial dosing date. 
5.1.7.5.
Progressive Disease Date on Prior Multiple Myeloma Therapy
For partially missing or completely missing progressive disease date on prior multiple myeloma 
therapy, the following imputation rules will be applied. Partially missing prior multiple myeloma 
therapy start/end dates will be imputed before imputing partially missing or completely missing
progressive disease date.

If only the day is missing, 
o
if the month and the year are the same as the month and the year of prior multiple 
myeloma therapy start date, then the day of prior multiple myeloma therapy start date 
will be used.
o
otherwise, the 15th of the month will be used  

If both the day and month are missing,
o
if the year is the same as the year of prior multiple myeloma therapy start date, then 
the month and day of prior multiple myeloma therapy start date will be used
o
otherwise, the 30th of June will be used

If progressive date is completely missing but participant progressed on the prior multiple 
myeloma line, impute to the latest end date of the medications in the prior line. If progressive 
date is completely missing but it is unknown whether the participant progressed on the prior 
line, progressive date will not be imputed
If the imputed progressive disease date is before the prior multiple myeloma therapy start date, 
further adjust the imputed progressive disease date as the start date of the prior multiple myeloma 
therapy. 
5.1.7.6.
Subsequent Antimyeloma Therapy Start Date 
If start date is completely missing or year of start date is missing, no imputation will be performed. 
If both the month and day components are missing, the following steps apply:

If the year is the same as the year of study intervention’s infusion date or the year of the first 
post-baseline progressive disease date as assessed by the investigator (recorded in disease 
progression CRF page), then the month and day of study intervention’s infusion date + 1 day 


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or the month and day of the first post-baseline progressive disease date + 1 day will be used, 
whichever is later.

Otherwise, the 30th of June or the stop date of subsequent antimyeloma therapy, whichever is 
earlier will be used.
If only the day component is missing, the following steps apply: 

If the month and year of the start date are the same as the month and year of the study 
intervention’s infusion date or the month and year of the first post-baseline progressive disease
date as assessed by the investigator, then the day of study intervention’s end date + 1 day or 
the day of the first post-baseline progressive disease date + 1 day will be used, whichever is 
later.

Otherwise, the first day of the month is imputed. 
If the imputed start date of subsequent antimyeloma therapy is after the stop date of subsequent 
therapy, further adjust the imputed start date of subsequent antimyeloma therapy as the stop date 
of subsequent therapy.
No imputation will be applied for missing or partial subsequent antimyeloma therapy end date.
5.1.7.7.
Death Date
For participants reported as dead, if the recorded death date is partial, impute as follows:
If only the death day is missing:

If the month and year of the date the participant is last known alive is the same as the year and 
month of the death date, impute the death date to last known alive date + 1 day

Otherwise, impute to the first day of the month
If death date is completely missing or if the month or year of death date is missing, no imputation 
will be done. 
5.1.8.
Other General Definition
5.1.8.1.
Measurable Disease of Multiple Myeloma and Measurable Type
Measurable disease at baseline is defined by any of the following:

Serum M-protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in the serum or the urine: Serum 
involved free light chain (FLC) ≥10 mg/dL and abnormal serum FLC ratio.
If a participant meets the criteria for serum M-protein, the measurable disease type is serum; 
otherwise, if a participant meets the criteria for urine M-protein, the measurable disease type is 
urine; otherwise, if a participant meets the criteria for FLC, the measurable disease type is FLC. If 
a participant meets both of the criteria for serum M-protein and urine M-protein, then the 
measurable disease type is “serum and urine”.


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5.1.8.2.
Type of Multiple Myeloma at Baseline
Type of myeloma at baseline for a participant is determined by baseline measured serum heavy 
chain or serum FLC or urine FLC. Serum heavy chain refers to serum immunoglobin of IgG, IgA, 
IgM, IgD, or IgE. Serum and urine FLC refer to kappa or lambda type.
A participant will be classified as IgG type of myeloma if any reported result contains serum heavy 
chain ‘IgG’ regardless of FLC reported, similarly for IgA, IgM, IgD and IgE type. A participant
will be classified as the light chain type of myeloma if any reported result is either ‘Lambda light 
chains’ or ‘Kappa light chains’ but without heavy chain reported. A participant will be reported as 
‘biclonal’ if distinct test results contain different heavy chain values or different FLC values. A 
participant will be classified as ‘Negative immunofixation’ if the reported result is ‘Not Detected’ 
with no serum heavy chain, serum light chain or urine light chain reported.
5.1.8.3.
End of Follow-up and Duration of Follow-up
For participants who died, the end of the follow-up is the date of death. Otherwise, the end of 
follow-up is defined as the maximum date of the following study evaluations: labs (hematology, 
chemistry, coagulation, immunology), adverse events, vital signs, ECOG performance status, bone 
marrow cytogenetics, lytic bone lesions, extra-medullary plasmacytomas, study drug 
administration, echocardiogram/MUGA, pre-infusion medications, post-infusion medications, 
concomitant medications, subsequent therapy, medical encounters, clinical events/disease 
response per investigator, and date of last known to be alive.
Duration of follow-up (in months) = (date of end of follow-up – start date of cilta-cel OOS infusion 
+ 1) /(365.25/12).
5.1.9.
Data Handling Rules for Efficacy Analyses
There is no imputation planned for missing efficacy endpoint values.
5.1.10.
Level of Significance
Unless specified otherwise, reported confidence intervals (CIs) will be 2-sided 95% CIs. As there 
is no formal statistical hypothesis testing, the level of significance is not applicable and reported 
95% CIs are not for hypothesis testing purpose.
5.2.
Participant Dispositions
The number of participants in the following disposition categories will be summarized for the all 
treated analysis set:

Participants who discontinued from the study

Reasons for discontinuation from the study
A listing of participants’ study disposition will be provided for the all treated analysis set. A listing 
of participants who received lymphodepleting chemotherapy but did not receive cilta-cel OOS 
may be provided.


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5.3.
Primary Endpoint(s) Analysis
5.3.1.
Definition of Endpoint(s)
The primary endpoint is Overall Response Rate (ORR), defined as the proportion of participants 
who achieve a PR or better according to the IMWG response criteria4, as assessed by computerized 
algorithm and by the investigator.
5.3.2.
Estimand
Primary Trial Objective: to evaluate the efficacy of cilta-cel OOS in adult participants with 
multiple myeloma
Estimand Scientific Question of Interest: What is the proportion of participants considered to 
have benefited from cilta-cel OOS?
Study treatment: a sequence of lymphodepleting chemotherapy (cyclophosphamide and 
fludarabine) and cilta-cel OOS infusion
Population: adult participants with multiple myeloma who met study inclusion/exclusion criteria, 
and received cilta-cel OOS
Variable: Overall response rate (ORR), defined as the proportion of participants in the all treated 
analysis set who have a best response of PR or better according to the International Myeloma 
Working Group (IMWG) response criteria. Participants with no post-baseline response evaluation 
data will be considered as non-responders. Disease assessment after the start of subsequent therapy 
will not be considered in deriving the ORR.
Summary measure (Population-level summary): proportion and 95% CI of the proportion
Intercurrent events and their corresponding strategies:
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and Its 
Description
Start of subsequent 
antimyeloma therapy
While on Treatment Strategy: disease assessment after the start of 
subsequent therapy will not be considered in deriving ORR. 
5.3.3.
Analysis Methods
The ORR per computerized algorithm and per investigator assessment (count and percentage) and 
its 2-sided 95% Clopper-Pearson exact CI will be presented for the all treated analysis set.
Similar analyses for ORR will be conducted for the response-evaluable analysis set.
A listing of disease response will be provided for the all treated analysis set. The listing will include 
the following for both  response per computerized algorithm and per investigator assessment: first 
confirmed response and date (study day), best confirmed response and the date (study day) when


