Clinical trial NCT03871829
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC
Start date: 2019-05-31; Completion date: 2023-01-10
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy (rate of very good partial response \[VGPR\] or better as best response as defined by the International Myeloma Working Group \[IMWG\] criteria) of daratumumab subcutaneous (Dara-SC) in combination with carfilzomib and dexamethasone (Kd) with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab to evaluate daratumumab retreatment.

Detailed description:
For relapsed or refractory multiple myeloma, the treatment is determined on an individual basis. Common standard of care regimens use either a proteasome inhibitor (PI) or an immunomodulatory agent (IMiD) in combination with dexamethasone with or without a monoclonal antibody (mAb) such as daratumumab. After relapse from PIs or IMiDs, patients are often retreated with drugs that have same mechanism of action to which they have been sensitive. The disease becomes refractory and all effective treatment options are exhausted. Daratumumab is a human IgG1 mAb that binds with high affinity to unique epitope on cluster of differentiation 38 (CD38) and attacks tumor cells that overexpress CD38. Study is to determine the efficacy of Dara-SC in combination with carfilzomib and dexamethasone (DKd) in adult participants with relapsed refractory MM who had 1 to 3 prior line(s) of treatment including a line containing daratumumab to evaluate daratumumab retreatment. The MM treatment is determined on an individual basis where patient's age, prior therapy, bone marrow function, co-morbidities, patient preference and time to relapse are considered. Common standard of care regimens use either PI or an IMiD in combination with dexamethasone with or without a mAb. It is a targeted immunotherapy that attacks tumor cells that overexpress CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including multiple myeloma. The study will be conducted in 3 phases: Screening (28 days), Treatment, and Follow-Up. Assessments like chest X-ray, spirometry test, electrocardiogram (ECG), will be performed during Screening phase. During the Treatment Phase, participants will be randomized to receive Kd or DKd. Efficacy assessments like bone marrow examination will be performed. Follow-up will continue until the end of study.

Arms: arm 1: Participants will receive carfilzomib 20 milligram per square meter (mg/m\^2) intravenously (IV) on Day 1 of Cycle 1 and then 70 mg/m\^2 on Days 8 and 15 of Cycle 1 and thereafter on Days 1, 8, 15 of Cycle 2 onwards. Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days. arm 2: Participants will receive daratumumab subcutaneous (Dara-SC) 1800 mg by SC injection on Days 1, 8, 15, 22 for Cycle 1 and 2, Days 1 and 15 for Cycle 3-6, Day 1 for Cycle 7 onwards. Participants will receive carfilzomib 20 mg/m\^2 IV on Cycle 1 Day 1 and then 70 mg/m\^2 on Day 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2. Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.
Interventions: intervention 1: Carfilzomib 20 mg/m^2 intervention 2: Carfilzomib 70 mg/m^2 intervention 3: Dexamethasone 40 mg intervention 4: Dara-SC 1800 mg intervention 5: Dexamethasone 20 mg
Intervention descriptions: intervention 1: Carfilzomib 20 mg/m\^2 will be administered intravenously (IV). intervention 2: Carfilzomib 70 mg/m\^2 will be administered IV. intervention 3: Dexamethasone 40 mg will be administered as IV infusion or orally. intervention 4: Dara-SC 1800 mg will be administered by SC injection. intervention 5: Dexamethasone 20 mg will be administered as IV infusion or orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 3 June 2021
Janssen Research & Development *
Clinical Protocol
A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in
Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib
and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been
Previously Treated with Daratumumab to Evaluate Daratumumab Retreatment
Protocol 54767414MMY2065; Phase 2
AMENDMENT 2
JNJ-54767414 (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations
(21 CFR Part 312).
EudraCT NUMBER: 2018-004185-34
Status: 
Approved
Date 
3 June 2021
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-ERI-171113763, 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.
NCT03871829


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Approved, Date: 3 June 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 2 
03-Jun-2021
Amendment 1 
14-Oct-2019
Original Protocol 
29-Jan-2019
Amendment 2 (03June 2021)
Overall Rationale for the Amendment: The overall rationale for the amendment is to expand
eligibility. This amendment expands eligibility to participants who received prior daratumumab
subcutaneous, participants who received up to 3 prior lines of therapy, and participants who are
seropositive for human immunodeficiency virus (HIV) and meet specified criteria for managing the
disease.
Section Number 
and Name
Description of Change 
Brief Rationale
Protocol Title 
1.1. Synopsis: 
Objectives and 
Endpoints,
Hypothesis, Overall
Design;
2.3. Benefit/Risk
Assessment;
3. Objectives and
Endpoints;
4.1. Overall Design;
5.1. Inclusion
Criteria (Criteria 3
and 5);
5.2. Exclusion
Criteria
(Criterion 4);
9.1. Statistical
Hypothesis
5.2. Exclusion 
Criteria (Criterion 1) 
‘Daratumumab intravenous (Dara-IV)’ was modified 
to ‘daratumumab’. 
Deleted Criterion 1 ‘Previous treatment with
Dara-SC’.
To expand eligibility to include
participants who received prior
subcutaneous (SC) daratumumab.
1.1. Synopsis: 
Hypothesis, Overall 
Design; 
3. Objectives and
Endpoints;
4.1. Overall Design;
4.2. Scientific
Rationale for Study
Design;
5.1. Inclusion
Criteria
(Criterion 5);
9.1. Statistical
Hypothesis
Eligibility criteria of ‘1 or 2 prior lines of therapy’ 
was modified to ‘1 to 3 prior lines of therapy’. 
To expand eligibility to include
participants who received up to
3 prior lines of therapy.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Approved, Date: 3 June 2021
Section Number
and Name
Description of Change 
Brief Rationale
1.3. Schedule of
Activities (Table 1):
TTE or MUGA
Added text ‘with the same methodology as used at 
screening’. 
To maintain consistency in
methodology used for
trans-esophageal echocardiogram
(TTE) and multiple-gated
acquisition (MUGA).
1.3. Schedule of
Activities (Table 1):
Vital signs and
Diary review
Added ‘Cycles 1 and 2, only’ to Vital signs in 
Arm B at Day 22. 
Added ‘Cycles 1 and 2, only’ to Diary review at
Day 22.
To clarify that timing of indicated
assessments will be recorded at
Day 22 only at Cycles 1 and 2.
1.3. Schedule of
Activities (Table 1):
HBV DNA testing
Added ‘±4 weeks’ to hepatitis B virus (HBV) DNA 
testing during treatment phase.
To add window period.
5.1. Inclusion
Criteria (Criterion 2)
Deleted ‘Multiple myeloma diagnosis according
to the International Myeloma Working Group
(IMWG) diagnostic criteria’. 
This study evaluates daratumumab
retreatment and therefore does not
apply the IMWG criteria.
5.2. Exclusion
Criteria (Criterion
18)
The exclusion criterion has been modified to exclude
only those participants who have tested seropositive
for HIV with 1 or more of the following:
 
Not receiving highly active antiretroviral
therapy (ART)
 
Had a change in ART within 6 months of the
start of screening
 
Receiving ART that may interfere with study
treatment (consult Sponsor for review of
medication prior to enrollment)
 
CD4 count <350 at screening
 
Acquired immunodeficiency syndrome (AIDS)-
defining opportunistic infection within 6 months
of start of screening
 
Not agreeing to start ART and be on ART >4
weeks plus having HIV viral load <400
copies/mL at end of 4-week period (to ensure
ART is tolerated and HIV controlled) 
To include participants who are
seropositive for HIV and meet
specified criteria for managing the
disease.
6.1.1.4. Dose
Modification
Text was revised. Text in strikethrough has been
deleted, text in bold has been added.
The study intervention must be held if any of the
following criteria are met, to allow for recovery from
toxicity, regardless of relationship to study
intervention
If any of the following criteria are met and the
toxicity is more than expected for the backbone
therapy (carfilzomib, dexamethasone), or
underlying multiple myeloma, the daratumumab
injection must be held to allow for recovery from
toxicity as noted below. If attribution is unclear,
then daratumumab should be held until recovery
To clarify that daratumumab should
be held only if events are not
attributed to carfilzomib or
dexamethasone (Kd).


JNJ-54767414  (daratumumab)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Approved, Date: 3 June 2021
Section Number
and Name
Description of Change 
Brief Rationale
from toxicity as noted below
6.5.2.2. 
Prevention of 
Steroid Induced 
Gastritis 
The information related to prevention of steroid
induced gastritis was moved from ‘6.5.1. Required
Therapies’ to ‘6.5.2. Recommended Therapies’.
Subsequent section numbers were renumbered as
shown below-
6.5.2.3. Therapy for Tumor Lysis Syndrome;
6.5.2.4. Therapy for Pneumocystis carinii/jirovecii;
6.5.2.5. Management of Hepatitis B Virus
Reactivation
To indicate that prevention of steroid
induced gastritis is a recommended
rather than required therapy so that it
is not mandatory.
6.5.3. Permitted 
Therapies 
6.5.4. Prohibited 
Therapies 
Text was added indicating vaccinations are allowed
per local guidelines with a reference to 6.5.4.
Prohibited Therapies.
Text was added clarifying the restriction of
live-attenuated and replication-competent viral
vector vaccines.
To clarify permitted/prohibited
vaccinations.
6.5.4. Prohibited 
Therapies 
Systemic corticosteroids, described as ‘>10 mg
prednisone’ was changed to ‘>10 mg
dexamethasone’.
To be consistent with daratumumab
protocol standard language.
Table 8 
Carfizomib dosing guidelines for tumor lysis
syndrome, neuropathy, hypertension, dyspnea,
pulmonary toxicity, and progressive multifocal
leukoencephalopathy were added to the table.
Carfizomib dosing guidelines for micro-angiopathy
were updated.
Elevation in liver function tests were categorized as
‘Hepatic dysfunction and related investigations’.
Updated table abbreviations based on the added text.
To update information about the
existing and new carfilzomib risks.
Table 10 
Progressive disease was revised to
Text in strikethrough has been deleted, text in bold
has been added.
‘Only in participants without measurable serum and
urine M-protein levels and without measurable
disease by free light chain levels, bone marrow
plasma cell percentage irrespective of baseline
status; the (absolute percentage must be ≥10%)
Bone marrow plasma cell percentage: the absolute
percentage must be >10%
To clarify that the absolute
percentage of bone marrow plasma
cell percentage is irrespective of
baseline status and to remove
redundant text.
9.4.2. Safety 
Analysis 
Deleted text ‘Change from baseline to the worst
adverse event (AE) grade experienced by the
participant during the study will be provided as shift
tables’.
The term ‘intervention-emergent AEs” was replaced
by ‘treatment-emergent AEs’.
To remove duplicate text. The text
was also mentioned in ‘Clinical
Laboratory Tests’ in the same
section. 
To maintain consistency within the
text.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Approved, Date: 3 June 2021
Section Number
and Name
Description of Change 
Brief Rationale 
10.16. Appendix 16: 
Hepatitis B Virus 
Testing
Added Appendix 16 including the information about
Hepatitis B Virus Testing.
Subsequent section number was renumbered as
10.17. Appendix 17: Protocol Amendment History.
Appendix 16 was cross-referred in 1.3. Schedule of
Activities (Table 1) and 5.2. Exclusion Criteria
(Criterion 18).
To include the information about the
HBV screening guide to be used to
determine participant eligibility for
the study.
Title Page 
The confidentiality statement in title page was
updated as per latest template.
To align with latest protocol
template.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes
were made.
The term ‘subject’ was replaced by ‘participant’.
The footer was updated as per latest template.
Minor errors were noted.
To maintain consistency within the
text.
To align with latest protocol
template.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Approved, Date: 3 June 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 9
1. 
PROTOCOL SUMMARY................................................................................................................... 10
1.1. 
Synopsis......................................................................................................................................... 10
1.2. 
Schema.......................................................................................................................................... 13
1.3. 
Schedule of Activities..................................................................................................................... 14
2. 
INTRODUCTION................................................................................................................................ 25
2.1. 
Background .................................................................................................................................... 25
2.1.1. 
Multiple Myeloma........................................................................................................................ 25
2.1.2. 
Daratumumab............................................................................................................................. 25
2.1.3. 
Daratumumab IV......................................................................................................................... 25
2.1.4. 
Daratumumab SC....................................................................................................................... 26
2.2. 
Study Rationale.............................................................................................................................. 27
2.3. 
Benefit/Risk Assessment ............................................................................................................... 28
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 29
4. 
STUDY DESIGN ................................................................................................................................ 30
4.1. 
Overall Design................................................................................................................................ 30
4.2. 
Scientific Rationale for Study Design............................................................................................. 31
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 33
4.3. 
Justification for Dose...................................................................................................................... 34
4.3.1. 
Rationale for Daratumumab SC Dose Regimen ........................................................................ 34
4.3.2. 
Rationale for Daratumumab Fixed Dose .................................................................................... 36
4.3.3. 
Rationale for Carfilzomib Dose Selection................................................................................... 37
4.4. 
End of Study Definition................................................................................................................... 37
5. 
STUDY POPULATION ...................................................................................................................... 38
5.1. 
Inclusion Criteria............................................................................................................................ 38
5.2. 
Exclusion Criteria........................................................................................................................... 40
5.3. 
Restrictions During Study Participation.......................................................................................... 44
5.4. 
Screen Failures.............................................................................................................................. 45
6. 
STUDY INTERVENTION................................................................................................................... 45
6.1. 
Study Interventions Administered .................................................................................................. 45
6.1.1. 
Daratumumab (Arm B Only)....................................................................................................... 46
6.1.1.1. 
Pre-administration Medication................................................................................................. 47
6.1.1.2. 
Post-administration Medication ............................................................................................... 47
6.1.1.3. 
Management of Injection-site and Infusion-related Reactions ................................................ 48
6.1.1.3.1. 
Local Injection-site Reactions .............................................................................................. 48
6.1.1.3.2. 
Infusion-related Reactions ................................................................................................... 48
6.1.1.4. 
Dose Modification .................................................................................................................... 49
6.1.2. 
Dexamethasone (Arms A and B)................................................................................................ 50
6.1.2.1. 
Dexamethasone:  Dosage Adjustments, Dosage Discontinuation.......................................... 51
6.1.3. 
Carfilzomib(Arms A and B)........................................................................................................ 53
6.1.3.1. 
Prehydration (for Arm A and Arm B)....................................................................................... 53
6.1.3.2. 
Carfilzomib:  Dosage Adjustments, Delays, Rules for Withholding or Restarting,
Permanent Discontinuation ..................................................................................................... 53
6.1.3.3. 
Carfilzomib:  Dose Reduction Levels ...................................................................................... 56
6.1.3.4. 
Carfilzomib:  Guidelines for Hematologic Toxicity................................................................... 57
6.1.3.5. 
Carfilzomib:  Guidelines of Nonhematologic Toxicity.............................................................. 57
6.1.4. 
Conditions Not Requiring Dose Reduction................................................................................. 57


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
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Approved, Date: 3 June 2021
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 57
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 58
6.4. 
Study Intervention Compliance...................................................................................................... 58
6.5. 
Concomitant Therapy..................................................................................................................... 59
6.5.1. 
Required Therapies .................................................................................................................... 59
6.5.1.1. 
Prophylaxis for Herpes Zoster Reactivation............................................................................ 59
6.5.2. 
Recommended Therapies .......................................................................................................... 59
6.5.2.1. 
Bisphosphonate Therapy......................................................................................................... 59
6.5.2.2. 
Prevention of Steroid Induced Gastritis................................................................................... 60
6.5.2.3. 
Therapy for Tumor Lysis Syndrome........................................................................................ 60
6.5.2.4. 
Therapy for Pneumocystis carinii/jirovecii ............................................................................... 60
6.5.2.5. 
Management of Hepatitis B Virus Reactivation....................................................................... 60
6.5.3. 
Permitted Therapies ................................................................................................................... 60
6.5.4. 
Prohibited Therapies................................................................................................................... 61
6.6. 
Intervention After the End of the Study.......................................................................................... 61
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 61
7.1. 
Completion..................................................................................................................................... 61
7.2. 
Discontinuation of Study Intervention ............................................................................................ 62
7.3. 
Participant Discontinuation/Withdrawal from the Study................................................................. 62
7.4. 
Lost to Follow-up............................................................................................................................ 63
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 63
8.1. 
Efficacy Assessments .................................................................................................................... 64
8.1.1. 
Response Categories ................................................................................................................. 64
8.1.2. 
Myeloma Protein Measurements in Serum and Urine................................................................ 67
8.1.3. 
Serum Calcium Corrected for Albumin....................................................................................... 68
8.1.4. 
β2-microglobulin and Albumin .................................................................................................... 69
8.1.5. 
Bone Marrow Examination.......................................................................................................... 69
8.2. 
Safety Assessments....................................................................................................................... 69
8.2.1. 
Physical Examination.................................................................................................................. 69
8.2.2. 
Vital Signs................................................................................................................................... 69
8.2.3. 
Electrocardiogram....................................................................................................................... 70
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 70
8.2.5. 
Pulmonary Function Test............................................................................................................ 70
8.2.6. 
Indirect Antiglobulin Test ............................................................................................................ 70
8.2.7. 
HBV Serology ............................................................................................................................. 71
8.2.8. 
HBV-DNA Test............................................................................................................................ 71
8.2.9. 
Eastern Cooperative Oncology Group Performance Status....................................................... 71
8.2.10. 
Transthoracic Echocardiogram or Multiple-Gated Acquisition Scan .......................................... 71
8.3. 
Adverse Events and Serious Adverse Events ............................................................................... 71
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 72
8.3.2. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 72
8.3.3. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 72
8.3.4. 
Pregnancy................................................................................................................................... 73
8.3.5. 
Disease-Related Events and Disease-Related Outcomes That Do Not Need to be
Reported as Adverse Events or Serious Adverse Events.......................................................... 73
8.4. 
Treatment of Overdose .................................................................................................................. 73
8.5. 
Pharmacokinetics........................................................................................................................... 73
8.5.1. 
Evaluations ................................................................................................................................. 74
8.5.2. 
Analytical Procedures................................................................................................................. 74
8.5.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 74
8.5.4. 
Immunogenicity Assessments .................................................................................................... 75
8.6. 
Biomarkers..................................................................................................................................... 75
8.7. 
Medical Resource Utilization.......................................................................................................... 76


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 76
9.1. 
Statistical Hypotheses.................................................................................................................... 76
9.2. 
Sample Size Determination ........................................................................................................... 76
9.3. 
Populations for Analyses................................................................................................................ 77
9.4. 
Statistical Analyses ........................................................................................................................ 77
9.4.1. 
Efficacy Analyses........................................................................................................................ 77
9.4.2. 
Safety Analyses.......................................................................................................................... 77
9.4.3. 
Other Analyses ........................................................................................................................... 78
9.5. 
Interim Analysis.............................................................................................................................. 79
9.5.1. 
Data Review Committee............................................................................................................. 80
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 81
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 81
10.2. 
Appendix 2: Anticipated Events ..................................................................................................... 84
10.3. 
Appendix 3: Clinical Laboratory Tests ........................................................................................... 86
10.4. 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations......................................... 87
10.5. 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 99
10.6. 
Appendix 6: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 105
10.7. 
Appendix 7:  Eastern Cooperative Oncology Group Performance Status Score ........................ 108
10.8. 
Appendix 8: Modified Diet in Renal Disease Formula................................................................. 109
10.9. 
Appendix 9: Serum Calcium Corrected for Albumin .................................................................... 110
10.10. Appendix 10: Conversion Table for Glucocorticosteroid Dose .................................................... 111
10.11. Appendix 11: Asthma Guidelines................................................................................................. 112
10.12. Appendix 12: New York Heart Association Functional Classification.......................................... 115
10.13. Appendix 13: Antihistamines That May Be Used Predose .......................................................... 116
10.14. Appendix 14: Body Surface Area Calculation.............................................................................. 117
10.15. Appendix 15: Interpretation of the SEBIA Hydrashift 2/4 Daratumumab Immunofixation
Electrophoresis Interference Test................................................................................................ 118
10.16. Appendix 16: Hepatitis B Virus Testing........................................................................................ 119
10.17. Appendix 17: Protocol Amendment History................................................................................. 120
11. REFERENCES................................................................................................................................. 125
INVESTIGATOR AGREEMENT............................................................................................................... 127