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this response was first achieved, and first confirmed progressive disease date and study day (if 
applicable), and a flag for participants in the response-evaluable analysis set.
5.4.
Secondary Endpoint(s) Analysis
The secondary efficacy endpoints include VGPR or better rate, CR or better rate, stringent 
complete response (sCR) rate, clinical benefit rate (CBR=ORR + MR (minimal response)), 
duration of response (DOR), minimal residual disease (MRD)-negative rate, progression-free 
survival (PFS), and overall survival (OS).
5.4.1.
Other Categories of Best Responses  
5.4.1.1.
Definition
VGPR or better rate is defined as the proportion of participants who achieve a best response of 
sCR, CR, or VGPR according to the IMWG response criteria4. Similarly, CR or better rate is 
defined as the proportion of participants who achieve a best response of sCR or CR according to 
the IMWG response criteria4. Clinical benefit rate is defined as the proportion of participants who 
achieve a best response of MR or better (including sCR, CR, VGPR, PR, and MR). 
Participants with no post-baseline response evaluation data will be considered as not achieving 
these response categories. Disease response assessments after the start of subsequent therapy will 
not be considered in deriving these endpoints.
5.4.1.2.
Analysis Methods
For each category, VGPR or better, CR or better, and clinical benefit rate, counts and percentages 
and the two-sided 95% Clopper-Pearson exact CIs for the percentages will be presented for the all 
treated analysis set. Similar statistics will be provided for each best response category (sCR, CR, 
VGPR, PR, MR, SD, not evaluable (NE), PD) for the all treated analysis set. This analysis will 
also be performed for the response-evaluable analysis set.
These analyses will be performed for responses based on investigator assessment and based on 
computerized algorithm assessment according to IMWG criteria.
5.4.2.
Minimal Residual Disease (MRD)-Negative Rate    
5.4.2.1.
Definition
MRD-negative rate is defined as the proportion of participants who have negative MRD by bone 
marrow aspirate at any timepoint after administration of cilta-cel OOS and before disease 
progression or start of subsequent anti-myeloma therapy. For the derivation of MRD negative rate, 
minimal residual disease positive participants include participants for whom all tested samples 
were found to be MRD positive or ambiguous, and participants with missing or unevaluable MRD 
status. 
For this study, the threshold value of 10-5 will be used for the primary MRD negativity analysis.  
Other threshold values (10-4 and 10-6) will also be explored.


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5.4.2.2.
Analysis Methods
The MRD-negative rate (at 10-5) and its two-sided 95% Clopper-Pearson exact CI will be presented
for the following analysis sets: (1) all treated analysis set, (2) the all treated analysis set with MRD-
evaluable sample at 10-5 (defined as participants in the all treated analysis set whose samples 
passed calibration and QC and included sufficient cells for evaluation at the testing threshold of 
10-5). 
Summary of diagnostic or baseline bone marrow aspirate sample calibration rate will be provided.
Participants whose MRD samples failed calibration or QC will be listed. Reasons for missing or 
unevaluable MRD status, if recorded, may be listed for the all treated analysis set. 
In addition, MRD-negative rate at 10-4 and 10-6 and corresponding 95% Clopper-Pearson exact CIs 
will be provided for the all treated analysis set with MRD-evaluable sample at 10-4 and 10-6 
respectively.
5.4.3.
Duration of Response
5.4.3.1.
Definition
Duration of response (DOR) will be calculated among responders (with a PR or better) from the 
date of initial documentation of a response (PR or better) to the date of first documented evidence 
of progressive disease, as defined in the IMWG criteria4, or death due to any cause, whichever 
occurs first. Participants who did not progress or die will be censored at the last disease evaluation 
date. For participants who receive subsequent antimyeloma therapy and have not progressed and 
are alive before the start of the subsequent therapy, data will be censored at the last disease 
evaluation before the start of any subsequent antimyeloma therapy.  
5.4.3.2.
Analysis Methods
Analysis of DOR will be based on participants in the all treated analysis set and in the response-
evaluable analysis set who achieve a PR or better response, using disease response based on 
computerized algorithm and disease response based on investigator’s assessment. The distribution 
of DOR will be estimated using the Kaplan-Meier method. The number and percentage of 
participants with DOR events or are censored will be included. The median DOR with 95% CI 
will be provided. The Kaplan-Meier curve for DOR will be provided. 
5.4.4.
Progression-free Survival 
5.4.4.1.
Definition
Progression-free survival is defined as the time from the date of the first infusion of cilta-cel OOS 
to the date of first documented disease progression, as defined in the IMWG criteria4, or death due 
to any cause, whichever occurs first. 
Determinations of dates of PFS event and dates for censoring are summarized in Table 2 as 
follows.


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Table 2: 
PFS Event and Censoring Method
Situation
Outcome
Date of Event or Censoring
Disease progression prior to start of subsequent 
antimyeloma therapy
PFS event
Earliest date that indicates disease progression
Death (without prior documented progressive 
disease or start of subsequent antimyeloma 
therapy)
PFS event
Date of death
No post-baseline disease assessment
Censored
Date of infusion of cilta-cel OOS
Other (prior to disease progression or death), 
such as:
Withdrawal of consent to study 
participation
Lost to follow-up
Start of subsequent antimyeloma 
therapy
Censored
Date of last disease assessment prior to:
Withdrawal of consent to study 
participation
Lost to follow-up
Start of subsequent antimyeloma 
therapy
5.4.4.2.
Analysis Methods
The analysis will be based on the all treated analysis set using PFS based on investigator 
assessment and PFS based on computerized algorithm according to IMWG criteria. The 
distribution of PFS will be estimated using the Kaplan-Meier method. The number and percentage 
of participants with PFS events or are censored will be included. The median PFS with 95% CI 
will be provided. The Kaplan-Meier curve for PFS will be provided. The reasons for PFS censoring 
will be summarized. 
5.4.5.
Overall Survival
5.4.5.1.
Definition
Overall survival is defined as the time from the date of the initial infusion of cilta-cel OOS to the 
date of the participant’s death for any reason. Participants who died after consent withdrawal or 
start of subsequent therapy will be considered as having an OS event. If the participant is alive or 
the survival status is unknown, then the participant’s data will be censored at the date the 
participant was last known to be alive. The date of last known alive will be determined by the 
maximum collection/assessment date from among selected data domains within the clinical 
database.
5.4.5.2.
Analysis Methods
The distribution of OS will be estimated using the Kaplan-Meier method. The number and 
percentage of participants with OS events or are censored will be included. The median OS with 
95% CI will be provided. The Kaplan-Meier curve for OS will be provided.
5.5.
Tertiary/Exploratory Endpoint(s) Analysis
See Section 5.7 for definitions and analyses of exploratory endpoints.
5.6.
Safety Analyses
All safety analyses will be based on the all treated analysis set, unless otherwise specified.


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For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
5.6.1.
Extent of Exposure
The number and percentage of participants in the all consented analysis set who receive study 
intervention (cilta-cel OOS), cyclophosphamide, and fludarabine, and alternative lymphodepleting 
chemotherapy infusions will be summarized. 
The following exposure summaries will be presented based on the all treated analysis set.
Descriptive statistics for total infused volume of the cilta-cel OOS, duration of cilta-cel OOS 
infusion, weight-adjusted CAR-positive viable T cells infused (x106 cells/kg) will be presented.
The total dose of the cyclophosphamide and fludarabine infusion (mg/m2) will be summarized
with descriptive statistics.
The number and percentage of participants with a dose adjustment (infusion aborted or interrupted 
for cilta-cel OOS infusion, infusion aborted for cyclophosphamide and fludarabine infusions) will 
be summarized. The reasons for dose adjustments (adverse event, other) will also be summarized.
The number and percentage of participants with delay of lymphodepleting chemotherapy and the 
reasons for delay (adverse event, other) will be summarized. Similar summaries will be provided 
for participants with delay of cilta-cel OOS infusion.
A summary of the number of participants and percentage in the all treated analysis set whose cilta-
cel product is out-of-specs in each commercial and clinical specification will be provided.
Listing of exposure information for cilta-cel OOS, and lymphodepleting regimen including 
cyclophosphamide, fludarabine and alternative lymphodepleting chemotherapy will be provided. 
A listing of commercial and clinical specifications that the cilta-cel OOS administered did not meet 
will be included. 
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the latest version of the MedDRA dictionary. AE severity will be graded using National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, with the 
exception of (1) Cytokine Release Syndrome (CRS) and Immune effector Cell-associated 
Neurotoxicity (ICANS), which will be evaluated according to the ASTCT3 consensus grading 
system (protocol section 10.7, Appendix 7, and protocol section 10.8, Appendix 8), and (2) AEs 
associated with changes in handwriting, which will be graded according to the Handwriting 
Adverse Event Toxicity Grading Criteria in protocol section 10.12, Appendix 12. 
Treatment-emergent adverse events (TEAEs) are defined as any AE that occurs on or after the start 
of cilta-cel OOS infusion through 100 days after the cilta-cel OOS infusion or the start of 
subsequent anti-myeloma therapy, whichever is earlier; or any AE that is considered related to 


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study intervention regardless of the start date of the event; or any AE that is present at baseline but 
worsens in toxicity grade or is subsequently considered related to study intervention by the 
investigator. If the event occurs on the day of the initial administration of study intervention, the 
event will be assumed to be treatment emergent. If the event onset date is recorded as partial or 
completely missing, then the event will be considered treatment emergent unless it is known to be 
prior to the first administration of study intervention based on partial onset date or resolution date. 
For each type of adverse event, the number and percentage of participants who experience at least 
1 occurrence of the given event will be summarized. Unless otherwise specified, at each level (e.g., 
system organ class [SOC] and/or preferred term [PT]) of participant summarization in reporting 
the incidence of an AE, a participant is counted once if one or more events were recorded.
Summary tables will be sorted by descending order of frequency.
The following summary tables will be provided for treatment-emergent adverse events:

An overview of TEAEs, including number of participants with TEAEs, treatment-emergent 
SAEs, TEAEs related to study intervention, treatment-emergent SAEs related to study 
intervention, TEAEs of maximum grade of 1 to 5, TEAEs with outcome of death, TEAEs with 
outcome of death that are related to study intervention.

TEAEs by SOC, PT, and relationship to study intervention

TEAEs by SOC, PT and worst toxicity grade 3 or higher

Most common (frequency of ≥10% in total) TEAEs by SOC, PT, and worst toxicity grade 3 
or higher

TEAEs by SOC, PT, and worst toxicity grade

Toxicity grade 3 or 4 TEAEs by SOC and PT

Toxicity grade 3 or 4 TEAEs by SOC, PT, and relationship to study intervention

Treatment-emergent SAEs by SOC and PT

Treatment-emergent SAEs by SOC, PT, and relationship to study intervention

Treatment-emergent SAEs by SOC, PT, and worst toxicity grade 3 or higher

TEAEs with outcome of death by SOC, PT and relationship to study intervention
In addition, AEs that occur on or after cilta-cel OOS infusion date by SOC, PT, and worst toxicity 
grade 3 or higher will be summarized. Overall summaries of treatment-emergent COVID-19 
adverse events and COVID-19 AEs with onset on or after cilta-cel OOS infusion date will be 
provided.
In addition, AE listings will be provided for:

TEAEs with toxicity grade 3 or higher

treatment-emergent serious AEs


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
TEAEs with outcome of death

AEs leading to withdrawal, interruption or dose reduction of any study drug (cilta-cel OOS, 
cyclophosphamide, fludarabine) defined as AEs with “Drug withdrawn”, “Drug Interrupted”, 
or “Dose reduced” as reported action taken with cilta-cel OOS, cyclophosphamide or 
fludarabine on CRF page “Adverse Events’/Serious AEs”

COVID-19 AEs of grade 3 or higher

AEs that occur on or after the administration start date of the lymphodepleting chemotherapies
and before cilta-cel OOS infusion date
A summary of deaths and primary cause of deaths will be presented. A listing of participants who 
died will be provided. The listing will include date of death, study day of  death  and relevant 
details about the deaths that are collected in the eCRF.
5.6.3.
Adverse Events of Special Interest
Adverse events of special interest will be summarized as specified below. See Appendix 8 Adverse 
Events of Special Interest for list of adverse events in each category.
5.6.3.1.
Cytokine Release Syndrome (CRS)
For treatment-emergent CRS events, a summary of maximum toxicity grade of CRS events
(according to ASTCT consensus grading system), the time from initial cilta-cel OOS infusion to 
first onset of CRS, the duration of CRS in days, the outcome of CRS, and the treatment measures
for CRS will be provided. 
In addition, treatment-emergent symptoms of CRS will be summarized by MedDRA SOC, PT and 
maximum toxicity grade.
A listing will be provided respectively for participants who had any treatment-emergent symptoms 
of CRS, and for participants who had any serious treatment-emergent symptoms of CRS.
5.6.3.2.
Neurological Adverse Events
Neurological adverse events include CAR-T cell neurotoxicity (ICANS, other neurotoxicities) and 
other neurologic adverse events. CAR-T cell neurotoxicity are defined as AEs marked as AESI 
category ‘Neurotoxicity’ and deemed related to cilta-cel OOS by investigators on the CRF page 
‘Adverse Events/Serious AEs’. Other neurotoxicities are defined as AEs that are reported as CAR-
T cell neurotoxicity that are neither ICANS nor the associated symptoms of ICANS.
CAR-T cell neurotoxicity (ICANS, other neurotoxicities)
CAR-T cell neurotoxicity with onset after cilta-cel OOS infusion will be summarized by MedDRA 
SOC, HLGT, HLT, PT, and worst toxicity grade (by All Grades, Grade 3 or 4, and Grade 5). The 
summary will include summaries for ICANS and other neurotoxicities separately as well as for the 
two categories combined. 