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 3 June 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities................................................................................................................ 14
Table 2: 
Pharmacokinetic and Immunogenicity Evaluations .................................................................. 23
Table 3: 
Bone Marrow Testing................................................................................................................ 24
Table 4: 
Study Interventions Administered............................................................................................. 45
Table 5: 
Daratumumab Administration Schedule for Dose Delays ........................................................ 50
Table 6: 
Treatment Guidelines for Dexamethasone-related Toxicity ..................................................... 52
Table 7: 
Carfilzomib Dosing Guidelines for Treatment-emergent Hematologic Toxicity........................ 54
Table 8: 
Carfilzomib Dosing Guidelines for Treatment-emergent Nonhematologic Toxicities ............... 54
Table 9: 
Dose Decrements for Carfilzomib............................................................................................. 57
Table 10: International Uniform Response Criteria Consensus Recommendations ................................ 65
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 13
Figure 2: Daratumumab Serum Concentration at Cycle 3 Day 1 Ctrough  Following Daratumumab
Administered Subcutaneously (Study MMY1004) or Intravenously (Study MMY2002)........... 35
Figure 3: Predicted Maximal Trough Concentrations at Cycle 3 Day 1 for Dara-MD 1800mg
(Subcutaneous Administration) and Dara-IV 16mg/kg (Intravenous Administration).............. 36
Figure 4: Predicted Median-normalized Maximal Trough Concentrations at Cycle 3 Day 1 (Ratio
of Trough Concentrations and Median Trough Concentration for Overall Population at
Each Dose) for Dara-MD 1800mg (Subcutaneous Administration) and Dara-IV
16mg/kg (Intravenous Administration)..................................................................................... 36


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2065 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Approved, Date: 3 June 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination with
Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib and Dexamethasone (Kd) in
Participants with Multiple Myeloma who have been Previously Treated with Daratumumab to Evaluate
Daratumumab Retreatment
OBJECTIVES AND ENDPOINTS
Objectives
Primary Objective
The primary objective is to compare the efficacy (rate of very good partial response [VGPR] or better as
best response as defined by the International Myeloma Working Group [IMWG] criteria) of Dara-SC in
combination with Kd with the efficacy of Kd in participants with relapsed refractory multiple myeloma
who were previously exposed to daratumumab to evaluate daratumumab retreatment.
Secondary Objectives
The secondary objectives are:
To further characterize the efficacy (progression-free survival [PFS], overall survival [OS], overall
response rate [ORR], rate of complete response [CR]/stringent complete response [sCR]) of Dara-SC in
combination with Kd
 
To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD
negativity status
 
To characterize the safety of Dara-SC in combination with Kd
 
To determine time to next treatment
 
To evaluate the pharmacokinetics (PK) of Dara-SC
 
To determine the immunogenicity  of daratumumab and recombinant human hyaluronidase
PH20 (rHuPH20)
Endpoints
Primary Endpoint
The primary endpoint of this study is the rate of VGPR or better as defined by the IMWG criteria.
Secondary Endpoints
The secondary endpoints are:
 
ORR (rate of partial response [PR], VGPR, CR, sCR)
 
Rate of CR/sCR
 
PFS
 
OS
 
MRD negativity rate
 
Time to next treatment


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 
Serum daratumumab concentrations
 
Prevalence and incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
Hypothesis
Daratumumab SC in combination with Kd will have a higher VGPR or better rate than Kd in participants
who have previously received 1 to 3 prior lines of therapy including a line containing daratumumab.
OVERALL DESIGN
This is a Phase 2, open-label, randomized, multicenter study to determine the efficacy of DKd in adult
participants with relapsed refractory multiple myeloma who had 1 to 3 prior line(s) of treatment including
a line containing daratumumab to evaluate daratumumab retreatment. Participants must have completed
daratumumab at least 3 months prior to randomization. The study will be conducted in 3 phases:
Screening, Treatment, and Follow-Up. During the Treatment Phase, participants will be randomized to
receive Kd or DKd. Participants will be stratified by prior proteasome inhibitor exposure and
daratumumab-free interval (3-6 months, >6 months). Participants in both arms will receive study
intervention until confirmed progressive disease (PD), death, intolerable toxicity, start of a new treatment
for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Follow up of
participants for disease progression and survival will continue during the Follow-up Phase.
NUMBER OF PARTICIPANTS
Approximately 230 participants will be randomized 1:1 in 2 treatment arms.
INTERVENTION GROUPS AND DURATION
Participants will be treated with Kd alone (Arm A) or Dara SC in combination with Kd (Arm B) in
28-day cycles.
EFFICACY EVALUATIONS
Assessment of tumor response and disease progression will be conducted in accordance with the IMWG
response criteria. Efficacy evaluations will include measurements of tumor burden/residual disease,
myeloma proteins, bone marrow examinations, extramedullary plasmacytomas, and serum calcium
corrected for albumin.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Samples will be collected from all participants to assess both the serum concentration (pharmacokinetics)
of daratumumab and the presence and generation of anti-daratumumab antibodies (ADAs;
immunogenicity) according to the Schedule of Activities. Samples will also be collected from all
participants in Arm B to evaluate the immunogenicity of rHuPH20 according to the Schedule of
Activities.
BIOMARKER EVALUATIONS
Bone marrow samples will be collected from all participants in both arms to evaluate MRD and high-risk
cytogenetics anomalies as outlined in the Schedule of Activities. Whole blood and plasma samples will be
collected from participants as specified in the Schedule of Activities for processing to plasma and
peripheral blood mononuclear cells and may be used to evaluate the mechanism of action of
daratumumab in combination with Kd.


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SAFETY EVALUATIONS
Safety evaluations will include a review of adverse events, clinical laboratory test results, vital sign
measurements, electrocardiograms (or multiple-gated acquisition [MUGA] scans), physical examination
findings, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status grade.
STATISTICAL METHODS
The primary endpoint of this study is the rate of VGPR or better as defined by the IMWG criteria. The
sample size is based on the assumption that the VGPR or better rate is 60% for DKd and 45% for Kd. In
the current study, 230 participants (assigned 1:1) are needed in order to detect an absolute 15% increase in
VGPR or better rate with 70% power using a 2-sided chi-squared test at the 10% significance level. The
rate of VGPR or better will be compared between the 2 treatment arms using the stratified
Cochran-Mantel-Haenszel test. The primary analysis will be conducted approximately 6 months after the
last participant receives the initial dose of study intervention. An interim futility analysis will occur when
40% of participants are enrolled and treated for 6 months.


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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
Screening
(within 28 days before randomization)
1:1 Randomization
Arm A
Kd (n = 115)
Carfilzomib IV:
Cycle1 Day 1: 20mg/m2
Cycle 1 Day 8, 15: 70mg/m2
Cycles 2+ Day 1, 8, 15:  70mg/m2
Dexamethasone: 40mg weekly
End of Treatment (EOT) Visit
Arm B
Dara-SC + Kd (n = 115)
Daratumumab SC: 1,800mg
Cycles 1-2: once weekly
Cycles 3-6: every 2weeks
Cycles 7+: every 4weeks
Same Kd schedule as Arm A
Enrollment
Follow-Up
Treatment continues until death, intolerable toxicity, start of a new treatment for
multiple myeloma, withdrawal of consent, or end of the study
Stratification
Daratumumab-free interval (3-6 months, >6 months)
Prior proteasome inhibitor exposure
Study End




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Table 1: 
Schedule of Activities
Screening 
Phase 
Treatment Phase
(28-day cycles) 
EOT  
Follow-up Phase
Treatment (C1+) 
Follow-upa 
Survivala
Assessments 
Days -28 to -1 
Day 1 
Day 8 
Day 15 
Day 22 
Post-treatment 
Week 4 
Post-treatment 
Week 8 
Every 16 weeks
after PD
Visit window  
±3 days 
(Except
Cycle 1)
±1 day  
±1 day  
±1 day  
+7 days 
±7 days 
±14 days
12-lead ECG  
Acceptable for screening 
if performed as part of
SOC within 42 days
before randomization
X 
As clinically indicated 
X
TTE or MUGAb 
X 
Every 6 months (±2 weeks) after C1D1, until end
of treatment, or if clinically indicated, with the
same methodology as used at screening
Physical 
examination 
Including neurological 
examinationc 
X 
A physical examination is to be performed at each treatment visit.
Physical examinations should be symptom- and disease-directed, as
clinically indicated
Vital signs 
(temperature, 
pulse/heart rate, 
respiratory rate, 
blood pressure) 
Arm A 
X 
X (measure prior to carfilzomib dosing)
Arm B, on C1D1, required 
immediately before, at end 
of, and at 0.5 and 1 hour 
after end of Dara-SC
administration. For other
Dara-SC administrations,
immediately prior to and
immediately after end of
administration. On
carfilzomib-only dosing
days, performed prior to
carfilzomib dosing.
X 
X 
X 
X 
X
Cycles 1 and
2, only
Weight 
X










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Table 1: 
Schedule of Activities
Screening 
Phase 
Treatment Phase
(28-day cycles) 
EOT  
Follow-up Phase
Treatment (C1+) 
Follow-upa 
Survivala
Assessments 
Days -28 to -1 
Day 1 
Day 8 
Day 15 
Day 22 
Post-treatment 
Week 4 
Post-treatment 
Week 8 
Every 16 weeks
after PD
Visit window  
±3 days 
(Except
Cycle 1)
±1 day  
±1 day  
±1 day  
+7 days 
±7 days 
±14 days
Prehydration for 
Carfilzomibj 
Adequate hydration is 
required prior to dosing in
Cycle 1, especially in
patients at high risk of
tumor lysis syndrome or
renal toxicity.
Prehydration is required
for C1.  Continue in
subsequent cycles if
participant’s condition or
risk factors require it.
X 
X 
X
Carfilzomib 
20 mg/m2 on 
C1D1, then
70 mg/m2
subsequent doses
30 minute (±5 minutes) IV 
infusion
X 
X 
X
Diary review  
Accountability/exposure 
check for dexamethasone 
PO 
X 
Except 
Cycle 1 
X 
X 
X 
Cycles 1 and
2, only
X
Pre-administration Medications, Arm B
Diphenhydramine
25-50 mg (or
equivalent)
Administer 1-3 hours before Dara-SC
administration onlyk
Paracetamol
650-1000 mg


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Table 1: 
Schedule of Activities
Screening 
Phase 
Treatment Phase
(28-day cycles) 
EOT  
Follow-up Phase
Treatment (C1+) 
Follow-upa 
Survivala
Assessments 
Days -28 to -1 
Day 1 
Day 8 
Day 15 
Day 22 
Post-treatment 
Week 4 
Post-treatment 
Week 8 
Every 16 weeks
after PD
Visit window  
±3 days 
(Except
Cycle 1)
±1 day  
±1 day  
±1 day  
+7 days 
±7 days 
±14 days
Montelukast 
10 mg 
Recommended prior to
Dara-SC C1D1 and
optional before all other
Dara-SC doses
Study intervention Administration, Arm B Only
Daratumumab 
1800 mg SCi 
Refer to IPPI for 
recommendations on 
Dara-SC administration
rate
On Days 1, 8, 15, 22 for Cycles 1 and 2; Days 1
and 15 for Cycles 3-6; Day 1 for Cycles 7+
a. For participants who discontinue study intervention before PD, disease evaluations should continue to be performed at the frequency specified in Table 3 until
confirmed PD, death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first.
b. All participants will have a baseline transthoracic ECHO (TTE) or multiple-gated acquisition (MUGA) scan during screening, including assessments of systolic and
diastolic left ventricular function and right ventricular function. Routine TTE or MUGA scan (every 6 months) should not be assessed within 4 days after Dara-SC
injection. However, TTE or MUGA scan should be performed within 72 hours of cardiac failure event initiation, regardless of the timing in relation to injection. A
trans-esophageal echocardiogram (TEE) will be an acceptable alternative to TTE or MUGA if performed as part of standard of care.
c. The participant’s neurological examination should be performed during the screening phase by the treating physician (a neurologic specialist is not required).
d. The screening pregnancy test must be within 14 days of randomization.  Serum or urine pregnancy tests are acceptable at every timepoint.
e. Cytogenetics include t(4;14); t(14;16) and del (17p) and optionally 1q. If local FISH testing is unavailable, this may be performed centrally upon approval of the
sponsor.
f. 
Blood samples for SPEP and SIFE must be collected on the same day that 24-hour urine samples for UPEP and UIFE starts or stops.
g. If the 24-hour urine collection (UPEP) began before informed consent was obtained as part of routine patient care, the sample can be used in this study as long as it
is sent to the central lab for analysis after the informed consent was obtained.
h. See Sections 6.1.2 and 6.1.2.1 for detailed dexamethasone administration information. Dexamethasone 40 mg weekly must be administered as 20 mg by IV infusion
or PO on Cycle 1 Day 1, then 20 mg by IV infusion or PO on Cycle 1 Day 2. Dexamethasone 40 mg doses subsequent to Cycle 1 Day 2 may be administered by IV
infusion or PO weekly.
i. 
For participants on Arm B, on days when more than 1 investigational product is administered, the required order of administration is as follows:  dexamethasone,
pre-administration medications for Dara-SC, Dara-SC, then carfilzomib.
j. 
See Section 6.1.3.1 for information regarding prehydration required prior to dosing in Cycle 1.


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k. See Section 6.1.1.1 for detailed administration information.
Abbreviations: C=Cycle; COPD=chronic obstructive pulmonary disease; CR=complete response; CT=computed tomography; CyTOF=mass cytometry; Dara-
SC=daratumumab administered subcutaneously; ECOG=Eastern Cooperative Oncology Group; ECG=electrocardiogram; EOT=End-of-Treatment; FEV1=Forced
Expiratory Volume (in 1 second); FLC=free light chain; HBV=hepatitis B virus; IAT=indirect antiglobulin test; ICF=informed consent form; Ig=immunoglobulin;
IPPI=Investigational Product Preparation Instructions; IV=intravenous; MRD=minimal residual disease; MUGA=multiple-gated acquisition; PD=progressive disease;
PFS2=progression-free survival on next line of therapy; PO=oral; Q4W=every 4 weeks; Q8W=every 8 weeks; Q12W=every 12 weeks; SAE=serious adverse event;
SC=subcutaneous; sCR=stringent CR; SIFE=serum immunofixation; SOC=standard of care; SPEP=serum M-protein quantitation by electrophoresis; SPM=second
primary malignancy; TEE= trans-esophageal echocardiogram; TTE=transthoracic echocardiogram; UIFE= urine immunofixation; UPEP=urine M-protein quantitation
by electrophoresis; VGPR=very good partial response.


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Table 2: 
Pharmacokinetic and Immunogenicity Evaluations
Treatment Phase 
Follow-up
Phase
Cycle 1 
Cycle 3 
Cycle 7 
Post-treatment
Week 8
(±1 week)
Day 1a 
Day 1a 
Day 1a
ARM A
Daratumumab 
pharmacokinetics
(serum)
X 
X
Daratumumab 
immunogenicityb
X
ARM B
Daratumumab 
pharmacokinetics 
(serum)
Xa 
predose 
Xa 
predose 
Xa 
predose
X
Daratumumab 
immunogenicityb,c 
Xa 
predose 
Xa 
predose
X
rHuPH20 
immunogenicity  
(plasma)c
Xa 
predose 
Xa 
predose
X
a. Predose timepoints have a window of 0 days as they should always be predose on the day of dosing. On dosing
days, sample collection may occur up to 2 hours before but not after the start of drug administration. Samples
collected on dosing days with visit windows should be collected on the actual day of study drug administration.
b. No additional sample needed; will be aliquoted from PK sample.
c. When an IRR occurs associated with the second or later daratumumab administration, 2 separate blood samples
should be obtained, if possible, for determination of anti-daratumumab antibodies and anti-rHuPH20 antibodies.
Abbreviations: IRR=infusion-related reaction; PK=pharmacokinetic; rHuPH20=recombinant human hyaluronidase.


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Table 3: 
Bone Marrow Testing
Local Testing 
Central Testing
Screening 
Disease characterization(morphology, 
and either immunohistochemistry, 
immunofluorescence, or flow cytometry). 
A fresh bone marrowaspirate will be
collected for cytogenetic analysisa by
conventional FISH performed locally.
A portion of fresh bone marrowaspirate collected
will be used for MRD index clone identification
(calibration) performed centrally.
During 
Treatment 
At time ofsuspected CR/sCR: 
Evaluate Plasma cell percentage in the bone 
marrow to confirm CR  
Evaluate clonality ofplasma cells (by flow  
cytometry, IHC or IFb) in the bone marrow
to confirm sCR
(IfsCRcriteriaare not met, repeat local
testingfor sCRwithsubsequent bone
marrow testing.)
MRD Assessments: Bone marrow aspirates will
be collected at time of suspected CR/sCR and for
participants who achieve CR, have not
progressed, and remain on the study, additional
bone marrow aspirate will be obtained at 12, 18,
and 24 months post Cycle 1 Day 1 (±1 month).c
a. Cytogenetics include t(4;14); t(14;16) and del (17p) and optionally Amplification 1q. If local FISH testing is
unavailable, this may be performed centrally upon approval of the sponsor.
b. Immunohistochemistry or immunofluorescence (both require kappa/lambda ratio from analysis of >100 cells) or
2- to 4-color flow cytometry are acceptable methods to evaluate plasma cell clonality.
c. If one of these time points occurs within 1 month of suspected CR/sCR, a repeat bone marrow will not be
requested.
Abbreviations:  CR=complete response; FISH=fluorescence in situ hybridization; IF=immunofluorescence;
IHC=immunohistochemistry; MRD=minimal residual disease; sCR=stringent complete response; VGPR=very
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2. 
INTRODUCTION
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer
to the latest version of the Investigator's Brochure (IB) for daratumumab. The term “study
intervention” used throughout the protocol, refers to daratumumab subcutaneous (Dara-SC)
administration in combination with carfilzomib and dexamethasone (DKd) or carfilzomib and
dexamethasone (Kd). 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.
2.1. 
Background
2.1.1. 
Multiple Myeloma
For relapsed or refractory multiple myeloma, the treatment is determined on an individual basis
where the patient’s age, prior therapy, bone marrow function, co-morbidities, patient preference
and time to relapse are considered. Common standard of care regimens use either a proteasome
inhibitor (PI) or an immunomodulatory agent (IMiD) in combination with dexamethasone with
or without a monoclonal antibody (mAb) such as daratumumab. With each successive relapse,
the depth and duration of response typically decreases. After relapse from PIs or IMiDs, patients
are often retreated with drugs that have the same mechanism of action to which they have been
sensitive. Ultimately, the disease becomes refractory and all effective treatment options are
exhausted and patients who are heavily pretreated or refractory to both a PI and an IMiD have a
dismal prognosis, are difficult to get back into a durable remission, and have a median overall
survival (OS) of only 8 to 9months.10,23,24 For patients who are refractory to at least 3 of the
common PIs (bortezomib or carfilzomib) and IMiDs (lenalidomide or pomalidomide), the
median OS decreases to only 5 months.23 As such, multiple myeloma remains incurable.
2.1.2. 
Daratumumab
Daratumumab is a human IgG1ĸ mAb that binds with high affinity to a unique epitope on cluster
of differentiation 38 (CD38). It is a targeted immunotherapy that attacks tumor cells that
overexpress CD38, a transmembrane glycoprotein, in a variety of hematological malignancies
including multiple myeloma. Daratumumab induces lysis of CD38-expressing tumor cells,
including multiple myeloma tumor cells that were freshly isolated from patients, by a number of
mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated
cytotoxicity, and antibody-dependent cellular phagocytosis, through activation of complement
proteins, natural killer (NK) cells, and macrophages, respectively.6,20
2.1.3. 
Daratumumab IV
In the European Union (EU), daratumumab is approved for the following indications:
 
As monotherapy for the treatment of adult patients with relapsed and refractory multiple
myeloma, whose prior therapy included a PI and an IMiD and who have demonstrated
disease progression on the last therapy.