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For treatment-emergent ICANS, the maximum toxicity grade of ICANs (according to ASTCT 
consensus grading system), the time from cilta-cel OOS infusion to first onset of ICANS, the 
duration of ICANS in days, the outcome of ICANS, the treatment of ICANS, and concurrent CRS 
will be summarized as well. A similar summary of ICANS following cilta-cel OOS infusion will
be provided. A
shift table from baseline to worst Immune-Effector Cell-Associated 
Encephalopathy (ICE) scores during the post infusion period will be provided.
In addition, treatment-emergent symptoms of ICANS by MedDRA SOC, PT and worst toxicity 
grade will be summarized. A listing of serious treatment-emergent symptoms of ICANS will be 
provided.
For other neurotoxicities after cilta-cel OOS infusion, the maximum toxicity grade, the time from 
initial cilta-cel OOS infusion to first onset of other neurotoxicities, the duration of other 
neurotoxicities in days, and the outcome of other neurotoxicities will be summarized. The 
following listings will be provided:

ICANS on or after cilta-cel OOS infusion date

other neurotoxicities on or after cilta-cel OOS infusion date
Other neurologic adverse events
Other neurologic adverse events with onset after cilta-cel OOS infusion, i.e., AEs with primary 
system organ class of "Nervous system disorders" or "Psychiatric disorders" that are not identified 
as AESI ‘Neurotoxicity’ related to cilta-cel OOS by investigators, will be summarized by 
MedDRA SOC, High Level Group Term (HLGT), High Level Term (HLT), PT, and relationship 
to study intervention, and by worst toxicity grade (by All Grades, Grade 3 or higher). 
In addition, a listing will also be provided for other neurologic adverse events observed after cilta-
cel OOS infusion.
5.6.3.3.
Prolonged and Recurrent Cytopenias
For definition of prolonged or recurrent cytopenias, see Appendix 8 Adverse Events of Special 
Interest. Incidences of prolonged or recurrent cytopenias following treatment with cilta-cel OOS 
will be summarized with count and percentage.
5.6.3.4.
Secondary Primary Malignancies
Secondary primary malignancies will be summarized by preferred term and by clinically-reviewed 
categories (cutaneous/non-invasive, non-cutaneous/invasive, or hematologic malignancies). If the
number of incidences of second primary malignancies is small, this summary will be replaced by 
the listing described below. 
A listing of participants who reported other malignancies (including second primary malignancies)
during the study will be provided.


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5.6.4.
Other Adverse Events
Treatment-emergent cytopenias by MedDRA SOC, PT and worst toxicity grade (All Grades, 
Grade 3 or 4, and Grade 5), hypogammaglobulinemia by SOC and PT, hypersensitivity reactions 
(including infusion-related reactions) by SOC, PT and relationship to study intervention, and 
infections (including the HBV reactivation) by SOC, HLGT, PT, and worst toxicity (by All grades,
Grade 3 or 4, and Grade 5) will be summarized. A summary of infection AEs with onset on or 
after cilta-cel OOS infusion by SOC, HLGT, PT, and worst toxicity (by All grades, Grade 3 or 4, 
and Grade 5) may be provided. In addition, a summary of cranial nerve palsy with onset on or after
cilta-cel OOS infusion date and a summary of peripheral neuropathies with onset on or after cilta-
cel OOS infusion date similar to the summary of ICANS will be provided, i.e. including summaries 
of maximum toxicity grade, time to first onset, time to recovery, duration and outcome of the 
cranial nerve palsy (peripheral neuropathies).
Corresponding listings for these AEs (a listing of treatment-emergent HBV DNA positive and 
HBV infection serious adverse event for the all treated analysis set, a listing of treatment-emergent 
hypersensitivity reactions (including infusion-related reactions) for the all treated analysis set, and 
a listing of fever, and/or hypotension, and/or hypoxia within 60 days of cilta-cel OOS infusion for 
participants in the all treated analysis set without CRS) will be provided. Movement and 
neurocognitive AEs following cilta-cel OOS infusion will be listed for the all treated analysis set. 
The following listings may be provided for the all treated analysis set for these AEs with onset 
after cilta-cel OOS infusion: peripheral neuropathies, cranial nerve palsies, autoimmune disorders, 
and Guillain-Barré Syndrome.
These AEs mentioned above are defined in the table below.
Table 3 – Definitions for Other AEs
AE 
Category
Subcategory
Preferred Term and Other Criteria
Other 
AEs
Hypersensitivity reactions
Hypersensitivity reactions (SMQ-Narrow).
(a) Limit to within 24 hours of infusion:
AE start date – cilta-cel OOS start date +1 <= 2 
or
(b) the AE record is marked as infusion reaction associated 
with cilta-cel OOS in CRF page “Adverse Events/Serious 
AEs”
Other  
AEs
Cytopenias
Preferred Term is "Neutropenia", "Thrombocytopenia", 
"Anaemia", "Leukopenia", or "Lymphopenia"
Other  
AEs
Hypogammaglobulinemia
Preferred Term is “Hypogammaglobulinaemia”
Other  
AEs
Infections
Coded body system is “Infections and infestations”
Other  
AEs
HBV Infection
Pathogen name (case-insensitive) entered in CRF page 
“Adverse Events/Serious AEs” for an infection serious 
adverse event is 'HBV' or 'HEPATITIS B VIRUS'
Other  
AEs
HBV DNA Positive
If HBV infections (as defined above) and lab result on CRF 
page ‘Serology’ for HBV DNA is positive 
Other  
AEs
fever, and/or hypotension, and/or 
hypoxia
Preferred Term (case-insensitive) is "PYREXIA", 
"HYPOTENSION", "HYPOXIA", "FEBRILE 
NEUTROPENIA", or "NEUTROPENIC FEVER"


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Other  
AEs
Peripheral Neuropathy
High level group term (case-insensitive) is 'PERIPHERAL 
NEUROPATHIES' 
Other  
AEs
Cranial Nerve Palsy
AEs that satisfy one of the following conditions (all text 
searches are case-insensitive):
(a) High level group term is 'CRANIAL NERVE 
DISORDERS (EXCL NEOPLASMS)' and preferred term is 
not in this list: 'ANOSMIA', ‘PAROSMIA', ‘'NUMB CHIN 
SYNDROME', 'OLFACTORY DYSFUNCTION', 
'HYPOSMIA', 'ACCESSORY NERVE DISORDER';
(b) High level group term is 'INNER EAR AND VIIITH 
CRANIAL NERVE DISORDERS' and preferred term is not 
in this list: 'TINNITUS', 'VERTIGO'
Other  
AEs
Guillain-Barré Syndrome
Preferred term (case-insensitive) is one of the following: 
'demyelinating polyneuropathy', 'guillain-barre syndrome'
Other  
AEs
movement and neurocognitive AEs
AE is marked as AESI of category ‘Neurotoxicity’ and 
related to cilta-cel OOS on CRF page ‘Adverse Events’ and 
have an onset more than 14 days after cilta-cel infusion for 
participants who had no CRS/ICANS events OR with onset 
after the recovery of ICANS and/or CRS period (i.e. more 
than 14 days after the end date of last CRS/ICANS) for 
participant who had CRS/ICANS events and preferred term 
(case-insensitive) falls in one of the following:
(1) Movement disorder: preferred term is 'Agraphia', 
'Ataxia', 'Balance disorder', 'Bradykinesia', 
'Cogwheel rigidity', 'Coordination abnormal',
'Dysgraphia', 'Dyskinesia',  'Dysmetria', 'Essential 
tremor', 'Extrapyramidal disorder', 'Gait disturbance',  
'Hand-eye coordination impaired', 'Head titubation', 
'Micrographia', 'Motor dysfunction', 'Myoclonus', 
'Parkinsonism', 'Posture abnormal', 'Resting tremor', 
'Stereotypy', 'Tremor';
(2) Cognitive disorder: preferred term is 'Amnesia', 
'Apraxia', 'Bradyphrenia', 'Cognitive disorder', 
'Confusional state', 'Depressed level of 
consciousness',  'Disturbance in attention', 
'Encephalopathy', 'Incoherent', 
'Leukoencephalopathy', 'Lack of consciousness', 
'Loss of consciousness', 'Memory impairment', 
'Mental impairment', 'Mental status changes', 
'Noninfective encephalitis', 'Psychomotor 
retardation', 'Mental disorder';
(3) Personality changes: preferred term is 'Affect 
lability', 'Apathy', 'Flat affect', 'Indifference',
Personality change', 'Reduced facial expression'
Other  
AEs
autoimmune disorders
identified through clinical review of AEs
   
5.6.5.
Additional Safety Assessments 
5.6.5.1.
Clinical Laboratory Tests
Clinical laboratory tests (hematology, coagulation, chemistry, quantitative immunoglobulin) will 
be analyzed for the all treated analysis set as specified below.


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Descriptive statistics will be presented for selected chemistry and hematology laboratory tests at 
scheduled time points. Change from baseline will be summarized with descriptive statistics for 
chemistry and hematology tests. The worst toxicity grade in hematology, coagulation, and 
chemistry after cilta-cel OOS infusion will be summarized by toxicity grade. Shift tables from 
baseline to worst toxicity grade during the post-infusion period will be provided for selected 
laboratory analytes.
Listings of laboratory results outside of reference range will be provided. A listing of ferritin values 
greater than > 500 µg/L will be provided.
5.6.5.2.
Vital Signs and Physical Examination Findings
Vital sign parameters include temperature, pulse, blood pressure (systolic and diastolic), and 
oxygen saturation (%).  Vital sign measurements and change from baseline will be summarized at 
each scheduled assessment time point. 
Treatment-emergent vital sign results are defined as results on or after the date (and time as 
applicable) of the cilta-cel OOS infusion. Incidence of treatment-emergent clinically important 
abnormal vital signs, as defined in Table 4, will be summarized for participants who had a baseline 
assessment and at least 1 post-baseline assessment for that vital sign. A listing of participants with 
treatment-emergent clinically important abnormalities in vital signs will be presented.
Table 4: 
Clinically Important Abnormal Vital Signs
Vital Sign
Criteria
Pulse
>110 bpm and with >20 bpm increase from baseline
<50 bpm and with >15 bpm decrease from baseline
Systolic blood pressure
>180 mm Hg and with >20 mm Hg increase from baseline
<90 mm Hg and with >20 mm Hg decrease from baseline
Diastolic blood pressure
>105 mm Hg and with >15 mm Hg increase from baseline
<50 mm Hg and with >15 mm Hg decrease from baseline
Temperature
>38oC and with ≥1oC increase from baseline
Respiratory rate
>20 or <7 breaths per minute
Oxygen saturation
<95%
5.6.5.3.
Cardiac Function Assessments
For MUGA scan (optional), a listing will be provided.
5.6.5.4.
ECOG Performance Score
ECOG performance status evaluates the effect of the disease status on the activities of daily living. 
Descriptive statistics will be used to summarize ECOG performance status at baseline and
scheduled post-baseline timepoints during the post-infusion period. Shift table from baseline to 
post-baseline scheduled visit and to worst score during the post-infusion period (Day 100 + 14 
days window) will be provided. In addition, a listing of ECOG scores may be provided. 


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5.7.
Other Analyses
5.7.1.
Pharmacokinetics
PK analyses will be performed on the PK analysis set and will be described in a separate analysis 
plan.
5.7.2.
Immunogenicity
5.7.2.1.
Immunogenicity Analysis
Immunogenicity analyses will be described in a separate analysis plan.
5.7.3.
Pharmacodynamics
Pharmacodynamic analyses, if performed, will be described in a separate analysis plan.
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships
Pharmacokinetic/pharmacodynamic modeling may be performed. If performed, details and results 
of the analysis will be presented in a separate report.
5.7.5.
Biomarkers
Biomarker analyses are designed to identify markers predictive of response (or resistance) to cilta-
cel OOS. Planned analyses are based on the availability of clinically valid assays and may be 
deferred if emerging study data show no likelihood of providing useful scientific information. 
Results of biomarker analyses may be presented in a separate report. 
5.7.5.1.
Minimal Residual Disease (MRD)
5.7.5.1.1.
Analysis Methods
Details on MRD negativity analyses are described in Section 5.4.2.
5.7.5.2.
Replication competent lentivirus (RCL)
Whole blood from participants treated with cilta-cel OOS will be evaluated for the presence of 
lentiviral vesicular stomatitis virus-G using a qPCR assay.
5.7.5.2.1.
Analysis Methods
The number and percentage of participants in the all treated analysis set with incidence of 
replication competent lentivirus (RCL) detected in blood samples will be summarized. A summary 
of reasons for missing RCL results will be provided if the data are available.
5.7.5.3.
Molecular Subtyping
5.7.5.3.1.
Molecular Subtypes
Bone marrow aspirate samples may be assessed for specific molecular subtypes having 
chromosomal aberrations such as del17p, t(4;14), t(14;16), and gain/amp1q.  


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5.7.5.3.2.
Molecular Risk Subgroup Analysis
Cytogenetic high-risk is defined as participants with any of the molecular subtypes del17p, 
t(14;16), and t(4;14) at baseline. Cytogenetic standard-risk is defined as participants without any 
of the molecular subtypes del17p, t(14;16), and t(4;14) at baseline. If results of all three molecular 
subtypes del17p, t(14;16), and t(4;14) at baseline are missing, cytogenetic risk is considered to be 
unknown. 
A different definition of high-risk molecular subgroup, called revised cytogenetic high-risk 
(defined as presence of any of the molecular subtypes del17p, t(14;16), t(4;14), and gain/amp1q at 
baseline), will also be used. Revised cytogenetic standard-risk is defined as participants without 
any of the molecular subtypes del17p, t(14;16), t(4;14), and gain/amp1q at baseline. If results of 
all molecular subtypes del17p, t(14;16), t(4;14), and gain/amp1q at baseline are missing, revised 
cytogenetic risk is considered to be unknown. To determine if cilta-cel OOS will lead to improved 
clinical responses in standard-risk as well as high-risk molecular subgroups, cytogenetic subgroup 
analyses are specified in Section 5.7.7.  
5.7.5.4.
Cytokine profiling
Graphs of cytokines (mean (+/-SD) and median) over time may be generated. Additionally, 
exploratory analyses summarizing cytokines (Cmax and exposure (AUC0-56d)) grouped by response 
categories (responder [PR or better] vs. non-responder, CR/sCR vs. non-CR/sCR), by worst CRS 
toxicity grade, or by CAR-T cell neurotoxicity (ICANS and Other Neurotoxicities) might be 
generated.
5.7.5.5.
Immunophenotyping
Immune cell populations (including CAR-T cells) in peripheral blood and malignant plasma cells 
in bone marrow from participants will be evaluated for expression of several markers including 
but not limited to immune-specific markers (CD4+, CD8+, etc.) and tumor associated markers 
(such as BCMA). Baseline BCMA samples were not collected.
Graphs of CD4+CAR+/CD8+CAR+ T cell ratio grouped by response categories (responder [PR 
or better] vs. non-responder, CR/sCR vs. non-CR/sCR), by worst CRS toxicity grade, or by CAR-
T cell neurotoxicity (ICANS and Other neurotoxicities) might be generated.
5.7.6.
Analyses for COVID-19   
Analyses for COVID-19 are described in Sections 5.6.2, 6.4, 6.5.3, and 6.6, i.e. including an 
overall summary of treatment-emergent COVID-19 AEs, an overall summary of COVID-19 AEs 
with onset on or after cilta-cel OOS infusion date, a listing of COVID-19 AEs of grade 3 or higher, 
a listing of minor protocol deviations due to COVID-19, a summary of concomitant medications 
used for COVID-19 AEs by preferred ATC class and drug name, and a summary and listing of 
COVID-19 medical history.