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 
In combination with lenalidomide and dexamethasone, or bortezomib and
dexamethasone, for the treatment of adult patients with multiple myeloma who have
received at least one prior therapy.
 
In combination with bortezomib, melphalan, and prednisone for the treatment of adult
patients with newly diagnosed multiple myeloma who are ineligible for autologous stem
cell transplant.
In the United States (US), daratumumab is approved for the following indications:
 
As monotherapy, for the treatment of adult patients with multiple myeloma who have
received at least 3 prior lines of therapy including a PI and an immunomodulatory agent
or who are double-refractory to a PI and an immunomodulatory agent.
 
In combination with lenalidomide and dexamethasone in newly diagnosed adult patients
who are ineligible for autologous stem cell transplant and in adult patients with relapsed
or refractory multiple myeloma who have received at least 1 prior therapy.
 
In combination with bortezomib and dexamethasone for the treatment of adult patients
with multiple myeloma who have received at least 1 prior therapy.
 
In combination with pomalidomide and dexamethasone for the treatment of adult
patients with multiple myeloma who have received at least 2 prior therapies including
lenalidomide and a PI.
 
In combination with bortezomib, melphalan, and prednisone for the treatment of adult
patients with newly diagnosed multiple myeloma who are ineligible for autologous stem
cell transplant.
 
In combination with bortezomib, thalidomide, and dexamethasone for the treatment of
adult patients with newly diagnosed multiple myeloma who are eligible for autologous
stem cell transplant.
2.1.4. 
Daratumumab SC
A new formulation of daratumumab for subcutaneous (SC) administration has been developed to
avoid the long infusion time that frequently requires hospitalization with intravenous (IV)
administration of daratumumab and to lessen the rate and severity of infusion-related reactions
(IRRs) observed with IV daratumumab. A recombinant human hyaluronidase PH20 (rHuPH20)
was used to facilitate the SC administration of daratumumab to decrease the volume required for
SC administration.
This SC formulation of daratumumab has been evaluated in Study MMY1004, an open-label,
multicenter, dose escalation Phase 1b study. Study MMY1004 was designed to assess the safety,
pharmacokinetics (PK), and efficacy of Dara-SC plus rHuPH20 in participants with relapsed or
refractory multiple myeloma. The fixed SC dose of 1800 mg was selected from Part 1 of the
study based on cumulative review of PK and safety data and confirmed with Dara-SC in Part 2.
Similar or greater maximum trough concentrations (Ctrough) were observed following


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administration of 1800 mg Dara-SC compared to 16 mg/kg daratumumab IV (Dara-IV). After a
median treatment duration of 5.6 months, 25 participants received at least 1 dose of 1800 mg
Dara-SC in Study MMY1004.22 The IRR rate was 16%; events were mostly Grade 1 or 2 and
included chills, dyspnea, sneezing and allergic rhinitis, and two Grade 3 events of hypertension.
None of the IRRs led to treatment discontinuation. Injection-site reactions (ISRs) included
erythema in 24% of participants, and induration at injection site was experienced by 1 participant
(4%). The overall response rate (ORR) was 52%, with 28% very good partial responses
(VGPRs). Median time to response was 1 month. Median progression free survival (PFS) has not
been reached.
The efficacy and AE profile of Dara-SC is consistent with that of Dara-IV with a lower rate of
IRRs (12% with Dara-SC versus 48% in Dara-IV monotherapy and combination studies), which
mainly occur with the first injection. Based on these clinical data and supported by the PK
profile of Dara-SC, the safety and efficacy profile of Dara-SC appears similar to the profile
Dara-IV. The profile of Dara-SC may be better with regard to IRR. The SC formulation is
currently being tested in Study MMY3012, a Phase 3 study of Dara-IV versus Dara-SC in
participants with relapsed or refractory multiple myeloma.
2.2. 
Study Rationale
Daratumumab responders who relapse have been reported to become re-sensitized (responded
again) following an adequate treatment break or by switching to a different
daratumumab-containing combination regimen.1,2 Two patients with triple refractory (IMiDs,
PIs, and cytostatics) multiple myeloma were retreated with Dara-IV with a partial response after
relapsing from a prior line of therapy containing daratumumab.2 A retrospective study of
41 patients at Emory University Hospital, using daratumumab in combination with
pomalidomide and dexamethasone, showed that patients with prior daratumumab exposure may
be effectively retreated with daratumumab in a re-intensified dosing schedule.1 These data
suggest that retreatment with daratumumab may result in a multiple myeloma disease response.
However, the clinical benefit of daratumumab retreatment has not been systematically evaluated.
As daratumumab moves into frontline treatment, evidence to support retreatment with
daratumumab among patients with disease progression is needed.
The dosing schedule of carfilzomib in combination with dexamethasone (Kd) to be used in this
study has been approved by the Food and Drug Administration (FDA) for patients with relapsed
or refractory multiple myeloma who had 1 to 3 prior line(s) of therapy. The Phase 3
ENDEAVOR study, in which 929 patients were enrolled compared the efficacy of Kd with
bortezomib-dexamethasone (Vd) in patients who progressed on 1 to 3 prior regimen(s).7
Participants (n 464) received twice weekly carfilzomib at 20 mg/m2 on Days 1-2 of Cycle 1, and
subsequent doses of 56 mg/m2 thereafter as a 30 minute IV infusion. All patients received 20 mg
dexamethasone (IV or oral [PO]) on Days 1, 2, 8, 9, 15, 16, 22, and 23 of every cycle. The Kd
group had an ORR of 77% compared with 63% in the Vd arm; median PFS of 18.7 months
compared with 9.4 months in the Vd arm; and median OS of 47.6 months compared with
40 months in the Vd arm. On-study deaths due to adverse events (AEs) occurred in 4% of


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participants. Forty eight percent (48%) of participants had serious adverse events (SAEs). The
most frequent Grade 3 or higher AEs were anemia (14%), hypertension (9%), thrombocytopenia
(8%) and pneumonia (7%).
To evaluate a more convenient carfilzomib dosing schedule, the Phase 3 ARROW study
compared once weekly (70 mg/m2) with twice weekly (27 mg/m2) carfilzomib dosing in
478 participants with relapsed or refractory multiple myeloma.15 The once weekly group
received carfilzomib (30 min IV infusion) on Days 1, 8, and 15 of all cycles (20 mg/m² Day 1
during Cycle 1; 70 mg/m² thereafter). The twice weekly group received carfilzomib (10-min IV
infusion) on Days 1, 2, 8, 9, 15, and 16 (20 mg/m² Days 1 and 2 during Cycle 1; 27 mg/m²
thereafter). All patients received dexamethasone (40 mg on Days 1, 8, 15 [all cycles] and
22 [Cycles 1 9 only]). The once weekly group had a higher median PFS compared to the twice
weekly group, 11 months compared with 8 months, respectively. The ORR in the once-weekly
group was 62.9% (95% confidence interval [CI], 56.5-69.0) compared with 40.8% (95% CI,
35.5-47.3) in the twice-weekly group (P <.0001); 7% of patients and 2% of patients,
respectively, achieved a complete response (CR) or stringent complete response (sCR). The
incidence of Grade 3 AEs was higher in the once weekly group (68%) compared with the twice
weekly group (62%). The most common events in the once weekly group were anemia (18%),
pneumonia (10%), and thrombocytopenia (7%). The once weekly group had 2% treatment-
related deaths and 58 total deaths, and the twice weekly group had 1% treatment-related deaths
and 68 total deaths. This study resulted in the recent FDA approval of the carfilzomib once
weekly (70 mg/m2) dose.
Study MMY1001 is a Phase 1b study evaluating the safety and efficacy of Dara-IV with Kd.
Participants received once weekly carfilzomib (30 min IV infusion) on Days 1, 8, and 15 of all
cycles (20 mg/m² Day 1 during Cycle 1; 70 mg/m² thereafter). Participants with 1-4 prior line(s)
of therapy (n 85) had a VGPR or better rate of 68% and an 81% ORR. In a subgroup analysis of
participants with 1-2 prior line(s) of therapy (n 60), the VGPR or better rate was 73% and the
ORR was 87%. Grade 3 or 4 treatment-emergent adverse events (TEAEs) were reported in 73%
of participants receiving DKd. The most frequently reported Grade 3 or 4 TEAEs (≥10%) in the
DKd cohort were thrombocytopenia (31%), anemia (21%), lymphopenia (22%), neutropenia
(21%), hypertension (14%), and asthenia (12%). For further details and the most up-to-date
information about Study MMY1001, refer to the most current IB.
Given the growing use of lenalidomide in newly diagnosed multiple myeloma (especially in the
maintenance setting), as well as safety and efficacy data of using carfilzomib in patients with
relapsed and refractory multiple myeloma, evaluation of the safety and efficacy of the addition of
Dara-SC to this regimen is proposed.
2.3. 
Benefit/Risk Assessment
The combination of Kd with Dara-SC is hypothesized to have a positive benefit-risk profile
when used for the treatment of patients with relapsed/refractory multiple myeloma who were
previously exposed to daratumumab. This hypothesis is based on the following:


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Daratumumab responders who relapse may respond following a treatment break or by switching
to a new daratumumab-containing combination regimen, as detailed in Section 2.2.
The Kd regimen to be used in this study has been approved for patients with relapsed or
refractory multiple myeloma who had 1 to 3 prior line(s) of therapy (see Section 2.1.1).
The addition of daratumumab to the Kd regimen may improve initial disease control and long-
term outcomes, based on data from an ongoing Phase 1b study (Study MMY1001) of the safety
and efficacy of Dara-IV with Kd (see Section 2.2).
Given the potential advantages of SC administration, Dara-SC will be used in this study. As
presented in Section 2.1.4  and the current daratumumab IB, the safety and tolerability of
Dara-SC has been demonstrated. Previous exposure-response analyses have demonstrated a
strong correlation between ORR and the maximum daratumumab Ctrough. Analysis of the
preliminary PK data indicated the 1800 mg Dara-SC dose achieved maximum Ctrough  values
comparable with, or higher than, those observed for Dara-IV 16 mg/kg as detailed in Section 4.2.
Considering the above, there is a strong rationale for evaluating Dara-SC in combination with Kd
for the treatment of relapsed refractory multiple myeloma patients previously exposed to
daratumumab. More detailed information about the known and expected benefits and risks of
daratumumab are provided in the IB.
3. 
OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objective
The primary objective is to compare the efficacy (rate of VGPR or better as best response as
defined by the International Myeloma Working Group [IMWG] criteria) of Dara-SC in
combination with Kd with the efficacy of Kd in participants with relapsed refractory multiple
myeloma who were previously exposed to daratumumab to evaluate daratumumab retreatment.
Secondary Objectives
The secondary objectives are:
 To further characterize the efficacy (PFS, OS, ORR, rate of CR/sCR) of Dara-SC in
combination with Kd
 To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD
negativity status
 To characterize the safety of Dara-SC in combination with Kd
 To determine time to next treatment
 To evaluate the PK of daratumumab
 To determine the immunogenicity of daratumumab rHuPH20


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ENDPOINTS
Primary Endpoint(s)
The primary endpoint of this study is the rate of VGPR or better as defined by the IMWG
criteria.
Secondary Endpoint(s)
The secondary endpoints are:
 ORR (rate of partial response, VGPR, CR, sCR)
 Rate of CR/sCR
 PFS
 OS
 MRD negativity rate
 Time to next treatment
 Serum daratumumab concentrations
 Prevalence and incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
Daratumumab SC in combination with Kd will have a higher VGPR or better rate than Kd in
participants who have previously received 1 to 3 prior lines of therapy including a line
containing daratumumab.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 2, open-label, randomized, multicenter study to determine the efficacy of DKd in
adult participants with relapsed refractory multiple myeloma who had 1 to 3 prior line(s) of
treatment including a line containing daratumumab to evaluate daratumumab retreatment.
Participants must have completed daratumumab at least 3 months prior to randomization. A
target of 230 participants will be randomized in 2 treatment arms of 115 each.  A diagram of the
study design is provided in Section 1.2 Schema.
The study will be conducted in 3 phases: Screening, Treatment, and Follow-Up. Screening
begins at the time the participant provides written consent for study participation. During the
Screening Phase, participants will be screened for study eligibility within 28 days prior to study
randomization. All eligibility criteria must be met prior to starting study intervention.


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During the Treatment Phase, participants will be stratified by prior PI exposure and
daratumumab-free interval (3-6 months, >6 months) and then assigned randomly to receive Kd
or DKd. Participants in both arms will receive study intervention until confirmed progressive
disease (PD), death, intolerable toxicity, start of a new treatment for multiple myeloma,
withdrawal of consent, or end of the study, whichever occurs first. Participants should start study
intervention within 3 days after randomization. Participants will be closely monitored for AEs,
laboratory abnormalities, and clinical response. Clinical evaluations and laboratory studies may
be repeated more frequently, if clinically indicated. If disease progression is confirmed, then the
participant will discontinue study intervention, complete the End-of-Treatment Visit, and enter
the Follow-up Phase.
Follow-up will continue until the end of study, no later than 2 years after the last participant has
received their initial dose of study intervention or when the sponsor decides to stop the study.
The sponsor will ensure that participants benefiting from treatment with Dara-SC or carfilzomib
continue to receive treatment after the end of the study.
All study evaluations will be conducted according to the Schedule of Activities (Table 1 to
Table 3). Myeloma protein measurements in serum and urine for disease evaluations will be
performed by a central laboratory (unless otherwise specified). Bone marrow testing will be
performed by both local and central laboratories. This study will use the IMWG consensus
recommendations for multiple myeloma treatment response criteria9,21 presented in Table 10.
Response will be determined using a validated computer algorithm.
Safety evaluations will include a review of AEs, laboratory test results, vital sign measurements,
physical examination findings, and assessment of Eastern Cooperative Oncology Group (ECOG)
performance status grade. Follow up of participants for disease progression and survival will
continue during the Follow-up Phase.
An interim futility analysis will be conducted after 40% of participants are enrolled and treated
for at least 6 months (approximately 1 year after first participant randomized). The primary
analysis will be conducted approximately 6 months after the last participant receives the initial
dose of study intervention. At this time, the clinical study report (CSR) will be written, or the
CSR will be written at the time of interim futility analysis if the results lead to stopping the
study. A final analysis will occur at study completion/end of the study to update PFS2, OS,
second primary malignancy, and safety. Study completion/end of the study will be no later than
2 years after the last participant has received the initial dose of study intervention.
4.2. 
Scientific Rationale for Study Design
This study will test the hypothesis that daratumumab retreatment in combination with Kd,
following at least a 3-month daratumumab-free interval, would result in an improved clinical
benefit over Kd alone, in relapsed and refractory multiple myeloma. The study population
includes patients who have had 1 to 3 prior line(s) of therapy and have demonstrated at least a
partial response for 4 months to daratumumab. Given the setting of retreatment with


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daratumumab, a clinically meaningful primary endpoint would be VGPR rate or better as it
represents a 90% or more reduction in detectable abnormal paraproteins.
The patients will be stratified based on daratumumab-free interval and prior PI exposure. It is
unknown whether the degree to which CD38 re-expression or the additional immune modulating
responses secondary to daratumumab may correlate to retreatment clinical benefit. The inclusion
of this stratification criterion is to guard against potential influence on patient response. Post hoc
analyses will examine the need for, and optimal length of a daratumumab-free interval prior to
retreatment with daratumumab.  CD38 expression starts to slowly increase when daratumumab is
gradually cleared. By the end of a 3-month daratumumab-free interval, daratumumab remaining
levels are very low, and CD38 expression starts to increase again. It can take up to 5 months for
CD38 expression to reach its initial levels.18 However, in previous studies CD38 expression
levels did not correlate with response to daratumumab treatment either in a monotherapy or in
combination setting. Stratification by 3-6 months and >6 months serves to address this point.
CD38-expressing immune cell populations are mostly depleted immediately after first
daratumumab infusion and remain like this as long as daratumumab is present.
Daratumumab has a mean linear half-life associated with linear elimination of 18 to 23 days
following monotherapy and combination treatment.  A 3-month daratumumab-free-interval is
4 to 5 half-lives, which allows time for washout of most of the daratumumab from serum prior to
initiation of study treatment. Hence, a minimum of 3-month daratumumab-free-interval is
necessary to determine the effect, if any at all, of daratumumab in retreatment.
Blinding, Control, Study Phase/Periods, Intervention Groups
This study is not blinded. An active control will be used to determine the sensitivity of the
clinical endpoints in this study. Randomization will be used to minimize bias in the assignment
of participants to intervention groups, to increase the likelihood that known and unknown
participant attributes (eg, demographic and baseline characteristics) are evenly balanced across
intervention groups, and to enhance the validity of statistical comparisons across intervention
groups.
Rationale for Subcutaneous Daratumumab
Subcutaneous administration of daratumumab has been chosen for this study to avoid the long
infusion time that frequently requires hospitalization with Dara-IV and to lessen the rate and
severity of IRRs observed with Dara-IV.
Biomarker Collection
This study provides an opportunity to evaluate whether daratumumab retreatment results in
significant and deep responses in participants who responded to initial treatment with
daratumumab. Having as a goal to achieve deep and sustained responses, the measurement of
MRD is important as a key differentiator. Daratumumab’s mechanisms of action are a
combination of direct on-tumor as well as immunomodulatory actions. In this study, by means of
immune profiling, the aim is to identify alterations in immune cell subgroups which might result


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in a secondary response to daratumumab. Being able to better understand the disease’s biology in
association with the clinical data might guide a rationale for combination therapies.
Pharmacokinetics and Immunogenicity Assessments
Data obtained from this study will provide information about the PK profile of DKd in
participants with multiple myeloma and previous daratumumab exposure.  Data will also be used
to assess the residual daratumumab serum concentration at the start of treatment in the Kd arm
following at least 3-month daratumumab-free interval. Therefore, samples will be obtained from
all participants for PK assessments. 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 daratumumab or rHuPH20 is possible. The prevalence and incidence of
daratumumab immunogenicity may be different in this population that has previously been
exposed to daratumumab, therefore, the presence of anti-daratumumab antibodies and
anti-rHuPH20 antibodies will be determined from samples collected from all participants.
Medical Resource Utilization Data Collection
Treatment of multiple myeloma with daratumumab SC administration in combination with Kd
versus Kd alone may result in lower utilization of:
 Duration of hospitalization (total length of stay, including duration by each hospital unit)
 Number and character of diagnostic and therapeutic tests and procedures
 Outpatient medical encounters (including physician, nurse practitioner or emergency
room visits, tests and procedures)
Therefore, comparison will be done across intervention groups.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential 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 primary ethical concerns based on the mode of action of daratumumab are infection and
hematological disturbances. Therefore, the protocol requires the review of past medical history of
infections and hematological laboratory results prior to study intervention administration. CD38
is distributed in erythrocytes and platelets. A significant reduction of platelets was reported in an
animal study. Across daratumumab trials, thrombocytopenia was also reported. However, safety
laboratory monitoring did not show a clinically meaningful reduction of platelets. Anemia was
also reported in daratumumab trials. Free hemoglobin was mildly elevated, but other parameters