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5.7.7.
Subgroup Analyses
5.7.7.1.
Definition of Subgroups
See Table 5 for definitions.
5.7.7.2.
Analyses
In general, subgroup analyses on the pre-specified subgroups in the all treated analysis set in Table
5 below will be performed for the primary efficacy endpoint ORR and PFS by computerized 
algorithm and by investigator assessment (efficacy analysis type (E) in Table 5). Additionally, for 
ORR, these subgroup analyses will also be performed for the response-evaluable analysis set. The 
overall summaries of TEAEs will be generated for subgroups with safety analysis type (S) in Table 
5 for the all treated analysis set.
Table 5: 
Subgroup Analyses
Subgroup
Definition
Analysis 
Type
Clinical specifications a
Met all clinical specifications 
Did not meet at least one clinical specification
E, S
Met commercial specification for 
post-thaw viability of cilta-cel 
product a
Yes
No
o
Met clinical specification
o
Did not meet clinical specification
E, S
Met commercial specification for 
vector copy number per transduced 
cell of cilta-cel product a
Yes
No
o
Met clinical specification
o
Did not meet clinical specification
E, S
Met commercial specification for 
CAR+ Viable T cells/kg in final 
container of cilta-cel product a
Yes
No
o
Met clinical specification
o
Did not meet clinical specification
E, S
Met commercial specification for 
CAR expression from viable T cells
of cilta-cel product a
Yes
No
o
Met clinical specification
o
Did not meet clinical specification
E, S
Number of lines of prior therapy
≤6
>6
E
Cytogenetic risk b
High-risk 
Standard risk 
E
Revised cytogenetic risk c
High-risk
Standard-risk
E
≥ 2 revised high-risk cytogenetic 
features d
Yes 
No 
E
Presence of extramedullary 
plasmacytomas subgroup
Yes
No
E
Plasmacytosis e
Yes 
No 
E, S
Triple class refractory disease f
Yes 
No
E
< 6 months to PD from start of last 
prior systemic therapy g
Yes 
No
E


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< 18 months to PD from start of last 
prior ASCT h
Yes 
No
E
High-risk (based on comorbidity) i
Yes
No
E, S
Age group
< 65 years
≥65 years
E, S
ECOG at baseline
0
1
≥ 2
E
Received prior BCMA therapy
Yes
No
E
Informed consent within 6 month of 
CARVYKTI approval j
Yes 
No 
E
Received alternative 
lymphodepleting chemotherapy k
Yes
No
E, S
Key: ASCT= autologous stem cell transplant, BCMA = B-cell maturation antigen, E = efficacy, PD = progressive disease, S = safety
a Clinical and commercial specifications at the time of CARVYKTI approval.
b High-risk is defined as abnormal in del17p, t(4;14) or t(14;16). Standard risk is not high-risk and had at least one 
normal cytogenetic testing result for the del17p, t(4:14), or t(14:16).
c High-risk is defined as abnormal in del17p, t(4;14), t(14;16), or gain/amp1q. Standard risk is not high-risk and had 
at least one normal cytogenetic testing result for the del17p, t(4:14), t(14:16), or gain/amp1q.
d Participant had at least 2 of the following abnormalities: del17p, t(4;14), t(14;16), or gain/amp1q
e Maximum of baseline plasma cells by aspirate and by biopsy ≥ 60%
f Participant with refractory to prior PI and anti-CD38 and IMiD
g Participants who progressed on the last prior systemic therapy less than 6 months from start of the last prior systemic 
therapy
h Participants who progressed on the last prior ASCT less than 18 months from the start of the last prior ASCT
i High-risk (based on comorbidity) is defined as meeting at least one of the following criteria: (1) having coded medical 
history/event from CRF page ‘General Medical History’ flagged by clinical review as prior malignancy, cardiac,
autoimmune disease, (2) having history of  stroke/CVA/ischemic stroke/transient ischemic attack from clinical review 
of coded medical history/event from CRF page “General Medical History” or if participant had a history of stroke 
from entry in CRF page “Neurologic History”, (3) revised International Staging System (ISS) at initial diagnosis is 
III, or (4) renal impairment (creatinine clearance at screening < 40 mL/min/1.73 m2).
j informed consent date is before or on August 31, 2022
k Participants who did not receive both fludarabine and cyclophosphamide as lymphodepleting chemotherapy
5.8.
Interim Analyses
No formal interim analysis is planned for the study.
A Data Review Committee (DRC) was established as detailed below to monitor safety. Analyses 
for DRC’s review are described in a separate DRC SAP.
5.8.1.
Data Review Committee (DRC) 
The DRC includes sponsor personnel independent of the study team, at least one medical expert
with expertise and clinical experience in the diagnosis and management of multiple myeloma, and 
at least one statistician. The membership, responsibilities, frequencies of planned meetings, and 
process and convention of the DRC are described in a separate DRC charter.
The DRC members perform periodic independent reviews, and if necessary, unscheduled reviews
of study data. After each review, the DRC make recommendations regarding the continuation of 
the study as well as any modifications of the study. Initially, data were to be reviewed by the DRC 


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after every 10 participants have been treated and followed for at least 3 months. There were 3 DRC 
meetings conducted: DRC1 when there were around 20 participants who completed Day 56 visit, 
DRC2 when 49 participants completed Day 56 visit, and DRC3 meeting after enrollment ended. 
The timing of DRC was changed slightly from the original timing specified in the protocol due to 
quick enrollment and for DRC1, to allow for sufficient efficacy data collection for DRC 
committee’s review. 


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
ADA
anti-drug antibody
AE
adverse event
ASTCT
American Society for Transplantation and Cellular Therapy
AUC
area under the curve
BCMA
B-cell maturation antigen
BSA
body surface area
CAR-T
Chimeric antigen receptor T (cells)
CI
confidence interval
cilta-cel
ciltacabtagene autoleucel
Cmax
maximum concentration
CBR
clinical benefit rate
COVID-19
Coronavirus Disease 2019
CR
complete response
CRS
cytokine release syndrome
CSR
Clinical Study Report
DNA
deoxyribonucleic acid
DOR
duration of response
DRC
Data Review Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOS
End of Study
FLC
free light chain
HLGT
high level group term
HLT
high level term
ICANS
Immune effector cell-associated neurotoxicity
ICE
Immune-effector cell-associated encephalopathy
IMWG
International Myeloma Working Group
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
MRD
minimal residual disease
MUGA
multiple-gated acquisition
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OOS
out-of-specifications
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PT
preferred term
qPCR
quantitative polymerase chain reaction
RCL
replication competent lentivirus
SAE
serious adverse event
SAP
Statistical Analysis Plan
sBCMA
soluble B-cell maturation antigen
sCR
stringent complete response
SD
standard deviation
SMQ
standardized MedDRA query
SOC
system organ class
SPEP
serum protein electrophoresis
SIFE
serum immunofixation