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did not support hemolysis. No bleeding events were observed. Routine safety laboratory
measurement of red blood cells (RBCs) and platelets will be closely monitored in this study.
In a previous study with SC administration of daratumumab (Study MMY1004), a lower
incidence of IRRs was observed compared to the IRR rate reported from studies with IV
administration of daratumumab. However, IRRs may still occur and may develop at a later
timepoint than previously observed with IV administration due to the more gradual absorption.
Participants will therefore be observed for at least 6 hours on their first day of Dara-SC
administration. Apart from IRRs, a similar toxicity profile has been shown for SC versus IV
administration for anemia, thrombocytopenia, and other toxicities. During this study local
tolerability at the SC injection site will be closely monitored as well.
The addition of Dara-IV in combination with Kd in a subgroup analysis of Study MMY1001
demonstrated a 73% VGPR rate or better in patients with relapsed or refractory multiple
myeloma previously treated with 1 to 2 prior lines of therapy. Carfilzomib weekly in
combination with dexamethasone in patients with relapsed or refractory multiple myeloma
demonstrate VGPR or better rate of 34% in ARROW study, and 44% in CHAMPION-1 study in
patients previously treated with 1 to 3 prior lines of therapy. The safety profile of weekly Kd and
the addition of daratumumab is comparable. For further details and the most up-to-date
information about single-agent studies, please refer to the Investigator's Brochure. The efficacy
of daratumumab retreatment in combination with Kd in patients who are carfilzomib naive is
unknown. In this study, participants randomized to Arm A or Arm B will be closely monitored
for both safety and efficacy.
Blood volumes drawn are provided in Section 8. The total blood volume to be collected is
considered to be acceptable for participants with multiple myeloma participating in a clinical study
and reasonable over the timeframe of the study.
4.3. 
Justification for Dose
4.3.1. 
Rationale for Daratumumab SC Dose Regimen
Previous exposure-response analyses have demonstrated a strong correlation between ORR and
the Ctrough, of daratumumab, which occurs at the end of weekly dosing (just prior to the Cycle 3
Day 1 dose in the 16 mg/kg monotherapy schedule). These analyses have also demonstrated the
lack of relationship between daratumumab concentrations and AEs in the therapeutic dose range.
Therefore, the dose of Dara-SC selected is intended to achieve a similar or greater maximum
Ctrough compared with 16 mg/kg IV administration.
Eighteen participants were evaluable for PK analyses in Study MMY1004 Part 2. Analysis of the
preliminary PK data indicated the 1800 mg Dara-SC (co-formulated) dose achieved maximum
Ctrough  values comparable to, or higher than, those observed for Dara-IV 16 mg/kg. The
maximum Ctrough  mean value was 904.42 µg/mL for the 1800 mg Dara-SC cohort (n 18),
compared with 754.62 µg/mL for the 1800 mg daratumumab and recombinant human
hyaluronidase for SC injection: mix and deliver formulation (Dara-MD) cohorts (n 38),


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617.17 µg/mL in Study GEN501 Part 2 (n 27), and 573.49µg/mL in Study MMY2002 (n 73).
The median value for maximum Ctrough  for Dara-SC (798.85 µg/mL) was similar to the value for
1800 mg Dara-MD (795.48 µg/mL) and slightly higher than the 16 mg/kg IV median values
from Studies MMY2002 (559.62 µg/mL) and GEN501 (713.85 µg/mL). The range of maximum
Ctrough  observations for the SC cohort is contained within the range observed following 16 mg/kg
IV dosing and variability was similar with a % coefficient of variation of 46 to 58% across the
SC and IV doses (Figure 2).The observed mean maximum observed concentration (Cmax) values
following the last (8th) weekly dose for the Dara-SC cohort was 1012.4 µg/mL, similar to the
mean Cmax of 914.9µg/mL observed after the Cycle 3 Day 1 (9th) dose for Dara-IV in
Study MMY2002. The observed Cmax  values from the Dara-SC cohort is within the range
observed for Dara-MD and 16 mg Dara-IV.
Figure 2: 
Daratumumab Serum Concentration at Cycle 3 Day 1 Ctrough Following Daratumumab
Administered Subcutaneously (Study MMY1004) or Intravenously (Study MMY2002)
Footnotes:
Dots are individual observations; PK evaluable population is presented
1200 mg MD = MMY1004 Part 1, 1200 mg mix & deliver cohort
1800 mg MD = MMY1004 Part 1, 1800 mg mix & deliver cohorts
1800 mg SC = MMY1004 Part 2, 1800 mg co-formulant
16 mg/kg IV data are from Study MMY2002
Study MMY1004 Part 2 also showed that 1800 mg Dara-SC can be administered SC by injection
with a median of 5 minutes (ranging from 2 to 11 minutes) and it is associated with a low
incidence of IRRs, as noted above. The safety profile for the Dara-SC cohort is consistent with
previously reported safety profiles for Dara-IV administration and SC administration with
Dara-MD. There are no new safety signals with the Dara-SC administration. Therefore, based on
the available safety and PK data, the dose of 1800 mg Dara-SC is selected for study in Phase 3
studies, as well as this Phase 2 study.
The daratumumab schedule utilized for this study is the same as has been used in the DKd cohort
of Study MMY1001 with Dara-IV and as monotherapy in Studies MMY1004 and MMY3012


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with Dara-SC. The dose regimen is 1800 mg Dara-SC weekly for 2 cycles, every 2 weeks for
4 cycles, and every 4 weeks thereafter (cycles are 4 weeks); this schedule is intended to quickly
achieve and maintain effective daratumumab concentrations.
4.3.2. 
Rationale for Daratumumab Fixed Dose
The body weight range in Part 1 of Study MMY1004 was 48 to 133 kg, which was similar to that
in Dara-IV studies (MMY2002 and GEN501, 38.4 to 160.2 kg). The preliminary
maximum Ctrough  data for the Dara-MD 1800 mg dose were assessed across a range of simulated
body weights and compared with the body weight based Dara-IV dosing. Across the quartiles of
weights for the simulated participants (n 1000), similar exposure was predicted for each dosing
approach (either Dara-MD  1800 mg or Dara-IV 16 mg/kg) (Figure 3). Furthermore, the
variability in the exposure for Dara-MD  1800 mg in all weight quartiles was predicted to be
similar compared with that for Dara-IV 16 mg/kg. The fixed Dara-MD 1800 mg dose results in a
median concentration that is close to the overall population median concentration, with a ratio of
approximately 1 in each weight quartile (Figure 4). Based on these simulations and observations
in the ongoing Study MMY1004, fixed dosing for SC administration is a feasible approach and
will be used in this study. Dara-IV exhibits a wide therapeutic window and there is no apparent
relationship between drug exposure in the therapeutic dose range and AEs of interest, which
further supports the feasibility of utilizing a fixed dose approach in SC administration.
Figure 3: 
Predicted Maximal Trough Concentrations at Cycle 3 Day 1 for Dara-MD 1800 mg
(Subcutaneous Administration) and Dara-IV 16 mg/kg (Intravenous Administration)
Dara-MD 1800 mg 
Dara-IV 16 mg/kg
Footnotes: Dashed line is the effective concentration of 274 µg/mL.
Figure 4: 
Predicted Median-normalized Maximal Trough Concentrations at Cycle 3 Day 1 (Ratio of
Trough Concentrations and Median Trough Concentration for Overall Population at Each


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Dose) for Dara-MD 1800 mg (Subcutaneous Administration) and Dara-IV 16 mg/kg
(Intravenous Administration)
Dara-MD 1800 mg 
Dara-IV 16 mg/kg
Footnotes: C3D1=Cycle 3 Day 1.
Ideal trough concentration is 1.0.
4.3.3. 
Rationale for Carfilzomib Dose Selection
The carfilzomib weekly dosing was chosen based on the Phase 3 ARROW study that compared
once weekly carfilzomib (70 mg/m2) with twice weekly carfilzomib (27 mg/m2) in combination
with dexamethasone.15 The once weekly carfilzomib regimen had a 3.6 month longer PFS and a
higher proportion of participants achieving response. No additional or new toxic effects were
identified in the once weekly dosing regimen and the safety profile was consistent with the
known safety profile of carfilzomib. Hence, this study will use the carfilzomib once weekly
(70 mg/m2) dosing regimen in combination with dexamethasone to reduce the dosing and
administration burden on participants.
Participants will receive 20 mg/m2 carfilzomib as a 30-minute IV infusion on Cycle 1 Day 1. The
second dose of carfilzomib will be escalated to 70 mg/m2, as a 30-minute IV infusion on Cycle 1
Days 8 and 15.
4.4. 
End of Study Definition
The end of study is no later than 2 years after the last participant has received their initial dose of
study intervention or when the sponsor decides to stop the study. 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.


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5. 
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before randomization. Refer
to Section 5.4, Screen Failures, for conditions under which the repeat of any screening
procedures is allowed. Screening begins at the time the participant provides written consent for
study participation.
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.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
At least 18 years of age.
2. 
Criterion modified per Amendment 2
2.1. Documented multiple myeloma as defined by the criteria below:
Measurable disease at screening as defined by any of the following:
Serum M-protein level ≥1.0 g/dL in participants with immunoglobulin G (IgG) type, or
serum M-protein level ≥0.5 g/dL in participants with non- IgG type, or urine M-protein
level ≥200 mg/24 hours; or
Light chain multiple myeloma without measurable disease in the serum or the urine:
Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum
immunoglobulin kappa lambda FLC ratio.
3. 
Criterion modified per Amendment 2
3.1. Evidence of a response (partial response or better based on investigator’s
determination of response by IMWG criteria) to daratumumab-containing therapy with
response duration of at least 4 months.
4. 
Criterion modified per Amendment 1
4.1. Participants must have progressed from or be refractory to their last line of
treatment. Relapsed or refractory disease as defined below:
Relapsed disease is defined as an initial response to previous treatment, followed by
confirmed PD by IMWG criteria >60 days after cessation of treatment.
Refractory disease is defined as <25% reduction in M-protein or confirmed PD by


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IMWG criteria during previous treatment or 60 days after cessation of treatment.
5. 
Criterion modified per Amendment 2
5.1. Received 1 to 3 prior line(s) of treatment of which one contained daratumumab and
completed daratumumab at least 3 months prior to randomization. A single line of
therapy may consist of 1 or more agents, and may include induction, hematopoietic stem
cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single
short course of corticosteroids (no more than the equivalent of dexamethasone
40 mg/day for 4 days) would not be considered prior lines of therapy.
6. 
ECOG Performance Status score of 0, 1, or 2 (Appendix 7).
7. 
Pretreatment clinical laboratory values meeting the following criteria during the
Screening Phase:
a) hemoglobin g/dL (≥5 mmol/L) (without prior RBC transfusion within 7 days
before the laboratory test; recombinant human erythropoietin use is permitted);
b) absolute neutrophil count (ANC) ≥1.0 × 109/L (prior growth factor support is
permitted but must be without support within the 7 days prior to the laboratory
test);
c) platelet count × 109/L for participants in whom <50% of bone marrow
nucleated cells are plasma cells; otherwise platelet count of ≥50 × 109/L.
Transfusions are not permitted within 7 days of testing to achieve this minimum
platelet count.
d) aspartate aminotransferase (AST) 2.5 × upper limit of normal (ULN);
e) alanine aminotransferase (ALT) 2.5 × ULN;
f) total bilirubin 1.5 × ULN; except in participants with congenital bilirubinemia,
such as Gilbert syndrome (in which case direct bilirubin  × ULN is
required);
g) estimated creatinine clearance (CrCl) 20 mL/min per 1.73 m2. CrCl to be
calculated using estimated glomerular filtration rate Modification of Diet in
Renal Disease (MDRD) formula (Appendix 8).
h) albumin-corrected serum calcium 14 mg/dL (3.5 mmol/L) or free ionized
calcium 6.5 mg/dL (1.6 mmol/L) (Appendix 9)
8. 
Criterion modified per Amendment 1
8.1. Women of childbearing potential must commit to either abstain continuously from


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heterosexual sexual intercourse or to use 2 methods of reliable birth control
simultaneously. This includes one highly effective form of contraception (tubal ligation,
intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal
rings or implants] or partner's vasectomy) and one additional effective contraceptive
method (male latex or synthetic condom, diaphragm, or cervical cap). A reduction in the
effectiveness of oral contraceptives during carfilzomib treatment cannot be excluded. In
addition, because of the increased risk of venous thromboembolic events associated
with carfilzomib, women should avoid the use of hormonal contraceptives that are
associated with a risk of thrombosis during treatment with carfilzomib. Women of
childbearing potential who are using oral contraceptives or a hormonal method of
contraception that is associated with a risk of thrombosis should switch to an alternative
method of highly effective contraception. Contraception must begin with study
treatment initiation  and continue for 3 months after discontinuing study treatment.
Reliable contraception is indicated even where there has been a history of infertility,
unless due to hysterectomy.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 3 months after receiving the last dose
of any component of the study treatment.
Male participants who are sexually active with women of childbearing potential or with
pregnant women must always use a latex or synthetic condom during the study and for
3 months after discontinuing study treatment (even after a successful vasectomy).
Male participants of reproductive potential must not donate sperm during the study or
for 3 months after the last dose of study treatment.
9. 
Women of childbearing potential must have a negative urine or serum pregnancy test at
screening within 14 days prior to randomization.
10. 
Criterion modified per Amendment 1
10.1. Each participant must sign an informed consent form (ICF) indicating that he or
she understands the purpose of, and procedures required for, the study and is willing to
participate in the study. Participants must be willing and able to adhere to the
prohibitions and restrictions specified in this protocol, as referenced in the ICF.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Criterion deleted per Amendment 2


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2. 
Previous treatment with carfilzomib.
3. 
Previous treatment with daratumumab within the last 3 months prior to randomization.
4. 
Criterion modified per Amendment 2
4.1. Discontinuation of daratumumab due to a daratumumab-related AE.
5. 
History of malignancy (other than multiple myeloma) unless all treatment of that
malignancy was completed at least 2 years before consent and the patient has no
evidence of disease. Further exceptions are squamous and basal cell carcinomas of the
skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in
the opinion of the investigator, with concurrence with the sponsor's medical monitor, is
considered cured with minimal risk of recurrence within 3 years.
6. 
Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, mAbs,
human proteins, or their excipients (refer to the IB), or known sensitivity to mammalian-
derived products. Known history of allergy to Captisol (a cyclodextrin derivative used
to solubilize carfilzomib).
7. 
Contraindications to the use of any components of the backbone treatment regimens, per
local prescribing information.
8. 
Criterion modified per Amendment 1
8.1. Received an investigational intervention (including investigational vaccines) or
used an invasive investigational medical device within 4 weeks before randomization
(except for investigational anti-myeloma treatments, which cannot be taken within
2 weeks or 5 PK half-lives of the treatment from the date of randomization, whichever
is longer).
9. 
Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study
or within 3 months after the last dose of study intervention.
10. 
Plans to father a child while enrolled in this study or within 3 months after the last dose
of study intervention.
11. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
12. 
Criterion modified per Amendment 1
12.1. Received anti-myeloma treatment within 2 weeks or 5 PK half-lives of the
treatment from the date of randomization, whichever is longer. The only exception is


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emergency use of a short course of corticosteroids (equivalent of dexamethasone
40 mg/day for a maximum of 4 days; see Appendix 10) up to 21 days before treatment.
A list of anti-myeloma treatments with the corresponding PK half-lives is provided in
the Site Investigational Product Procedures Manual.
13. 
Received autologous stem cell transplant within 12 weeks before the date of
randomization, or the participant has previously received allogeneic stem cell transplant
(regardless of timing).
14. 
Plans to undergo a stem cell transplant prior to progression of disease on this study.
15. 
Focal radiation therapy within 14 days prior to randomization with the exception of
palliative radiotherapy for symptomatic management but not on measurable
extramedullary plasmacytoma. Radiotherapy within 14 days prior to randomization on
measurable extramedullary plasmacytoma is not permitted even in the setting of
palliation for symptomatic management.
16. 
Clinical signs of meningeal involvement of multiple myeloma.
17. 
Either of the following:
a) Known chronic obstructive pulmonary disease (COPD) with a forced expiratory
volume in 1 second (FEV1) is <50% of predicted normal. Note that FEV1
testing also is required for participants suspected of having COPD and
participants must be excluded if FEV1 is <50% of predicted normal.
b) Known moderate or severe persistent asthma, or a history of asthma within the
last 2 years, or currently has uncontrolled asthma of any classification
(Appendix 11). (Participants who currently have controlled intermittent asthma
or controlled mild persistent asthma are allowed to participate in the study.)
18. 
Criterion modified per Amendment 2
18.1. Participant is:
a) known to be seropositive for human immunodeficiency virus (HIV), with 1 or
more of the following:
i. Not receiving highly active antiretroviral therapy (ART)
ii. Had a change in ART within 6 months of the start of screening
iii. Receiving ART that may interfere with study treatment (consult
Sponsor for review of medication prior to enrollment)
iv. CD4 count <350 at screening
v. Acquired 
immunodeficiency 
syndrome 
(AIDS)-defining


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opportunistic infection within 6 months of start of screening
vi. Not agreeing to start ART and be on ART >4 weeks plus having
HIV viral load <400 copies/mL at end of 4-week period (to ensure
ART is tolerated and HIV controlled)
b) seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Participants with resolved infection (ie, participants who are
HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-
HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be
screened using real-time polymerase chain reaction (PCR) measurement of
hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be
excluded. EXCEPTION: Participants with serologic findings suggestive of HBV
vaccination (anti-HBs positivity as the only serologic marker) AND a known
history of prior HBV vaccination, do not need to be tested for HBV DNA by
PCR (See Appendix 16).
c) known to be seropositive for hepatitis C (except in the setting of a sustained
virologic response [SVR], defined as aviremia at least 12 weeks after completion
of antiviral therapy).
19. 
Concurrent medical or psychiatric condition or disease (eg, active systemic infection,
uncontrolled diabetes, acute diffuse infiltrative pulmonary disease, pulmonary
hypertension) that is likely to interfere with study procedures or results, or that in the
opinion of the investigator would constitute a hazard for participating in this study.
20. 
Uncontrolled hypertension, defined as an average systolic blood pressure >159mmHg
or diastolic >99 mmHg despite optimal treatment (measured following European
Society of Hypertension/European Society of Cardiology 2013 guidelines).
21. 
Clinically significant cardiac disease, including:
Myocardial infarction within 6 months before date of randomization, or unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable
angina, congestive heart failure, New York Heart Association Class III-IV;
Appendix 12).
Uncontrolled cardiac arrhythmia (Grade 2 or higher by National Cancer Institute
Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 4.03) or
clinically significant electrocardiogram (ECG) abnormalities.
Transthoracic echocardiogram or MUGA scan showing left ventricular ejection fraction
<40%.
22. 
Gastrointestinal disease that may significantly alter the absorption of oral drugs.
23. 
Myelodysplastic syndrome, plasma cell leukemia (>2.0 × 109/L circulating plasma cells
by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome


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(polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) or
amyloidosis.
24. 
Not able to comply with the study protocol (eg, because of alcoholism, drug
dependency, or psychological disorder) or the participant has any condition for which,
in the opinion of the investigator, participation would not be in the best interest of the
participant (eg, compromise their well-being) or that could prevent, limit, or confound
the protocol-specified assessments.
25. 
Major surgery within 2 weeks before randomization, or has not fully recovered from an
earlier surgery, or has major surgery planned during the time the participant is expected
to participate in the study or within 2 weeks after the last dose of study intervention
administration. Kyphoplasty or vertebroplasty are not considered major surgery. Note:
participants with planned surgical procedures to be conducted under local anesthesia
may participate. If there is a question whether a procedure is considered a major
surgery, the investigator must consult with the appropriate sponsor representative and
resolve any issues before enrolling a participant in the study.
26. 
Plasmapheresis within 28 days before randomization. Pleural effusions requiring
thoracentesis within 14 days prior to randomization. Ascites requiring paracentesis
within 14 days prior to randomization. Grade 3 or worse neuropathy within 14 days
prior to randomization.
27. 
Cirrhosis of the liver.
28. 
Intolerance to hydration due to preexisting pulmonary or cardiac impairment.
NOTE: Investigators should ensure that all study enrollment criteria have been met at 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 intervention is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The
required source documentation to support meeting the enrollment criteria are noted in
Appendix 4.
5.3. 
Restrictions During Study Participation
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.5, Concomitant Therapy for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).


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5.4. 
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 criteria for participation in this study (screen failure) may be
rescreened once their condition changes. Rescreening must be discussed with and approved by
the sponsor on a case-by-case basis. Participants who are determined to be eligible for the study
after rescreening must sign a new ICF and will be assigned a new participant number.
6. 
STUDY INTERVENTION
6.1. 
Study Interventions Administered
Participants will be treated with Kd alone (Arm A) or Dara-SC in combination with Kd (Arm B)
in 28-day cycles as detailed in Table 4.
Table 4: 
Study Interventions Administered
Study Intervention Dose 
Study Intervention Schedule
Daratumumab 1800 mg SC 
(Arm B only) 
On Days 1, 8, 15, 22 for Cycles 1 and 2, Days 1 and 15 for Cycles 3-6,
Day 1 for Cycles 7+
Dexamethasone 40 mg 
(Arms A and B)
On Days 1,8, 15, 22 for Cycles 1-9a, then on Days 1, 8, 15 for Cycles 10+
Carfilzomib 20 mg/m2 on Cycle 1 
Day 1, then 70 mg/m2 thereafter
(Arms A and B)
On Days 1, 8, and 15 of each cycle
a For Cycle 1 only, dexamethasone dose will be 20 mg on Cycle 1 Day 1, a second dose of 20 mg will be given on
Cycle 1 Day 2.  From Cycle 1 Day 8 onward, dexamethasone will be given as a single 40 mg dose as described.
Dara-SC and carfilzomib will be administered by qualified site staff, and the details of each
administration will be recorded in the electronic case report form (eCRF). Participants will be
provided with a treatment diary which will be used to assess compliance with dexamethasone
treatment. Additional details are provided in the Site Investigational Product Procedures Manual
(SIPPM) or equivalent document.
Guidelines 
regarding 
the 
discontinuation 
of 
study 
intervention 
and 
participant
discontinuation/withdrawal are provided in Section 7.


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6.1.1. 
Daratumumab (Arm B Only)
Dara-SC will be administered by SC injection at a fixed dose of 1800 mg. The dose of Dara-SC
will remain constant throughout the study, and dose modification of Dara-SC (increase or
decrease) is not permitted. On days when more than one investigational product is administered,
the required order of administration is as follows:  dexamethasone (see Section 6.1.2),
pre-administration medications for Dara-SC  (see Sections 6.1.1.1), Dara-SC, then carfilzomib
(see Section 6.1.3). Dose delay is the primary method for managing daratumumab-related
toxicities as summarized in Section 6.1.1.4.
Doses will be administered by manual push over 3-5 minutes in the abdominal SC tissue in
left/right locations, alternating between individual doses. The volume of the SC solution for
injection will be 15 mL for the 1800 mg dose. Refer to the Investigational Product Preparation
Instructions (IPPI) for additional guidance on SC administration of Dara-SC. Participants will
receive pre-administration medications and post-administration medications as outlined in
Sections 6.1.1.1 and 6.1.1.2, respectively. All participants in Arm B will be observed for at least
6 hours after the end of the SC injection during Cycle 1 Day 1 and, if deemed necessary by the
investigator, after subsequent injections. Reasons for continued observation on subsequent
Dara-SC injections may include but are not limited to the following: participants with a higher risk
of respiratory complications (eg, participants with mild asthma or participants with COPD who
have an FEV1 <80% at screening or developed FEV1 <80% during the study without any medical
history), participants with IRR with first injection of Dara-SC, or participants with a decreased
condition on day of dosing compared to prior dosing day.
If an IRR develops, then the injection should be temporarily interrupted or slowed down (see
Section 6.1.1.3.2). In the event of a life-threatening IRR (which may include pulmonary or
cardiac events) or anaphylactic reaction, Dara-SC  should be discontinued and no additional
Dara-SC should be administered to the participant. See Section 6.1.1.3.1 for instructions on the
management of local ISRs.
Dara-SC  will be administered in an outpatient setting. As noted in the Schedule of Activities
(Table 1), vital signs should be monitored extensively on Cycle 1 Day 1 before and after the first
administration of Dara-SC. For all other administrations, vital signs should be measured before the
start of injection and at the end of the injection. If the participant experiences a significant medical
event, then the investigator should assess whether the participant should stay overnight for
observation. If the participant has not experienced a significant medical event but is hospitalized
overnight only for observation, then the hospitalization should not be reported as a SAE.
Dara-SC will be manufactured and provided under the responsibility of the sponsor. Refer to the
IB for a list of excipients. For a definition of study intervention overdose, refer to Section 8.4,
Treatment of Overdose.


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6.1.1.1. 
Pre-administration Medication
On days when more than 1 investigational product is administered, the required order of
administration is as follows: dexamethasone (see Section 6.1.2), pre-administration medications
for Dara-SC, Dara-SC, then carfilzomib.
To decrease the risk of IRRs, all participants on Arm B will receive the following medications
1-3 hours prior to each Dara-SC administration:
 An antihistamine: diphenhydramine 25-50 mg IV or PO, or equivalent (see Appendix 13
for list of antihistamines that may be used). Avoid IV promethazine.
 Paracetamol (acetaminophen) 650-1000 mg IV or PO.
 Montelukast 10 mg is recommended on Cycle 1 Day 1 only up to 3 hours prior to the
Dara-SC injection and is optional before all other doses.
If necessary, due to timing constraints, all PO pre-administration medications may be administered
outside of the clinic on the day of the Dara-SC injection, provided they are taken within 1-3 hours
before the injection.
6.1.1.2. 
Post-administration Medication
For participants with a higher risk of respiratory complications (e.g., participants with mild asthma
or participants with COPD who have an FEV1 <80% at screening or developed FEV1 <80%
during the study without any medical history), the following post-injection medications should be
considered:
 Antihistamine
 Short-acting β2 adrenergic receptor agonist such as salbutamol
 Control medications for lung disease (e.g., inhaled corticosteroids ± long-acting β2
adrenergic receptor agonists for participants with asthma; long-acting bronchodilators
such as tiotropium or salmeterol ± inhaled corticosteroids for participants with COPD)
In addition, participants at-risk for respiratory complications may be hospitalized for monitoring
for up to 2 nights after an injection after Dara-SC administration. If participants are hospitalized,
then their FEV1 should be measured before discharge. If these participants are not hospitalized,
then a follow-up telephone call should be made to monitor their condition within 48 hours after all
injections. If the participant has not experienced a significant medical event but is hospitalized
overnight only for observation, then the hospitalization should not be reported as a SAE.
Investigators may prescribe bronchodilators, antihistamines, and corticosteroids that are deemed
necessary to provide adequate supportive care in the event that bronchospasm occurs after a
participant is released from the hospital/clinic. If, after 4 full doses, an at-risk participant
experiences no major IRR, then these post-injection medications may be stopped.


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6.1.1.3. 
Management of Injection-site and Infusion-related Reactions
6.1.1.3.1. 
Local Injection-site Reactions
Injection-site reactions are localized reactions at the injection site. In Study MMY1004 Part 1, SC
administration of daratumumab in abdominal SC tissue was associated with local ISRs, such as
induration and erythema, in some participants. The reactions usually resolved within 60 minutes.
Local ISRs should be managed per institutional standards.
6.1.1.3.2. 
Infusion-related Reactions
Infusion-related reactions (IRRs) are systemic reactions related to daratumumab administration.
Participants should be observed carefully during daratumumab administrations. Trained study staff
at the clinic should be prepared to intervene in case of any IRRs, and resources necessary for
resuscitation (e.g., agents such as epinephrine and aerosolized bronchodilator, medical equipment
such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at the
bedside. Attention to staffing should be considered when multiple participants will be dosed at the
same time.
If an IRR develops, then Dara-SC administration should be temporarily interrupted. Participants
who experience AEs during Dara-SC  administration must be treated for their symptoms.
Participants should be treated with paracetamol (acetaminophen), antihistamine, or corticosteroids,
as needed. Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea,
participants may require antihistamines, oxygen, corticosteroids, or bronchodilators. For
hypotension, participants may require vasopressors. In the event of a life-threatening IRR (which
may include pulmonary or cardiac events) or an anaphylactic reaction, Dara-SC  should be
discontinued.
Infusion-related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1-2 IRR to be related to administration of study intervention,
then the Dara-SC administration should be interrupted. When the participant's condition is stable,
Dara-SC administration may be restarted at the investigator's discretion. Refer to the SIPPM for
further details regarding continuation of Dara-SC administration.
If the participant experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher
event of bronchospasm that does not respond to systemic therapy and does not resolve within
6 hours from onset, then the participant must be permanently discontinued from Dara-SC
treatment.
Infusion-related Reactions of Grade 3 or Higher
For IRR AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the Dara-SC
administration must be stopped, and the participant must be observed carefully until resolution of
the AE or until the intensity of the event decreases to Grade 1, at which point the Dara-SC
administration may be restarted at the investigator’s discretion. Refer to the SIPPM for further
details regarding continuation of Dara-SC administration.


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If the intensity of the AE returns to Grade 3 after restart of the Dara-SC administration, then the
participant must be permanently discontinued from Dara-SC treatment.
For IRR AEs that are Grade 4, the Dara-SC administration must be stopped, and the participant
permanently discontinued from Dara-SC treatment.
Recurrent Infusion-related Reactions
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of
bronchospasm) recurs during or within 24 hours after a subsequent Dara-SC administration, the
participant must be permanently discontinued from Dara-SC treatment.
6.1.1.4. 
Dose Modification
Dose modification of 1800 mg Dara-SC (increase or decrease) is not permitted. Dose delay is the
primary method for managing daratumumab-related toxicities. On the first day  of each new
treatment cycle and before each dose of study intervention, the participant will be evaluated by
the treating physician for possible toxicities that may have occurred after the previous dose(s).
Toxicities are to be assessed according to NCI-CTCAE, Version 4.03. Cycle delays will be based
on the toxicity experienced during the previous cycle of therapy or newly encountered on Day 1
of a cycle.
If any of the following criteria are met and the toxicity is more than expected for the backbone
therapy (carfilzomib, dexamethasone), or underlying multiple myeloma, the daratumumab
injection must be held to allow for recovery from toxicity as noted below. If attribution is
unclear, then daratumumab should be held until recovery from toxicity as noted below:
 Grade 4 hematologic toxicity, except for Grade 4 lymphopenia
 Grade 3 or higher thrombocytopenia with bleeding
 Febrile neutropenia of any grade
 Neutropenia with infection, of any grade
 Grade 3 or higher nonhematologic toxicities with the following exceptions:
o Grade 3 nausea that responds to antiemetic treatment within 7 days
o Grade 3 vomiting that responds to antiemetic treatment within 7 days
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
o Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last
administration of Dara-SC
o Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last
administration of Dara-SC
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Study intervention should be resumed when the toxicity has resolved to Grade 2. If study
intervention administration does not commence within the prespecified window of the scheduled
administration date (Table 5), then the dose will be considered a missed dose. Administration
may resume at the next planned dosing date. A missed dose will not be made up.
Table 5: 
Daratumumab Administration Schedule for Dose Delays
Cycles 
Frequency  
Dose 
Held
Dosing Restart
1 and 2 
Weekly (q1wk) 
>3 days 
Next planned weekly dosing date
3 to 6 
Every 2 weeks 
(q2wks) 
>7 days 
Next planned every 2 weeks
dosing date
7+ 
Every 4 weeks 
(q4wks) 
>14 days Next planned every 4 weeks
dosing date
Any dose hold of more than 28 days due to toxicity will result in permanent discontinuation of
Dara-SC. Dose holds of more than 28 days for other reasons should be discussed with the
sponsor. If a dose delay occurs, then PK and pharmacodynamic assessments should be
performed on the actual day of study intervention administration, not on the original scheduled
administration day.
Delay of Day 1 drug dosing in any given cycle should not result in a skipped dose but should
lead to a delay of the entire cycle instead. A minimum of 4 days between Dara-SC doses must be
observed.
A study intervention dose held for more than 3 days from the per-protocol administration date
for any reason other than toxicities suspected to be related to daratumumab should be brought to
the attention of the sponsor at the earliest possible time. Participants missing ≥3 consecutive
planned doses of study intervention for reasons other than toxicity should be withdrawn from
study intervention, unless, upon consultation with the sponsor and the review of safety and
efficacy, continuation is agreed upon.
6.1.2. 
Dexamethasone (Arms A and B)
Dexamethasone 40 mg weekly must be administered as 20 mg by IV infusion or PO on Cycle 1
Day 1, then 20 mg by IV infusion or PO on Cycle 1 Day 2. Dexamethasone 40 mg doses
subsequent to Cycle 1 Day 2 may be administered by IV infusion or PO weekly. For days when
dexamethasone is given in the absence of carfilzomib and in the absence of Dara-SC, it may be
given within ±2 days for each scheduled dose. 
On days when more than 1 investigational product is administered, the required order of
administration is as follows: dexamethasone, pre-administration  medications for Dara-SC,
Dara-SC, then carfilzomib.
For Arm A, dexamethasone will be administered between 30 minutes to 4 hours prior to
carfilzomib followed by carfilzomib dosing.


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For Arm B, during weeks when dexamethasone, Dara-SC and carfilzomib will be administered,
dexamethasone will be administered within 1 to 3 hours prior to the Dara-SC, followed by
Dara-SC dosing and then carfilzomib dosing (dexamethasone must be administered no more than
4 hours prior to carfilzomib dosing). During weeks when dexamethasone and Dara-SC will be
administered; dexamethasone will be administered within 1 to 3 hours prior to the Dara-SC,
followed by Dara-SC  dosing. During weeks when dexamethasone and carfilzomib will be
administered, dexamethasone will be administered between 30 minutes to 4 hours prior to
carfilzomib followed by carfilzomib dosing.
6.1.2.1. 
Dexamethasone:  Dosage Adjustments, Dosage Discontinuation
All dexamethasone administrations must be within 2 days of the scheduled administration.
However, it must be given on days carfilzomib or Dara-SC will be administered.
For participants 75 years of age or older, initial starting dexamethasone dose of 20 mg weekly
IV/PO is permitted. Dexamethasone 20 mg weekly must be administered as 20 mg by IV
infusion or PO on Cycle 1 Day 1 and subsequently administered by IV infusion or PO weekly. If
participant is intolerant to dexamethasone 20 mg weekly IV/PO, dose reduction to 12 mg weekly
IV/PO is permitted and may be administered as a split dose over 2 days; 8 mg on the first day
and 4 mg on the second day. If participant is intolerant to dexamethasone 12 mg weekly IV/PO,
dose reduction to 8 mg weekly IV/PO is permitted and must be administered as a single dose.
For participants younger than 75 years of age, or underweight (body mass index [BMI]<18.5), or
who are intolerant to dexamethasone 40 mg once weekly IV/PO, subsequent dexamethasone may
be administered at a split dose of 20 mg twice weekly IV/PO. If a participant is intolerant of a
split dose of 20 mg twice weekly IV/PO, then dexamethasone dose reduction to 20 mg weekly
IV/PO is permitted and may be administered at a split dose of 10 mg twice weekly IV/PO. If
participant is intolerant to dexamethasone 20 mg weekly IV/PO, dose reduction to 12 mg weekly
IV/PO is permitted and may be administered as a split dose over 2 days; 8 mg on the first day
and 4 mg on the second day.
Dexamethasone will be permanently discontinued after 2 dose reductions in the event of
additional dexamethasone-related toxicities. At the investigator’s discretion, dexamethasone may
be tapered prior to complete discontinuation according to institutional practice. The participant
may continue on treatment with the other protocol specified drug(s). Guidelines for
dexamethasone-related toxicities are summarized in Table 6.
Note that the dose modifications above are suggested, but physician discretion and clinical
judgment should prevail.


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Table 6: 
Treatment Guidelines for Dexamethasone-related Toxicity
Symptom  
Findings 
Recommended Action
Cardiovascular 
Edema >Grade 3 (anasarca or 
limiting function and 
unresponsive to therapy) 
 
Diuretics as needed, and restart dexamethasone at 1
dose decrement; if edema persists despite above
measures, decrease dose by another dose decrement.
 
Discontinue dexamethasone permanently if symptoms
persist despite second reduction.
Gastrointestinal 
Toxicity  
Dyspepsia, gastric or duodenal 
ulcer, or gastritis Grade 1 or 2 
(requiring medical management) 
 
Continue dexamethasone at same dose and treat with
therapeutic doses of histamine 2 (H2) blockers, or
proton pump inhibitor.
 
Consider adding sucralfate or other antiulcer treatment
as clinically indicated.
 
If symptoms persist despite above measures, decrease
dexamethasone dose by 1 dose level.
Dyspepsia, gastric or duodenal 
ulcer, or gastritis ≥Grade 3 
(requiring hospitalization or 
surgery) 
 
Hold dexamethasone until symptoms return to baseline.
 
Restart dexamethasone at 1 dose decrement along with
concurrent therapy with H2 blockers, sucralfate, or
omeprazole.
 
Ifsymptoms persist despite above measures,
discontinue dexamethasone permanently.
Acute pancreatitis 
 
Discontinue dexamethasone permanently.
General Disorders Limb edema >Grade 3 (>30% 
limb discrepancy in volume; 
gross deviation from normal 
anatomic contour; limiting 
self-care activities of daily 
living) 
 
Hold dexamethasone until symptoms return to baseline.
 
Diuretics as needed, and restart dexamethasone at 1
dose decrement; if edema persists despite above
measures, decrease dose by another dose decrement.
 
Discontinue dexamethasone permanently if symptoms
persist despite second reduction.
Psychiatric 
Disorders 
Confusion or mood alteration 
≥Grade 2 (interfering with 
function ± interfering with 
activities of daily living) 
 
Hold dexamethasone until symptoms return to baseline.
 
Restart dexamethasone at 1 dose decrement.
 
Ifsymptoms persist despite above measures, reduce by
another dose decrement.
Musculoskeletal 
Muscle weakness ≥Grade 2 
(symptomatic and interfering 
with function ± interfering with 
activities of daily living) 
 
Decrease dexamethasone by 1 dose decrement.
 
If weakness persists, decrease dose by another dose
decrement.
 
Discontinue dexamethasone permanently if symptoms
persist.
Metabolism and 
Nutrition Disorders 
Hyperglycemia ≥Grade 3 
(fasting glucose >250 mg/dL) 
 
Withhold dexamethasone, treat with insulin or other
hypoglycemic agents as needed until glucose is ≤Grade
2 (<250 mg/dL) then resume dexamethasone.
 
If uncontrolled despite above measures, decrease dose
by 1 dose decrement until ≤Grade 2 (<250 mg/dL).
All Other 
Other toxicity ≥Grade 3 felt 
related to dexamethasone 
 
Hold dexamethasone dose.  Resume at 1 dose
decrement when toxicity has resolved to ≤Grade 2.
 
If toxicity recurs, hold dexamethasone dose until
toxicity has resolved to ≤Grade 2 and resume
dexamethasone dose by another dose decrement.
 
If toxicity recurs despite 2 dose decrements, discontinue
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6.1.3. 
Carfilzomib (Arms A and B)
Carfilzomib will be administered in 28-day cycles. All cycles will start 28 days (±3) after the
start of the prior cycle. Once-weekly carfilzomib must never be administered within the 5 days
following a previous carfilzomib infusion. Carfilzomib IV will be administered at a dose of
20 mg/m2 on Cycle 1 Day 1, then 70 mg/m2 thereafter over 30 minutes (±5 minutes). On days
when more than 1 investigational product is administered, the required order of administration is
as follows: dexamethasone, pre-administration  medications for Dara-SC, Dara-SC, then
carfilzomib.
The amount (in mg) of carfilzomib to be administered will be determined by body surface area
(BSA), which will be calculated according to a standard nomogram (Appendix 14). The
calculated dose of carfilzomib may be rounded to the nearest milligram (eg, a calculated dose of
152.5 mg may be rounded to 153 mg). Additionally, participants with BSA >2.2 m2 should be
given a dose based on a BSA of 2.2 m2. Dose adjustments must be made for weight gains/losses
of ≥20% of baseline body weight.
6.1.3.1. 
Prehydration (for Arm A and Arm B)
Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high risk of
tumor lysis syndrome or renal toxicity. The recommended hydration includes both oral fluids
(30 mL per kg at least 48 hours before Cycle 1 Day 1) and intravenous fluids (250 mL to 500 mL
of normal saline or other appropriate IV fluid prior to each dose in Cycle 1). If needed,
administer an additional 250 mL to 500 mL of intravenous fluids following carfilzomib
administration. Continue oral or intravenous hydration as needed in subsequent cycles, if the
participant’s condition or risk factors require it. Monitor patients for evidence of volume
overload and adjust hydration to the participant's needs, especially in patients with or at risk for
cardiac failure. The total volume of prehydration and the reason for prehydration after Cycle 1
will be recorded.
6.1.3.2. 
Carfilzomib:  Dosage Adjustments, Delays, Rules for Withholding or
Restarting, Permanent Discontinuation
Carfilzomib may be discontinued, temporarily delayed, or dosage temporarily reduced, in the
event of a treatment-related toxicity that, in the opinion of the investigator, warrants the
discontinuation, temporary delay or dose reduction, as indicated in Table 7 and Table 8.  The
participant will be considered on protocol treatment while receiving either carfilzomib or
Dara-SC (ie, if either carfilzomib or Dara-SC are discontinued or interrupted, the participant is
still considered on treatment if still taking the other investigational product). 
If Day 1 of a cycle is delayed, all subsequent doses within the cycle and day 1 of subsequent
cycles should be adjusted accordingly to maintain the 28-day cycle duration.  However, if a
within-cycle dose is delayed, then the dates of the subsequent within-cycle doses should not be
adjusted.  For within-cycle doses, if administration does not commence within the allowable
window of the scheduled administration date, then the dose will be considered a missed dose. 