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TEAE
treatment-emergent adverse event
Tmax
time to maximum concentration
UPEP
urine protein electrophoresis
UIFE
urine immunofixation
USPI
United States prescribing information
VGPR
very good partial response
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
There are no changes to protocol-planned analyses.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in the all treated analysis set will be presented.
Table 6 presents a list of the demographic variables that will be summarized for the all treated
analysis set.  
Table 6: Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Surface Area (BSA) (m2)
Categorical Variables
Age (<65 years, 65-75 years, >75 years)
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female, undifferentiated, unknown)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Not reported, 
Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not reported)
Baseline ECOG score
a If multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 7 presents a list of the baseline disease characteristics variables that will be summarized for 
all treated analysis set.  
Table 7: Baseline Disease Characteristics Variables
Continuous Variables
Summary Type
Time since initial multiple myeloma diagnosis (years), defined as cilta-cel infusion 
start date – date of initial multiple myeloma diagnosis + 1, divided by 365.25
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum]).
Categorical Variables
Type of multiple myeloma (IgG, IgA, IgM, IgD, IgE, free light chain only, 
biclonal, or negative immunofixation)
Frequency distribution with the number 
and percentage of participants in each 
category.
Type of measurable disease (Serum only, Serum and urine, Urine only, or Serum 
FLC)
Number of lytic bone lesions (None, 1-3, 4-10, more than 10)
Presence of extramedullary plasmacytomas (Yes, No)
Bone marrow % plasma cells (<10, 10-30, >30-<60, ≥60) by biopsy or aspirate
Bone marrow cellularity (hypercellular, normocellular, hypocellular, 
indeterminate) by biopsy or aspirate
High-risk cytogenetic abnormalities (del17p, t(4;14), or t(14;16))
Cytogenetic standard risk (participants with cytogenetic test results and do not have 
del17p, t(4;14) or t(14;16)
Revised high-risk cytogenetic abnormalities (del17p, t(4;14), t(14;16), or 
gain1q/amp1q)
Revised cytogenetic standard risk (participants with cytogenetic test results and do 
not have del17p, t(4;14), t(14;16) or gain1q/amp1q)
Listings of demographic and baseline disease characteristics will be provided for the all treated 
analysis set.
As a reference to the patient population in CARTITUDE-1, a table summarizing count and 
percentage of participants in the all treated analysis set with the following baseline 


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characteristics listed in Table 8 which result in participants would not have met the 
CARTITUDE-1 key inclusion/exclusion criteria will be provided
Table 8: Baseline Characteristics Not Meeting the CARTITUDE-1 Key Inclusion/Exclusion Criteria
Baseline Characteristics 
Any grade 3-4 baseline cytopenia:
Hemoglobin < 8 g/dL
Platelets < 50,000/µL 
Absolute neutrophils count (ANC) <0.75×109/L
Lymphocyte count < 0.3 x 109/L
Prior anti-BCMA therapy:
Belantamab mafodotin
BCMA-directed CAR-T cell therapy
Other anti-BCMA therapies  
History of allogenic stem cell transplant
Organ dysfunction
Renal impairment (creatinine clearance < 40 mL/min/1.73 m2)
Liver impairment (total bilirubin > 2.0 × ULN)
Impaired cardiac function (LVEF < 45%)
Disease characteristics: rare subtypes (PCL, amyloidosis, POEMS)
Other:
Baseline ECOG performance status ≥2
History of prior malignancies
Corrected calcium > 12.5 mg/dL
AST or ALT > 3.0 × upper limit of normal (ULN)
On chronic immunosuppressive therapy
With no criteria above         
With 1 criterion above
With >1 criterion above


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6.4.
Appendix 4 Protocol Deviations
Participants with major protocol deviations will be identified prior to database lock. Participants 
with major protocol deviations will be summarized by category for the all treated analysis set. A 
summary of minor protocol deviations due to COVID-19 will be generated if there is a large 
number of these deviations.   
A listing of all major protocol deviations will be provided for the all consented analysis set. A 
listing of minor protocol deviations due to COVID-19 will be provided.


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6.5.
Appendix 5 Prior, Concomitant and Follow-Up Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study intervention (cilta-cel OOS) infusion. Concomitant medications 
are defined as any therapy used on or after the same day as the first dose of study intervention, 
including those that started before and continue on after the first dose of study intervention.
6.5.1.
Prior Exposure to Multiple Myeloma Therapies   
A summary of prior exposure to multiple myeloma therapies (systemic therapy, stem cell 
transplant, radiotherapy, or cancer-related surgery/procedure) will be provided. Specifically, the 
number of prior lines of therapy will be summarized with descriptive statistics and summarized by 
grouped categories, such as <3, 3, and >3 with frequencies. A summary of prior systemic therapies 
by therapeutic class, pharmacologic class, and drug name will be provided.
Additionally, the summary of prior systemic therapies will be presented by therapy class and 
therapy. The therapy classes include proteasome inhibitors (PI), immunomodulatory drugs (IMiD), 
anti-CD38 antibody, steroids, alkylating agents and anthracyclines. Therapies included in the PI 
class are: bortezomib, carfilzomib, oprozomib, marizomib, and ixazomib; IMiD class: 
lenalidomide, pomalidomide, and thalidomide; anti-CD38 antibody class: daratumumab, and 
isatuximab; monoclonal antibody class: elotuzumab; and steroids class: dexamethasone and 
prednisone, among others.
The number of participants who had prior exposure to multiple therapy classes (e.g., PI + IMiD) 
may be provided, if the number of participants who exposed to those therapy classes is sufficient.
6.5.2.
Refractory Disease
Refractory is defined as being nonresponsive (either failure to achieve minimal response or 
development of progressive disease) while on therapy or progressed within 60 days of the
therapy’s end date.
For each participant, refractory status (yes, no) to a particular prior multiple myeloma therapy class 
(e.g., PI/IMiD) or prior multiple myeloma therapy (e.g., bortezomib or thalidomide) refers to 
refractory to any prior therapy-containing line.
The number and percentage of participants’ refractory status to PI, IMiD, or anti-CD38 antibody 
therapy class will be summarized by the following categories: any PI, any IMiD, any anti-CD38
antibody, both PI and IMiD, both anti-CD38 and IMiD, both PI and anti-CD38 antibody, PI and
anti-CD38 and IMiD (triple refractory), and at least 2 PIs and at least 2 IMiDs and 1 anti-CD38 
antibody (penta refractory). Refractory to specific prior multiple myeloma therapy, such as 
bortezomib, carfilzomib, ixazomib, lenalidomide, pomalidomide, thalidomide, daratumumab or 
isatuximab, elotuzumab and the relevant combinations of the aforementioned therapies, will be 
provided. 