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Administration may resume at the next planned dosing date.  A missed dose will not be made up.
Administration may be within ±2 days for each scheduled dose.
If a participant requires an interruption of carfilzomib of more than 4 weeks, the participant
should be removed from study treatment. Exceptions to this must be discussed with the study
medical monitor.
Table 7: 
Carfilzomib Dosing Guidelines for Treatment-emergent Hematologic Toxicity
Hematologic Toxicity  
Recommended Actiona
Thrombocytopenia
When platelets fall to ≤30 × 109/L 
If platelets 10–30 × 109/L without 
evidence of bleeding
Continue at same dose
Ifevidence of bleeding or platelets 
<10 × 109/L 
Withhold dose until platelets return
to ≥10 × 109/L and/or bleeding is
controlled, then resume at same
dose.
For each subsequent drop to ≤30 × 
109/L 
If platelets 10–30 × 109/L without 
evidence of bleeding
Continue at same dose
If evidence of bleeding or platelets 
<10 × 109/L 
Withhold dose until platelets return
to ≥10 × 109/L and/or bleeding is
controlled, then resume at 1 dose
decrement.
Neutropenia
When ANC falls to ≤0.75 × 109/L 
If ANC 0.5–0.75 × 109/L 
Continue at same dose.
If ANC <0.5 × 109/L 
Withhold dose until ANC returns to
≥0.5 × 109/L, then resume at
same dose.
For each subsequent drop to ≤0.75 × 
109/L 
If ANC 0.5–0.75 × 109/L 
Continue at same dose.
If ANC <0.5 × 109/L 
Withhold dose until ANC returns to
≥0.5 × 109/L, then resume at 1
dose decrement.
Neutropenic fever 
If <1000/mm3 and single 
temperature >38.3°C OR 
temperature >38.0°C for more 
than 1 hour
Withhold dose until ANC returns to
baseline grade, then resume at
same dose.
a. The maximum allowed dose interruption is 28 days.
Abbreviations: ANC = absolute neutrophil count.
Table 8: 
Carfilzomib Dosing Guidelines for Treatment-emergent Nonhematologic Toxicities
Nonhematologic Toxicity  
Recommended Actiona
Renal Dysfunction
Serum creatinine equal to or greater 
than 2 × baseline, or CrCl <15 
mL/min (or CrCl decreases to ≤50% 
of baseline), or need for dialysis 
 
Withhold dose and continue monitoring renal function (serum
creatinine or creatinine clearance).
 
If attributable to carfilzomib, resume when renal function has recovered
to within 25% of baseline; start at 1 dose level reduction.
 
If not attributable to carfilzomib, dosing may be resumed at the
discretion of the physician.
 
If tolerated, the reduced dose may be escalated to the previous dose at
the discretion of the physician.  For patients on dialysis receiving
carfilzomib, the dose is to be administered after the dialysis procedure.
Hepatic Dysfunction and Related Investigations
≥Grade 3 elevation in liver function 
tests (AST, ALT, or total bilirubin)b 
 
Withhold dose. Resume at 1 dose decrement when toxicity has resolved
to baseline.c


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Table 8: 
Carfilzomib Dosing Guidelines for Treatment-emergent Nonhematologic Toxicities
Nonhematologic Toxicity  
Recommended Actiona
Grade 3 Infection 
 
Withhold carfilzomib until infection resolves.  Resume carfilzomib at
same dose.
Congestive heart failure 
 
Any participant with symptoms of congestive heart failure, whether or
not drug related, must have the dose held until resolution or return to
baseline, after which treatment may continue at a reduced dose, or the
participant may be permanently discontinued.
 
If no resolution after 4 weeks, the participant will be withdrawn from
all study treatment.
LVEF Reductions
For resting LVEF <40% or reduction 
of LVEF to <55% if the drop is 
greater than 20% from baseline
 
Withhold until LVEF returns to >40% or, if held due to a drop to
<55%, to within 15% of baseline. Resume at 1 dose decrement.c
Micro-Angiopathy
Thrombotic thrombocytopenic 
purpura/hemolytic uremic syndrome 
(TTP/HUS) 
 
If suspected TTP/HUS, withhold carfilzomib.
 
Manage symptoms per standard of care including plasma exchange as
clinically indicated.
 
If the diagnosis of TTP/HUS is excluded, carfilzomib administration
may resume if clinically appropriate.
 
If TTP/HUS is confirmed, permanently discontinue carfilzomib.
Tumor Lysis Syndrome
3 or more of the following: 
 Increase in creatinine of≥50% 
from baseline
 Increase in uric acid of ≥50% from
baseline
 Increase in phosphate of ≥50%
from baseline
 Increase in potassium of ≥30%
from baseline
 Decrease in calcium from baseline
OR
 Increase in LDH of ≥2-fold from
baseline
 
Hold carfilzomib until all abnormalities in serum chemistries have
resolved; resume at full dose.
Neuropathy
Grade 2 with emergent pain or 
Grade 3 
Grade 4 
 
Hold carfilzomib until resolved to ≤Grade 2 without pain; then resume
at 1 dose decrement.
 
Permanently discontinue carfilzomib.
Hypertension (SBP ≥140 and/or DBP ≥90)
<Grade 3 
≥Grade 3 
 
Continue at the same dose if initiation of appropriate treatment controls
hypertension
 
Hold carfilzomib until resolution to normal or baseline. Initiate
appropriate anti-hypertensive therapy prior to resuming carfilzomib at 1
dose decrement.
Dyspnea (≥Grade 2) 
 
Hold carfilzomib until resolution to Grade 1 or baseline, then resume at
1 dose decrement. Investigate cause and record findings. If caused by
another adverse event listed in this table, follow recommendations for
that adverse event.


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Table 8: 
Carfilzomib Dosing Guidelines for Treatment-emergent Nonhematologic Toxicities
Nonhematologic Toxicity  
Recommended Actiona
Pulmonary toxicity: non-infectious 
interstitial lung disease, acute 
respiratory failure, ARDS
(≥Grade 3)
 
Hold carfilzomib until resolution to Grade 1 or baseline and restart at 1
dose decrement.
Progressive Multifocal 
Leukoencephalopathy (PML) 
 
Participants should be monitored for any new or worsening neurologic,
cognitive, or behavioral signs or symptoms that may be suggestive of
PML as part of the differential diagnosis of CNS disorders.
 
If PML is suspected, withhold administration of carfilzomib;
participants should be promptly referred to a specialist and appropriate
diagnostic testing should be initiated.
 
Discontinue carfilzomib if PML diagnosis is confirmed. If the
diagnosis is excluded, carfilzomib can be restarted at the same dose.
Any Other Drug-Related 
Nonhematologic Toxicity 
≥Grade 3 
 
For carfilzomib attribution, withhold dose.
 
Resume at 1 dose decrement when toxicity has resolved to Grade 2 or
less or to baseline grade.
 
If tolerated, the reduced dose may be escalated to the previous dose at
the discretion of the physician.
 
Additional dose modification guidance for adverse drug reactions are
per the carfilzomib IB.
Pulmonary Hypertension 
 
Withhold until resolved or returned to baseline
 
Restart at the dose used prior to the event or reduce dose by 1 dose
level (ie, 27 mg/m2 to 20 mg/m2 for the twice weekly schedule or
70 mg/m2 to 56 mg/m2 for the once weekly schedule), at the discretion
of the physician.
 
If tolerated, the reduced dose may be escalated to the previous dose at
the discretion of the physician.
Posterior reversible 
encephalopathy syndrome (PRES; 
with symptoms including 
headaches, altered mental status, 
seizures, visual loss, and 
hypertension)
 
If suspected PRES, withhold carfilzomib.
 
Consider evaluation with neuroradiological imaging for onset of visual
or neurological symptoms suggestive of PRES.
 
If the diagnosis of PRES is excluded, carfilzomib administration may
resume if clinically appropriate.
Note: Carfilzomib dose schedule does not need to be adjusted for baseline renal dysfunction.
a. The maximum allowed dose interruption is 28 days.
b. If AST or ALT is ≥3 × ULN, the “evaluation of treatment-emergent liver abnormalities” eCRF should be
completed.
c. Dose reduction should be attempted first to manage treatment-emergent toxicities.
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; ARDS = Acute respiratory
distress syndrome; AST = aspartate aminotransferase; CNS = central nervous system; CrCl = creatinine
clearance; DBP = diastolic blood pressure; eCRF = electronic Case Report Form; HUS=hemolytic uremic
syndrome; IB = Investigator’s Brochure; LDH = lactate dehydrogenase; LVEF = left ventricular ejection
fraction; mL = milliliter(s); PRES=posterior reversible encephalopathy syndrome; SBP = systolic blood
pressure; ULN = upper limit of normal; TTP=thrombotic thrombocytopenic purpura.
6.1.3.3. 
Carfilzomib:  Dose Reduction Levels
Dose reduction levels of carfilzomib for toxicity management of individual participants are
provided in Table 9.  Participants that require a dose level reduction and tolerate the reduced
dose for 1 full cycle, may at the discretion of the treating physician increase the dose to a prior
dose starting with the next cycle except when the dose reduction is due to:  pulmonary


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hypertension, pulmonary toxicity, Grade 3 or worse cardiac failure, and drug-induced
hepatotoxicity.
Table 9: 
Dose Decrements for Carfilzomib
Dosea, b 
(mg/m2) 
First Dose Reduction 
Dose -1 
(mg/m2) 
Second Dose Reduction 
Dose -2 
(mg/m2) 
Third Dose Reduction
Dose -3
(mg/m2)
70 
56 
45 
36
a. If dose reduction of carfilzomib is required on Cycle 1 Day 1, the investigator should contact the medical
monitor to discuss the situation, before any additional doses of carfilzomib are administered.
b. For patients with baseline chronic hepatic impairment (mild, moderate), reduce the starting and subsequent doses
of carfilzomib by 25% (ie, 15 mg/m2 Cycle 1 Day 1 and 52.5 mg/m2 Cycle 1 Day 8 and thereafter).
Abbreviations: CxDx = Cycle X Day X
6.1.3.4. 
Carfilzomib:  Guidelines for Hematologic Toxicity
Guidelines for carfilzomib dose modification in the event of thrombocytopenia and neutropenia
are summarized in Table 7.
6.1.3.5. 
Carfilzomib:  Guidelines of Nonhematologic Toxicity
Guidelines for dose modification in the event of nonhematologic toxicities are summarized in
Table 8.
6.1.4. 
Conditions Not Requiring Dose Reduction
Carfilzomib, Dara-SC, and dexamethasone do not need to be held in the following cases:
 Grade 3 nausea, vomiting, or diarrhea (that responds within 7 days to adequate treatment
of antiemetics and/or antidiarrheal agents)
 Grade 3 dexamethasone-related hyperglycemia
 Isolated Grade 3 g-glutamyl transferase elevation
 Grade 3 fatigue (unless persisting for >7 days)
 Alopecia
6.2. 
Preparation/Handling/Storage/Accountability
Detailed instructions for preparation, handling, and storage of study interventions will be
supplied in the SIPPM, IPPI, or equivalent document.
Refer to the SIPPM for additional guidance on study intervention preparation, handling, and
storage.
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. All study intervention will be stored and


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disposed of according to the sponsor's instructions. Study-site personnel must not combine
contents of the study intervention containers.
Study intervention 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 intervention 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 intervention will be documented on the intervention return form. When
the study site is an authorized destruction unit and study intervention supplies are destroyed
on-site, this must also be documented on the intervention return form.
Potentially  hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for intervention accountability purposes.
Study intervention 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 intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even  to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared
before the study by or under the supervision of the sponsor. The randomization will be balanced
by using randomly permuted blocks and will be stratified by prior protease inhibitor exposure
and daratumumab-free interval (3-6 months, >6 months). The interactive web response system
(IWRS) will assign a unique intervention code, which will dictate the intervention assignment
and matching study intervention kit for the participant. The requestor must use his or her own
user identification and personal identification number when contacting the IWRS and will then
give the relevant participant details to uniquely identify the participant.
Blinding
As this is an open study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
Study intervention will be administered by qualified site staff, and the details of each
administration will be recorded in the eCRF. Additional details are provided in the SIPPM or
equivalent document.


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6.5. 
Concomitant Therapy
Throughout the study, investigators may prescribe any concomitant medications or treatments
deemed necessary to provide adequate supportive care except for those listed in Section 6.5.4.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
All prestudy antineoplastic and multiple myeloma therapies must be recorded at screening. Other
prestudy therapies administered from the signing of the ICF must be recorded at screening.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a participant into the study.
Routine systemic use of clinically significant concomitant medications will be collected in the
eCRF and recorded in the source documents beginning with signing of the ICF to 30 days after
the last dose of the last component of study intervention or until the start of subsequent
anticancer treatment, if earlier.
Concomitant medications to manage AEs and SAEs will be recorded. Concomitant therapies
should also be recorded beyond 30 days only in conjunction with SAEs that meet the criteria
outlined in SAEs in Section 8.3.1, Time Period and Frequency for Collecting Adverse Events
and Serious Adverse Events Information.
Recorded information will include a description of the type of therapy, duration of use, dosing
regimen, route of administration, and indication.
6.5.1. 
Required Therapies
6.5.1.1. 
Prophylaxis for Herpes Zoster Reactivation
The initiation of antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after
starting study intervention and continuing for 3 months following study intervention is required.
Acceptable antiviral therapy includes acyclovir (eg, 400 mg given PO 3 times a day, or 800 mg
given PO 2 times a day or per institutional standards), famcyclovir (eg, 125 mg given PO, twice
a day or per institutional standards), or valacyclovir (eg, 500 mg given PO, twice a day or per
institutional standards), initiated within 1 week after the start of study intervention.
6.5.2. 
Recommended Therapies
6.5.2.1. 
Bisphosphonate Therapy
Bisphosphonate therapy is strongly recommended for all participants with evidence of lytic
destruction of bone or with osteopenia. Bisphosphonate therapy is recommended to be continued
per treatment guidelines.16,17 Commercially available IV bisphosphonates (pamidronate and
zoledronic acid) are preferred when available, and should be used according to the
manufacturer's recommendations, as described in the prescribing information, for participants
with osteolytic or osteopenic myelomatous bone disease. Oral bisphosphonates may be used as


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alternatives if IV bisphosphonates are not available at the study site. It is preferred that
investigators use the same route of bisphosphonate therapy for all participants at their sites.
Participants who are currently using bisphosphonate therapy when they enter the study should
continue the same treatment.
6.5.2.2. 
Prevention of Steroid Induced Gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are
strongly recommended. Acceptable therapies include proton pump inhibitors (omeprazole or
equivalent), sucralfate, or H2 blockers (ranitidine or equivalent) initiated within 1 week after the
start of study intervention.
6.5.2.3. 
Therapy for Tumor Lysis Syndrome
Participants should be monitored for symptoms of tumor lysis syndrome. Management of tumor
lysis syndrome, including hydration for abnormal laboratory test results such as hyperkalemia,
hyperuricemia, and hypocalcemia, is highly recommended. High-risk participants (ie, those with
a high tumor burden) should be treated prophylactically in accordance with local standards
(eg, vigorous hydration, diuretics, allopurinol 300 mg daily, and medication to increase urate
excretion).
6.5.2.4. 
Therapy for Pneumocystis carinii/jirovecii
Pneumocystis carinii/jirovecii pneumonia prophylaxis should be considered, as per institutional
guidelines.
6.5.2.5. 
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA
testing by PCR is mandatory for participants at risk for HBV reactivation see Section 8.2.8.
For participants who are diagnosed with HBV reactivation while on treatment, study treatment
should be interrupted until the infection is adequately controlled. If the benefits outweigh the
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local
standard of care. Consult a liver disease specialist as clinically indicated.
6.5.3. 
Permitted Therapies
Participants are to receive full supportive care during the study. The following medications and
supportive therapies are examples of support therapies that may be used during the study:
 Antivirals
 Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells are
allowed.
 Laxatives or stool softeners
 Adequate hydration is recommended for prevention of myeloma-related kidney disease.


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 Vaccination is allowed per local guidelines (see Section 6.5.4 for Prohibited Therapies).
Other symptoms may be managed according to institutional guidelines provided prohibited
therapies are not administered (see Section 6.5.4, Prohibited Therapies).
6.5.4. 
Prohibited Therapies
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances of
administration of prohibited therapies. Use of the treatments listed below is prohibited during the
study:
 Concomitant administration of any other antineoplastic therapy for the intention of
treating multiple myeloma is prohibited, including medications that target CD38, as well
as medications used for other indications that have anti-myeloma properties (eg,
interferon and clarithromycin). Continuation of study intervention (during or after
emergency orthopedic surgery or radiotherapy because of participant benefit) may only
occur in the absence of disease progression and after consultation with and approval by
the sponsor.
 Concomitant administration of investigational agents and of commercially available
agents with activity against or under investigation for multiple myeloma are prohibited.
 Systemic corticosteroids (>10 mg dexamethasone per day or equivalent) other than those
given as backbone therapy and for IRRs should be avoided.
 Nonsteroidal anti-inflammatory agents should be avoided to prevent myeloma-related
kidney disease.
 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 in a participant for whom delay of systemic therapy is not
appropriate, but radiotherapy field must not include a measurable extramedullary
plasmacytoma. Radiotherapy must occur within the first 2 cycles of study intervention
and only if disease progression has not occurred. Before radiotherapy, the sponsor will
review the participant data and confirm that disease progression has not occurred.
 Administration of live-attenuated and replication-competent viral vector vaccines are
prohibited.
6.6. 
Intervention After the End of the Study
The sponsor will ensure that participants benefiting from study treatment will be able to continue
receiving Dara-SC and carfilzomib after the end of the study until these agents are commercially
available or available from another source. Subsequent therapy is left to the investigator's
discretion.  Subsequent therapy should be documented in the CRF.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Completion


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A participant will be considered to have completed the study if he or she has finished all
protocol-specified procedures before the end of the study, has not been lost to follow-up, died,
and has not withdrawn consent for study participation before the end of the study.
7.2. 
Discontinuation of Study Intervention
A participant will not be automatically withdrawn from the study if he or she has to discontinue
intervention. The End-of-Treatment Visit and Follow-up visit assessments should continue as
specified in Schedule of Activities (Table 1).
A participant's study intervention must be discontinued if:
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in
the best interest of the participant to discontinue all study interventions. End of
treatment is defined as discontinuation of all study interventions. Participants who
discontinue one of the 3 study interventions may continue the other study interventions.
 
The participant becomes pregnant unless the participant, investigator, and sponsor agree
the benefits outweigh the risks to the fetus and continuation of study intervention is in
the best interests of the participant. Refer to Appendix 6.
 
The participant withdraws consent for administration of additional study intervention
 
The participant starts concurrent (non-protocol) treatment for multiple myeloma
 
The participant experiences intolerable toxicity, including IRRs (see Section 6.1.1.3)
 
The participant experiences disease progression as defined by IMWG criteria (see
Table 10). Neither relapse from CR nor clinical relapse are considered as disease
progression.
 
The participant experiences a second primary malignancy that cannot be treated by
surgery alone. However, a participant who develops a malignancy that can be cured
surgically may continue to receive the assigned study treatment and should continue to
be followed for subsequent progression of multiple myeloma.
 
The participant initiates treatment with a prohibited medication.
If a participant discontinues study intervention for any reason before the end of the Treatment
Phase, disease assessments should be obtained and scheduled assessments should be continued
until disease progression is confirmed. The participant will complete the End-of-Treatment Visit
and enter the Follow up Phase. Follow-up will continue until the end of study. If the reason for
withdrawal from the study is withdrawal of consent then no additional assessments are allowed.
The primary reason for discontinuation of study treatment is to be recorded in the CRF.
7.3. 
Participant Discontinuation/Withdrawal from the Study
A participant will not be automatically withdrawn from the study if they have to discontinue
study intervention before the end of the intervention regimen.
A participant will be withdrawn from the study for any of the following reasons:


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 Lost to follow-up
 Withdrawal of consent
 Death
 The study investigator or sponsor for any reason, stops the study or stops the participant’s
participation in the study
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. Study intervention assigned to the
withdrawn participant may not be assigned to another participant. Additional participants will
not be entered. If a participant discontinues study intervention and withdraws from the study
before the end of the Treatment Phase, End-of-Treatment and Follow-up assessments should be
obtained. If the reason for withdrawal from the study is withdrawal of consent to study
intervention and all procedures and follow-up, then no additional assessments are allowed.
7.4. 
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study site
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The
measures taken to follow up must be documented. Refer to Section  7.3, Participant
Discontinuation/Withdrawal from the Study.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (Table 1 to Table 3) summarizes the frequency and timing of
efficacy, PK, immunogenicity, biomarker, medical resource utilization, and safety.
Urine and blood collections for PK 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 eCRF.
Additional serum or urine 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.
Medical resource utilization data will be collected. Refer to Section 8.7, Medical Resource
Utilization for details.


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The total blood volume (based on a median of 16 cycles) is 766 mL. This includes screening,
cycles inclusive of safety, blood typing, daratumumab PK and immunogenicity and rHuPH20
immunogenicity, biomarkers, disease evaluations and pregnancy testing and EOT and follow up.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
Refer to the Schedule of Activities (Table 1 to Table 3) for the timing and frequency of all
sample collections. The actual dates and times of sample collection must be recorded in the
eCRF or laboratory requisition form. If blood samples are collected via an indwelling cannula, an
appropriate amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume
of the lock will be removed from the cannula and discarded before each blood sample is taken.
After blood sample collection, the cannula will be flushed with  0.9% sodium chloride, US
Pharmacopeia (or equivalent) sodium heparin of 10 U/mL and charged with a volume equal to
the dead space volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is
not expected.
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:
 IBs for daratumumab and carfilzomib
 Investigational Product Preparation Instructions
 Site Investigational Product Procedures Manual
 Laboratory manual
 IWRS Manual
 eCRF completion guidelines
 ICF
 Participant identification wallet card, including space for blood type and indirect
antiglobulin test (IAT) result
 Participant treatment diary
 Other manuals and guidance documents as needed
8.1. 
Efficacy Assessments
8.1.1. 
Response Categories


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During study treatment, disease evaluations must be performed every 28 days (±7 days) until
disease progression. If a participant discontinues study treatment for reasons other than disease
progression, disease evaluations should be conducted every 8 weeks (±7 days) until confirmed
disease progression, death, start of a new treatment for multiple myeloma, withdrawal of
consent, or the end of the study, whichever occurs first. Disease evaluations will be performed by
a central laboratory (unless otherwise specified). This study will use the IMWG consensus
recommendations for multiple myeloma treatment response criteria8,11,21 presented in Table 10.
All serum and urine disease evaluations will be performed by a central laboratory according to
Section 1.3. For quantitative immunoglobulin, M-protein, and immunofixation measurements in
serum and 24-hour urine, the investigator will use results provided by the central laboratory. For
participants with light chain multiple myeloma, only serum FLC assay will be performed
routinely. Otherwise, serum FLC assay test results will be analyzed by the central laboratory
only for the assessment of sCR. For participants with suspected daratumumab interference on
serum M-protein quantitation by electrophoresis (SPEP) and immunofixation, a reflex assay will
be performed (Appendix 15). Participants with confirmed daratumumab interference who meet
all other clinical criteria for CR or sCR will be considered CR/sCR.
Table 10: 
International Uniform Response Criteria Consensus Recommendations
Response 
Response Criteria
Stringent 
complete response 
(sCR) 
 
CR as defined below, plus
 
Normal FLC ratio, and
 
Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2- to 4-color
flow cytometry
Complete 
response (CR)* 
 
Negative immunofixation on the serum and urine, and
 
Disappearance of any soft tissue plasmacytomas, and
 
<5% PCs in bone marrow
Very good partial 
Response
(VGPR)*
 
Serum and urine M-component detectable by immunofixation but not on electrophoresis,
or
 
≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours
Partial response 
(PR) 
 
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%
or to <200 mg/24 hours
 
If the serum and urine M-protein are not measurable, a decrease of ≥50% in the difference
between involved and uninvolved FLC levels is required in place of the M-protein criteria
 
If serum and urine M-protein are not measurable, and serum free light assay is also not
measurable, ≥50% reduction in bone marrow PCs is required in place of M-protein,
provided baseline bone marrow plasma cell percentage was ≥30%
 
In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft
tissue plasmacytomas is also required.
Minimal response 
(MR) 
 
25% but 49% reduction of serum M-protein, and
 
Reduction in 24-h urine M-protein by 50–89%
 
In addition to the above criteria, if present at baseline, a 25% to 49% reduction in the size
of soft tissue plasmacytomas also is required
Stable disease 
(SD)
 
Not meeting criteria for CR, VGPR, PR, MR, or PD


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Table 10: 
International Uniform Response Criteria Consensus Recommendations
Progressive 
disease (PD)† 
 
Increase of 25% from lowest response value in any one of the following:
 
Serum M-component (absolute increase must be ≥0.5 g/dL),
 
Urine M-component (absolute increase must be ≥200 mg/24 hours),
 
Only in participants without measurable serum and urine M-protein levels: the difference
between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL)
 
Only in participants without measurable serum and urine M-protein levels and without
measurable disease by FLC levels, bone marrow PC percentage irrespective of baseline
status; the absolute percentage must be ≥10%
 
Definite development of new bone lesions or soft tissue plasmacytomas or definite
increase in the size of existing bone lesions or soft tissue plasmacytomas
 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be
attributed solely to the PC proliferative disorder
CR complete response; FLC free light chain; IMWG International Myeloma Working Group; M protein monoclonal
paraprotein; MR minimal response; PC plasma cell; PD progressive disease; PR partial response; sCR stringent complete
response; SD stable disease; VGPR very good partial response
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution
of any new therapy; CR, sCR, VGPR, PR, and SD 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 PD, serum M component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting M component is
≥5 g/dL.
* Clarifications to IMWG criteria for coding CR and VGPR in participants in whom the only measurable disease is by serum
FLC levels: CR in such participants indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR
in such participants requires a >90% decrease in the difference between involved and uninvolved FLC levels.
† Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in participants without
measurable disease by M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone marrow results, and
does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not need to
be a confirmed value.
a Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by
immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio
reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
Clinical Relapse
Clinical relapse is defined using the definition of clinical relapse in IMWG criteria.9,11,21 In IMWG criteria, clinical relapse is
defined as requiring one or more of the following direct indicators of increasing disease or end organ dysfunction that are
considered related to the underlying plasma cell proliferative disorder:
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other
imaging
2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least
1 cm) increase as measured serially by the sum of the products of the cross diameters of the measurable lesion
3. Hypercalcemia (>11.5 mg/dL; >2.875mM/L)
4. Decrease in hemoglobin of more than 2 g/dL (1.25 mM) or to less than 10 g/dL
5. Rise in serum creatinine by more than or equal to 2 mg/dL (≥177 mM/L)
6. Hyperviscosity
In some participants, bone pain may be the initial symptom of relapse in the absence of any of the above features. However, bone
pain without imaging confirmation is not adequate to meet these criteria in studies.


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Disease progression must be consistently documented across clinical study sites using the criteria
in Table 10. Disease evaluations will continue beyond relapse from CR until disease progression
is confirmed. It is important that instances of disease progression be reported to the sponsor as
soon as possible. Diagnosis and documentation of disease progression will be reported to the
sponsor within 24 hours of suspected disease progression. The medical monitor will review the
information to confirm that the IMWG criteria for disease progression have been met. If the
medical monitor agrees that disease progression has occurred, then a confirmation will be
returned to the investigator, and the participant will be withdrawn from study intervention. If the
medical monitor considers that the IMWG criteria for disease progression have not been met,
then the medical monitor will contact the investigator to discuss the participant.
For continuation of study intervention, the IMWG response will be determined on an ongoing
basis by the investigator. For data analysis and reporting, however, the sponsor will use a
validated computer algorithm that has been shown to provide consistent review of the data
necessary to determine disease progression and response according to IMWG criteria.
For participants who discontinue study intervention before disease progression, disease
evaluations should continue to be performed as described in the Schedule of Activities (Table 1
to Table 3), until confirmed disease progression, death, start of a new treatment for multiple
myeloma, withdrawal of consent, or the end of the study, whichever occurs first. Blood and urine
for disease evaluations scheduled for treatment days should be collected before study
intervention is administered.
8.1.2. 
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples will be collected as specified in the Schedule of Activities
(Table 1 to Table 3) until the development of confirmed disease progression. Samples for
M-protein measurements will be sent to and analyzed by a central laboratory. Only one serum
and one 24-hour urine sample per time point are required by the central laboratory to perform the
following tests:
 Serum Quantitative Immunoglobulins: All participants will be evaluated for IgG,
immunoglobin A (IgA), immunoglobin M (IgM), immunoglobin D (IgD), and
immunoglobin E (IgE) at screening. During the study, participants with IgD or IgE
disease will be evaluated for IgG, IgA, IgM, IgE, and IgD and participants with IgG, IgA,
or IgM disease will be evaluated for IgG, IgA, and IgM.
 Serum M-Protein quantification by electrophoresis (SPEP)
 Serum immunofixation at screening and thereafter when a CR is suspected. If
daratumumab interference is suspected based on SPEP and immunofixation
electrophoresis (IFE) results, additional reflex IFE testing may be performed.
 Serum FLC assay
 24-hour urine M-protein quantitation by electrophoresis (UPEP)
 Urine immunofixation at screening and thereafter when a CR is suspected


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Disease progression based on one of the laboratory tests alone must be confirmed by at least one
repeat investigation.
Participants with a urine M-protein on UPEP >100 mg/24h at screening will provide samples for
UPEP assessment on the same schedule as SPEP throughout the study according to the Schedule
of Activities (Table 1).  Blood samples for SPEP and SIFE must be collected on the same day
that 24-hour urine samples for UPEP and UIFE starts or stops. Participants may stop collecting
samples for UPEP assessments after Cycle 1 Day 1 only if 1) they have urine M-protein
<100 mg/24h at screening, or 2) they have measurable urine M-protein >100 mg/24h at
screening but then urine M-protein <100 mg/24h at 2 consecutive post-baseline
measurements. A urine sample for UPEP assessment should be obtained to document VGPR,
CR, and sCR and at suspected disease progression for all participants with measurable disease by
SPEP or UPEP (non-FLC), regardless of UPEP collection exemptions as described above.
Serum and urine immunofixation tests and serum FLC assay will be performed at screening,
Day 1 of each cycle, and thereafter when a CR is suspected (when serum or 24-hour urine
M-protein electrophoresis [by SPEP or UPEP] are 0 or nonquantifiable). For participants with
suspected daratumumab interference on serum immunofixation, another reflex assay using the
anti-idiotype mAb will be used to confirm daratumumab migration on immunofixation.
Participants that meet all other IMWG criteria for CR, and whose positive immunofixation is
confirmed to be daratumumab, will be considered complete responders. However, for
participants with light chain multiple myeloma, serum FLC assay will be performed routinely.
Serum immunofixation assay samples will be split into 2 aliquots, with 1 reserved for potential
follow-on testing if daratumumab interference with immunofixation is suspected. As
daratumumab is a monoclonal IgG antibody, additional serum samples may be utilized to
monitor for potential daratumumab interference with immunofixation.
Note: All attempts should be made to determine eligibility of the participant based on the central
laboratory results of screening blood and urine M-protein measurements. In exceptional
circumstances, the local laboratory results of blood and urine M-protein measurements may be
used to determine eligibility, but only if the results are clearly (eg, 25% or more) above the
thresholds for measurability. In such cases, central laboratory results are still required to be
obtained in order to establish baseline values and confirm the results from the local laboratory.
8.1.3. 
Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected as specified
in the Schedule of Activities (Table 1) and analyzed centrally until the development of confirmed
disease progression. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or
2.8 mmol/L) can indicate disease progression or relapse if it is not attributable to any other cause
(see disease response criteria in Table 10). Calcium binds to albumin and only the unbound (free)
calcium is biologically active; therefore, the serum calcium level must be adjusted for abnormal
albumin levels (“corrected serum calcium”). The formula for adjustment is presented in
Appendix 9.


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When blood is analyzed at a local laboratory, measurement of free ionized calcium is an
acceptable alternative to corrected serum calcium to determine hypercalcemia. Free ionized
calcium levels greater than the ULN (local laboratory reference ranges) are considered to be
hypercalcemic for this study.
8.1.4. 
β2-microglobulin and Albumin
Blood samples for β2-microglobulin and albumin are to be collected at screening and will be
analyzed by the central laboratory and used for the assessment of International Staging System
staging at study entry. The central laboratory will also measure albumin at any time during the
study that a serum calcium sample is taken.
8.1.5. 
Bone Marrow Examination
Bone marrow assessments to be performed locally and centrally are summarized in Table 3.
MRD evaluation will be performed centrally, while the cytogenetic analysis will be performed
locally. If cytogenetic analysis is not available locally, this may be done centrally with agreement
of the sponsor. The following FISH probes should be used for cytogenetic analysis:
 Required: t(4;14); t(14;16), del (17p)
 Optional: Amplification 1q
8.2. 
Safety Assessments
AEs will be reported and followed by the investigator as specified in Section 8.3, Adverse
Events and Serious Adverse Events and Appendix 5. Any clinically relevant changes occurring
during the study must be recorded on the AE section of the eCRF. 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 Schedule of Activities (Table 1).
8.2.1. 
Physical Examination
A complete physical examination (including neurological examination) should be performed
during screening. Thereafter, a physical examination  that is symptom- and disease-directed as
clinically indicated is to be performed at each treatment visit. Abnormalities will be recorded in
the appropriate section of the eCRF.
8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed sitting with a completely
automated device. Manual techniques will be used only if an automated device is not available.


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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. 
Electrocardiogram
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or
vital sign measurement is scheduled for the same time point as ECG recording, the procedures
should be performed in the following order: ECG(s), vital signs, blood draw.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Appendix 3.
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 eCRF. The
laboratory reports must be filed with the source documents.
8.2.5. 
Pulmonary Function Test
Participants with known or suspected COPD must have a spirometry FEV1 test during screening.
8.2.6. 
Indirect Antiglobulin Test
Blood group and type, Rh, and IAT should be done before the first dose of Dara-SC. Participant
RBC phenotyping (standard or extended) is an alternative option to the IAT test, if locally
required. Either method must be completed prior to first study intervention administration.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to
identify a participant's antibodies to minor antigens so that suitable donor blood can be given for
transfusion. Daratumumab does not interfere with ABO/rhesus D antigen (RhD) typing. CD38 is
expressed at very low levels on erythrocytes. Daratumumab binds to the CD38 on erythrocytes,
which results in a positive IAT (Indirect Coombs Test). This positive result masks the detection
of antibodies to minor antigens and may prevent or delay blood banks from issuing donor blood
for transfusion. This effect occurs during daratumumab treatment and for up to 6 months after
treatment ends. Participants will receive a participant identification wallet card for the study that
includes the blood profile (ABO, Rh, and IAT or phenotyping) determined before the first study
intervention administration, along with information on the IAT interference for healthcare
providers/blood banks. Participants are to carry this card throughout the Treatment Phase and for
at least 6 months after study intervention ends. Blood banks can eliminate the daratumumab
interference with IAT by treating reagent RBCs with dithiothreitol.4,5
Possible methods for blood banks to provide safe RBCs for transfusion to participants receiving
daratumumab include:
a. Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or
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b. Providing ABO/RhD compatible, K-negative units after ruling out or identifying
alloantibodies using dithiothreitol-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is
needed emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant
hemolysis has been observed in daratumumab studies. For additional details, refer to the
daratumumab IB
8.2.7. 
HBV Serology
All participants will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface
antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc) at Screening unless this was
performed as part of standard of care within 3 months prior to first dose.
8.2.8. 
HBV-DNA Test
Participants who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B
DNA by PCR. Participants with serologic findings suggestive of HBV vaccination (Anti-HBs
positivity as the only serologic marker) and a known history of prior HBV vaccination do not
need to be tested for HBV DNA by PCR. During and following study treatment, participants
who have history of HBV infection will be closely monitored for clinical and laboratory signs of
reactivation of HBV as specified in the Schedule of Activities (Table 1). Where required by local
law, the results of HBV testing may be reported to the local health authorities.
8.2.9. 
Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be used to evaluate the effect of the disease status on the
activities of daily living. When scheduled, ECOG Performance Status assessments should be
obtained prior to any other study procedures planned for the same day whenever possible.
8.2.10. 
Transthoracic Echocardiogram or Multiple-Gated Acquisition Scan
Participants must have a transthoracic echocardiogram  (TTE) or Multiple-Gated acquisition
(MUGA) scan according to the Schedule of Activities (Table 1) showing left ventricular ejection
fraction >40%. A trans-esophageal echocardiogram (TEE) will be an acceptable alternative to
TTE or MUGA if performed as part of standard of care.
8.3. 
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information 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.