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The incidence of participants who are refractory to any prior line, and who are refractory to their 
last line of therapy will be reported. 
A listing of prior systemic therapies may be provided.
6.5.3.
Concomitant Medications 
Summaries of concomitant medications will be presented by ATC term. The proportion of 
participants who receive each concomitant medication will be summarized as well as the 
proportion of participants who receive at least 1 concomitant medication. 
In addition, concomitant medications of special interest will be presented. These include 
medications given for CRS and symptoms of CRS, for cilta-cel OOS-related neurotoxicity and 
symptoms of cilta-cel OOS-related neurotoxicity, medications given for ICANS and symptoms 
of ICANS, as well as use of intravenous immunoglobulin (IVIG), prophylactic antimicrobial 
medications (antiviral prophylactic, antibacterial prophylactic, antifungal prophylactic), growth 
factor, and systemic steroids. See Appendix 9 for list of medications in each category. Pre-
infusion medications, bridging therapy, and therapeutic/surgical procedures will be summarized.
A summary of concomitant medications used for COVID-19 AEs by preferred ATC class and 
drug name will be provided. Transfusions and oxygen supplementation will be summarized as 
well. Oxygen supplementation summary will include frequencies and percentages of types of 
oxygen delivery method and positive pressure.
6.5.4.
Subsequent Antimyeloma Therapy 
The total number of participants in the all treated analysis set who received subsequent 
antimyeloma therapy will be reported. A summary of subsequent antimyeloma therapy for the all 
treated analysis set will be presented by therapeutic class, pharmacologic class, and drug name, 
coded using the WHO-DD. In addition, for participants who received subsequent antimyeloma 
therapy, their best response to the first subsequent antimyeloma therapy will be summarized.
Time to subsequent antimyeloma treatment is defined as the time from the start date of cilta-cel 
OOS infusion to the start date of subsequent antimyeloma treatment. Death due to progressive 
disease without the start of any subsequent therapy will be considered as event. For censored 
participants, participants who die due to causes other than progressive disease will be censored at 
the date of death; others will be censored at the last date known to be alive. The distribution of 
time to subsequent therapy will be estimated using the Kaplan-Meier method. The median time 
to subsequent therapy with 95% CI will be provided. In addition, the number and percentage of 
participants who had a subsequent therapy event or were censored will be reported. The Kaplan-
Meier curve for time to subsequent therapy will be provided. 


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6.6.
Appendix 6 Medical History
Medical history data will be summarized by MedDRA system organ class and preferred term. 
Neurological history data will be summarized by MedDRA system organ class and preferred term, 
and for those ongoing at study entry, also by toxicity grade. COVID-19 medical history data may 
be summarized and listed.


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6.7.
Appendix 7 Treatment Compliance
Not applicable since cilta-cel OOS is scheduled to be administer via a single infusion.


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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest are defined as follows:
AE Special Interest Category
Subcategory
Preferred Term and Other Criteria
Cytokine Release Syndrome 
(CRS)
Preferred Term is “Cytokine release syndrome” and 
marked as AESI category “Cytokine Release 
Syndrome” in CRF page “Adverse Events/Serious 
AEs’
Symptoms of CRS
Preferred Term is not “Cytokine release syndrome” 
and marked as AESI category “Cytokine Release 
Syndrome” in CRF page “Adverse Events/Serious 
AEs’
ICANS
Preferred Term is “CAR T-cell-related 
encephalopathy syndrome”, or preferred term 
(case-insensitive) contains ‘IMMUNE EFFECTOR 
CELL-ASSOCIATED NEUROTOXICITY 
SYNDROME’, or verbatim term (case-insensitive) 
contains ’ICANS’, or verbatim term (case-
insensitive) contains ‘IMMUNE EFFECTOR 
CELL ASSOCIATED NEUROTOXICITY 
SYNDROME’ 
Symptom of ICANS
marked as “Neurotoxicity” in CRF page “Adverse 
Events/Serious AEs”, are related to cilta-cel OOS, 
and with duration overlapping event identified in 
ICANS above
Other Neurotoxicities
marked as “Neurotoxicity” in CRF page “Adverse 
Events/Serious AEs”, are related to cilta-cel OOS, 
and are not ICANS nor symptom of ICANS.
Other Neurologic Adverse 
Event
primary system organ class equals “Nervous 
system disorders” or “Psychiatric disorders”, and 
not marked as “Neurotoxicity” in CRF page 
“Adverse Events/Serious AEs”
Prolonged or recurrent 
cytopenias
Lab results (graded according to CTCAE v5.0 
grading criteria of "Neutropenia", 
"Thrombocytopenia", "Anaemia", "Leukopenia", 
and "Lymphopenia") with initial grade 3 or 4 
during the first 100 days after cilta-cel OOS 
infusion that satisfy at least one of the following 
criteria: 
(a) Initial Grade 3 or 4 not recovered to <= Grade 2 
by Day 30
(b) Initial Grade 3 or 4 not recovered to <= Grade 2 
by Day 60
(c) Grade 3 or 4 after Day 60 after initial recovery 
of Grade 3 or 4 within 40 days)
For (a), (b) and (c), for recovery determination, the 
lab result with the worst toxicity grade will be used 
for a calendar day. If the recovery period <=10 
days, participants must have consecutive Grade 
<=2 results from separate days to be considered 
recovery.
Secondary primary 
malignancies
Marked as “Second Primary Malignancy” in CRF 
page “Other Malignancies”


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Status: Approved, Date: 21 February 2024
6.9.
Appendix 9 Medications of Special Interest
Concomitant medications of special interest are defined as follows:
Concomitant Medication Special 
Interest Category
Standard Medication Name and/or Other Criteria
Antiviral prophylactic
Indication in CRF page ‘Concomitant Therapy is 'Prophylaxis' and 
High Level Group Term (case-insensitive) is “VIRAL INFECTIOUS 
DISORDERS”
Antibacterial prophylactic
Indication in CRF page ‘Concomitant Therapy is 'Prophylaxis' and 
High Level Group Term (case-insensitive) is "BACTERIAL 
INFECTIOUS DISORDERS"
Antifungal prophylactic
Indication in CRF page ‘Concomitant Therapy is 'Prophylaxis' and 
High Level Group Term (case-insensitive) is "FUNGAL 
INFECTIOUS DISORDERS"
Medications given for CRS and 
Symptoms of CRS
Medications that have indication ‘Adverse Event’ and the 
corresponding primary AEs in CRF page “Concomitant Therapy”
satisfy the criteria for CRS and/or Symptoms of CRS in Appendix 8 
Adverse Events of Special Interest.
Medications given for cilta-cel OOS-
related neurotoxicity and symptoms of 
cilta-cel OOS-related neurotoxicity
Medications that have indication ‘Adverse Event’ and the 
corresponding primary AEs in CRF page “Concomitant Therapy”
match with the AEs that are marked as ‘Neurotoxicity’ AESI related to 
cilta-cel OOS
Medications given for ICANS and 
symptoms of ICANS 
Medications that have indication ‘Adverse Event’ and the 
corresponding primary AEs in CRF page “Concomitant Therapy”
match with the AEs that are ICANS or symptoms of ICANS (see 
Appendix 8 Adverse Events of Special Interestfor definition of ICANS 
and symptoms of ICANS)
Intravenous immunoglobulin (IVIG)
Coded medication class (case-insensitive) contains 
“IMMUNOGLOBULIN”
Growth factor
CMLVL4CD=’L03AA’
Systemic steroid
CMCLASCD='H02AB'


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Statistical Analysis Plan 68284528MMY2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
43
Status: Approved, Date: 21 February 2024
6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0’.
Pre-baseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken pre-baseline and on baseline.
Text in gray italic in the below table is present in the grading scale but is not applied by Janssen 
when grading lab data.












JNJ-68284528  (ciltacabtagene autoleucel)
Statistical Analysis Plan 68284528MMY2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
49
Status: Approved, Date: 21 February 2024
6.11.
Appendix 11 Progressive Disease and Response Algorithm based on
IMWG Criteria for Multiple Myeloma
IMWG criteria used for progressive disease and response are outlined in protocol Appendix 10. 
The detailed computerized algorithm for determining response based on IMWG criteria for 
multiple myeloma will be outlined in a separate document.


JNJ-68284528  (ciltacabtagene autoleucel)
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Status: Approved, Date: 21 February 2024
7.
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