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Adverse events will be reported by the participant (or, when appropriate, by a caregiver or
surrogate) for the duration of the study. Anticipated events will be recorded and reported as
described in Appendix 2.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality
complaints, refer to Appendix 5.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from
the time a signed and dated ICF is obtained until 30 days after the last dose of study intervention;
during the follow-up phase, only treatment-related SAEs will be reported. The sponsor will
evaluate any safety information that is spontaneously reported by an investigator beyond the time
frame specified in the protocol.
Serious Adverse Events
All SAEs 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.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
eCRF, which must be completed and reviewed by a physician from the study site, and
transmitted to the sponsor within 24 hours. In the event that the Serious Adverse Event eCRF
cannot be completed, 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 a serious
adverse event should be transmitted electronically or by facsimile (fax).
8.3.2. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in
Appendix 5.
8.3.3. 
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). For anticipated
events reported as individual SAEs, the sponsor will make a determination of relatedness in
addition to and independent of the investigator’s assessment. The sponsor will periodically
evaluate the accumulating data and, when there is sufficient evidence and the sponsor has
determined there is a reasonable possibility that the intervention caused a serious anticipated
event, they will submit a safety report in narrative format to the investigators (and the head of the


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institute where required). The sponsor assumes responsibility for appropriate reporting of
anticipated events to the regulatory authorities according to requirements of the countries in
which the studies are conducted. 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 required and documented by the
IEC/IRB.
8.3.4. 
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 the Serious Adverse Event Form. Any participant
who becomes pregnant during the study must be promptly withdrawn from the study and
discontinue further study intervention unless the participant, investigator, and sponsor agree the
benefits outweigh the risks to the fetus and continuation of study intervention  is in the best
interests of the participant. Follow-up information regarding the outcome of the pregnancy and
any postnatal sequelae in the infant will be required.
8.3.5. 
Disease-Related Events and Disease-Related Outcomes That Do Not
Need to be Reported as Adverse Events or Serious Adverse Events
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.
8.4. 
Treatment of Overdose
No maximum tolerated dose has been reached for daratumumab. However, if the dose exceeds
the maximum tested dose of 2000 mg, then it will be considered as an overdose in this study.
In the event of an overdose, the investigator or treating physician should:
 Contact the Medical Monitor immediately.
 Closely monitor the participant for AE/SAE and laboratory abnormalities until
daratumumab can no longer be detected systemically (at least 3 months).
 Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5. 
Pharmacokinetics


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Serum samples will be used to evaluate the PK of daratumumab. Serum 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.
8.5.1. 
Evaluations
Venous blood samples will be collected for measurement of serum concentrations of
daratumumab and anti-daratumumab antibodies according to the Schedule of Activities (Table 1
and Table 2).
Samples will also be collected from all participants in Arm B to evaluate the immunogenicity of
rHuPH20 according to Table 2.
Venous blood samples will be collected, and each serum sample will be divided into 3 aliquots
(1 each for PK, anti-daratumumab antibodies, and a back-up). Samples collected for analyses of
daratumumab serum concentration and antibody to daratumumab 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. Additional information about the collection, handling, and shipment of biological
samples can be found in the Laboratory Manual.
8.5.2. 
Analytical Procedures
Pharmacokinetics
Serum samples will be analyzed to determine concentrations of daratumumab using a validated,
specific, and sensitive immunoassay method by or under the supervision of the sponsor.
Immunogenicity
For the daratumumab immunogenicity assessments, serum samples will be screened for
antibodies binding to daratumumab and serum titer will also be determined from confirmed
positive samples. Other immunogenicity analyses (eg, assessment of neutralizing capabilities)
may be performed to further characterize the immune responses that are generated.
For the rHuPH20 immunogenicity assessments, plasma samples will be screened for antibodies
binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary.
Neutralizing antibody assessments may also be performed to further characterize immune
responses that are generated.
8.5.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
The trough concentrations will be reported by visit and treatment. Data from this study may be
pooled with other studies to conduct a population PK analysis of serum concentration-time data


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of daratumumab. If performed, details will be provided in a population PK analysis plan and
results of the analysis will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, then other PK/pharmacodynamic modeling may be performed,
including exploring the relationship between serum concentrations of daratumumab and
endpoints of clinical efficacy and safety. If these analyzes are performed, then the details and
results will be presented in a separate report.
8.5.4. 
Immunogenicity Assessments
Daratumumab concentration will be evaluated at all immunogenicity time points to ensure
appropriate interpretation of immunogenicity data. When both daratumumab serum
concentration and immunogenicity analyses are specified, they will be performed on aliquots
from the same blood draw and no additional sampling is required. Plasma samples will also be
collected from all participants receiving daratumumab (Arm B) and assessed for anti-rHuPH20
antibodies. Procedures for sample collection, preparation, identification, storage, and shipment
will be provided in the Laboratory Manual or equivalent document.
When an IRR occurs associated with daratumumab administration, 2 blood samples should be
obtained, if possible, for determination of antibodies to daratumumab and antibodies to
rHuPH20. Daratumumab serum concentration will also be determined from the daratumumab
IRR sample for interpreting immunogenicity data. If the infusion  reaction results in treatment
discontinuation, then participants should undergo all scheduled safety and efficacy evaluations.
Procedures for sample collection, preparation, identification, storage, and shipment will be
provided in the Laboratory Manual or equivalent document. Samples collected for the analysis of
daratumumab immunogenicity/serum concentration or rHuPH20 immunogenicity may be used to
evaluate safety or efficacy questions that arise during or after the study period or for the
evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
Participants who discontinue study intervention or withdraw from the study before confirmation
of PD should have samples collected at the time of early discontinuation. Participants who
discontinue study intervention will also be asked to return for immunogenicity evaluation during
the Follow-up Phase.
8.6. 
Biomarkers
Bone marrow aspirate samples collected at screening will be subjected to DNA sequencing to
establish a multiple myeloma clone for MRD monitoring (calibration). MRD assessment by via
the FDA cleared clonoSEQ V2.0 next generation sequencing (NGS) for the assessment of MRD
for patients with multiple myeloma and several studies have demonstrated that MRD status is
correlated with PFS and OS.12,14 In this study, bone marrow samples will be collected when a
bone marrow aspirate is performed at screening and at the subsequent points outlined in  the
Schedule of Activities (Table 1 and Table 3). Bone marrow aspirates will be utilized for
assessment of MRD by NGS of immunoglobulin heavy and light chains as specified. If this


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methodology is unavailable, or determined to be scientifically inferior, then alternative methods
for MRD assessment may be utilized.
Whole blood samples will be collected from participants as outlined in the Schedule of Activities
(Table 1) and processed to isolate plasma and peripheral blood mononuclear cell (PBMCs).
Changes in immune subpopulations; including T cells (cytotoxic, regulatory memory), B cells,
NK cells and myeloid derived suppressor cells, as a result to treatment with daratumumab, could
be contributing factors to its duration of response. Therefore, subsequent PD might come as a
result of alterations in the daratumumab-induced equilibrium. The data will be analyzed using
mass cytometry (CyTOF) and fluorescence-activated cell sorting and in association with clinical
data may be examined to identify specific signatures associated with response and resistance.
8.7. 
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the
eCRF by the investigator and study-site personnel for all participants throughout the study.
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be
used to conduct exploratory economic analyses and will include:
 Number and duration of medical care encounters, including surgeries, and other selected
procedures (inpatient and outpatient)
 Duration of hospitalization (total days length of stay, including duration by wards;
eg, intensive care unit)
 Number and character of diagnostic and therapeutic tests and procedures
 Outpatient medical encounters and treatments (including physician or emergency room
visits, tests and procedures, and medications)
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.
9.1. 
Statistical Hypotheses
Dara-SC in combination with Kd will have a higher VGPR or better rate as the best response
than Kd in participants who have previously received 1 to 3 prior line(s) of therapy including
daratumumab.
9.2. 
Sample Size Determination
Based on Study MMY1001 study data, the rate of VGPR or better as the best response was 68%
for DKd participants not previously treated with daratumumab. If VGPR or better rate is
assumed to be 60% for DKd and 45% for Kd in the current study, 230 participants (assigned 1:1)
are needed in order to detect an absolute 15% increase in VGPR or better rate with 70% power
using a 2-sided chi-squared test at the 10% significance level.


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9.3. 
Populations for Analyses
Analysis of the primary and secondary efficacy endpoints will be based on the
intent-to-treat (ITT) analysis set, which will include all randomized participants. All safety
analyses are to be performed on data from the all treated analysis set, which will include all
participants who received at least 1 dose of study intervention. Pharmacokinetic analyses will be
performed on the PK-evaluable population, defined as participants who have at least one PK
sample concentration value.
9.4. 
Statistical Analyses
9.4.1. 
Efficacy Analyses
The primary endpoint of VGPR rate or better is defined as the proportion of participants who
achieve VGPR, CR, or sCR as the best response according to the IMWG criteria, after initial
dose of study intervention and before disease progression or start of subsequent anti-myeloma
treatment. The rate of VGPR or better will be compared between the treatment arms using the
stratified Cochran-Mantel-Haenszel test. The stratification factors are prior PI exposure and
daratumumab-free interval (3-6 months, >6 months) at randomization.
Categorical secondary endpoints including ORR, rate of CR/sCR, and MRD negativity rate, will
be analyzed similarly as the primary endpoint. The time-to-event efficacy  endpoints, such as
PFS, OS, and time to next treatment, will be analyzed using the Kaplan-Meier method.
The primary analysis will be carried out with a 2-sided alpha level of 0.10. The secondary
efficacy  analyses will be carried out using 2-sided alpha level of 0.10 without multiplicity
adjustment.
The primary analysis will be conducted approximately 6 months after the last participant
receives the initial dose of study intervention. An interim futility analysis will occur when 40%
of participants are enrolled and treated for 6 months. A final analysis will occur at study
completion/end of the study to update PFS, survival, second primary malignancy and safety.
9.4.2. 
Safety Analyses
The baseline value for safety assessment is defined as the value collected at the time closest to,
but prior to, the start of study intervention administration. The safety parameters to be evaluated
are the incidence, severity, and type of AEs, clinically significant changes in the participant’s
physical examination findings, vital signs measurements, and clinical laboratory results.
Exposure to investigational product and reasons for discontinuation of study intervention will be
tabulated.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities. Treatment-emergent AEs are AEs with onset
during the intervention phase or that are a consequence of a pre-existing condition that has


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worsened since baseline. All reported AEs will be included in the analysis. Adverse events will
be summarized by system organ class, preferred term, worst grade experienced by the
participant, and by dose level. For each AE, the percentage of participants who experience at
least 1 occurrence of the given event will be summarized by intervention group. In addition,
comparisons between intervention groups will be provided if appropriate.
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 a
SAE.
Parameters with predefined NCI-CTCAE toxicity grades will be summarized.
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 analytes at
baseline and for observed values and changes from baseline at each scheduled time point.
Changes from baseline results will be presented in pre- versus post-intervention cross-tabulations
(with classes for below, within, and above normal ranges). 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.
Electrocardiogram
Electrocardiogram data will be summarized on categories of normal, abnormal, either clinically
significant or not clinically significant.
Vital Sign
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled
time point. The percentage of participants with values beyond clinically important limits will be
summarized.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
9.4.3. 
Other Analyses
Pharmacokinetic Analyses
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. Concentrations below the lowest quantifiable concentration
will be treated as zero in the summary statistics.


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Descriptive statistics will be used to summarize daratumumab serum concentrations at each
sampling time point.
If sufficient data are available, then population PK analysis of serum concentration-time data of
daratumumab may be performed using nonlinear mixed effects modeling and may include data
from other studies. If the population PK analysis is conducted, details will be given in a
population PK analysis plan and the results of the analysis will be presented in a separate report.
Biomarkers Analyses
Baseline bone marrow aspirate samples will be evaluated by a NGS assay to establish the
myeloma clone (calibration) and for MRD monitoring. In this study, bone marrow samples will
be collected when a bone marrow aspirate is performed at screening and at the subsequent
timepoints outlined in the Schedule of Activities (Table 1 and Table 3). Whole blood sample will
be collected from participants as outlined in the Schedule of Activities (Table 1 to Table 3) and
processed to plasma and PBMCs.
Any biomarker measurements will be listed, tabulated, and where appropriate, plotted. Statistical
analyses will be done to aid in the understanding of the results. Results of biomarker may be
presented in a separate report.
Immunogenicity Analyses
The prevalence and incidence of anti-daratumumab antibodies will be summarized for all
participants who have at least 1 anti-daratumumab antibody value. The prevalence and incidence
of anti-rHuPH20 antibodies will be summarized for all participants who receive a dose of
daratumumab and have at least 1 sample for detection of anti-rHuPH20 antibodies obtained after
the first dose of daratumumab. A listing of participants who are positive for anti-daratumumab or
anti-rHuPH20 antibodies will be provided.
Pharmacokinetic/Pharmacodynamic Analyses
PK/pharmacodynamic modeling may be performed, including exploring the relationship between
serum concentrations of daratumumab and endpoints of clinical efficacy or safety. Details and
results of any analysis performed will be presented in a separate report.
Medical Resource Utilization Analyses
Medical resource utilization will be descriptively summarized by intervention group.
9.5. 
Interim Analysis
An interim futility analysis will be conducted after 40% of participants are enrolled and treated
for 6 months.  The rate of VGPR or better will be the primary endpoint for the futility analysis. If
the observed rate of VGPR or better in the DKd group is no higher than the rate in the Kd group,
then the null hypothesis (no treatment difference in rate of VGPR or better) will be accepted, and
the study will be terminated. This criterion only serves as a statistical guidance. Assuming the
rate of VGPR or better in the Kd group is 45%, the probability of early termination is at least


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53% if in fact the rate in the DKd group is no higher than 45%, and the probability of termination
is no greater than 8% if in fact the rate of VGPR or better in the DKd group is at least 60%.
9.5.1. 
Data Review Committee
An internal Data Review Committee (DRC) will be established as noted in Committees Structure
in Appendix 4.  The scheduled DRC  meetings will take place when the first 60 participants
complete 1 cycle of the study treatment, and every 6 months thereafter. In addition, there will be
a scheduled meeting to review the results of the interim futility analysis.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
ADA  
anti-daratumumab antibodies
AE 
adverse event
ALT  
alanine aminotransferase
ANC  
absolute neutrophil count
antiHBC  
antibodies to hepatitis B core antigen
antiHBS  
antibodies to hepatitis B surface antigen
ART  
antiretroviral therapy
AST  
aspartate aminotransferase
BMI 
body mass index
BSA 
body surface area
Cmax  
maximum observed concentration
Cmin  
mean minimum observed concentration
CD38 
cluster of differentiation 38
COPD  
chronic obstructive pulmonary disease
CR  
complete response
CrCl 
creatinine clearance
CSR  
clinical study report
CT  
computed tomography
Ctrough  
maximum trough concentration
CyTOF  
mass cytometry
Dara-IV  
daratumumab administered intravenously
Dara-MD  
daratumumab and recombinant human hyaluronidase for SC injection: mix and deliver
formulation
Dara-SC 
daratumumab subcutaneous
DKd 
daratumumab SC in combination with carfilzomib and dexamethasone
DRC  
Data Review Committee
DNA  
deoxyribonucleic acid
ECG  
electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
e-GFR  
estimated glomerular filtration rate
EOT  
end of treatment
EU  
European Union
FDA  
Food and Drug Administration
FEV1 
forced expiratory volume in 1 second
FISH  
fluorescence in situ hybridization
FLC  
free light chain
FVC  
forced vital capacity
GCP  
Good Clinical Practice
H2 
histamine 2
HBV  
hepatitis B virus
HCV  
hepatitis C virus
HRT  
hormonal replacement therapy
IAT  
indirect antiglobulin test
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Conference on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
IF  
immunofluorescence


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IFE 
immunofixation electrophoresis
IgA  
immunoglobin A
IgD  
immunoglobin D
IgE 
immunoglobin E
IgG  
immunoglobin G
IgM  
immunoglobin M
IHC  
immunohistochemistry
IMiD  
immunomodulatory agents
IMWG  
International Myeloma Working Group
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
IRR  
infusion-related reaction
ISR  
injection-site reaction
ITT  
intent-to-treat
IV  
intravenous(ly)
IWRS  
interactive web response system
Kd 
carfilzomib and dexamethasone
LDH  
lactic acid dehydrogenase
LVEF  
left ventricular ejection fraction
mAb 
monoclonal antibody
MDRD  
Modified Diet in Renal Disease
MRD  
minimal residual disease
MUGA  
multiple-gated acquisition
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS  
next generation sequencing
NK  
natural killer
NYHA  
New York Heart Association
ORR  
overall response rate
OS  
overall survival
PBMC  
peripheral blood mononuclear cell
PCR  
polymerase chain reaction
PD 
progressive disease
PFS  
progression free survival
PFS2 
progression-free survival on next line of therapy
PI 
proteasome inhibitor
PK 
pharmacokinetic(s)
PO 
oral
PQC  
product quality complaint
PRES  
posterior reversible encephalopathy syndrome
RBC  
red blood cell
RhD  
rhesus D antigen
rHuPH20 
recombinant human hyaluronidase PH20
SAC  
Safety Assessment Committee
SAE 
serious adverse event
SC 
subcutaneous(ly)
sCR  
stringent complete response
SIFE 
serum immunofixation
SIPPM  
Site Investigational Product Procedures Manual
SOC  
standard of care
SPEP  
serum M-protein quantitation by electrophoresis
SPM  
second primary malignancy
SUSAR  
suspected unexpected serious adverse reaction
TEAE 
Treatment-emergent adverse event
TEE 
trans-esophageal echocardiogram
TTE 
transthoracic echocardiogram
TTP/HUS  
thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
UIFE 
urine immunofixation


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ULN  
upper limit of normal
UPEP  
urine M-protein quantitation by electrophoresis
Vd 
bortezomib-dexamethasone
VGPR  
very good partial response


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10.2. Appendix 2: Anticipated Events
Anticipated Event
An anticipated event is an AE (serious or non-serious) that commonly occurs as a consequence
of the underlying disease or condition under investigation (disease related) or background
regimen.
For the purposes of this study the following events will be considered anticipated events:
Bleeding
Bone diseases
Hypercalcemia
Hyperuricemia
Hyperviscosity syndrome
Infection
Renal failure or insufficiency
Reporting of Anticipated Events
All AEs will be recorded in the eCRF regardless of whether considered to be anticipated events
and will be reported to the sponsor as described under All AEs in Appendix 5. Any anticipated
event that meets SAE criteria will be reported to the sponsor as described in Section 8.3.1, Time
Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information.
Each anticipated event will be assessed by the investigator at the individual case level and if
considered to be drug-related will undergo expedited reporting (if appropriate) as per applicable
clinical trial legislation to Health Authorities and IRBs/IECs. If an anticipated event is
considered disease-related or not related to study drug the event will be exempt from expedited
reporting.
To meet U.S. regulatory clinical trial legislation, the sponsor will perform aggregate review of
anticipated events as outlined below and, if determined to be drug-related, will implement
expedited reporting of these events to Health Authorities and IRBs/IECs. If an interim analysis
of trial results leads to an unblinded, aggregate review of safety data by the study team, the
sponsor may terminate the review of pre-specified anticipated events outlined above.
Safety Assessment Committee (SAC)
A SAC will be established to perform reviews of pre-specified anticipated events at an aggregate
level. The SAC is a safety committee within the sponsor’s organization that is independent of the
sponsor’s study team. The SAC will meet to aid in the recommendation to the sponsor’s study
team as to whether there is a reasonable possibility that an anticipated event is related to the
study intervention based on a review of the aggregate data by arm.


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Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate
Anticipated Events Safety Monitoring Plan.




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10.4. Appendix 4: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current 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 eCRF 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.


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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
 
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


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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)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
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
intervention


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 
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).
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 (if applicable, the notification will be submitted through the head of
investigational institution).
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise
help ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
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.


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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.
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 for the treatment of his or her
disease. Participants will be told that alternative treatments are available if they refuse to take
part and that such refusal will not prejudice future treatment. 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, which includes permission to obtain information about his or her survival status. 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.
Participants who are rescreened are required to sign a new ICF
Where local regulations require, a separate ICF may be used for the required DNA component of
the study.
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.


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When prior consent of the participant is not possible, enrollment procedures should be described
in the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights,
safety, and well-being of the participant and to ensure compliance with applicable regulatory
requirements. The participant must be informed about the study as soon as possible and give
consent to continue.
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.
Exploratory PK and immunogenicity research is not conducted under standards appropriate for
the return of data to participants. In addition, the sponsor cannot make decisions as to the
significance of any findings resulting from exploratory research. Therefore, exploratory research
data will not be returned to participants or investigators, unless required by law or local
regulations. Privacy and confidentiality of data generated in the future on stored samples will be
protected by the same standards applicable to all other clinical data.
DATA REVIEW COMMITTEE (DRC) STRUCTURE
A DRC will be established to ensure the continuing safety of the participants enrolled in this
study and to review safety results at the planned interim analyses. Committee membership
responsibilities, authorities, and procedures will be documented in its charter.


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PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding daratumumab 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 daratumumab, 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 CSR generated by the sponsor and will contain data
from all study sites that participated in the study as 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 CSR has been issued will be reported in a separate report and will not require
a revision of the CSR.
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 substudy 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 from the individual study site until the combined results
from the completed study have been submitted for publication, within 18 months after the study


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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 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.
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, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory 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.
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 eCRF 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.
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


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into eCRF in English. The eCRF 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.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
an eCRF  are needed after the initial entry into the eCRF, 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.
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 intervention administration information; and date of
study completion and reason for early discontinuation of study intervention 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
(ie, must be recorded in patient medical records):
Race
Blood pressure and pulse/heart rate
Height and weight
Details of physical examination
ECOG, medical resource utilization data
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. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include
the eSource system but information collected through eSource may not be limited to that found
in the eCRF.
MONITORING
The sponsor will use a combination of monitoring techniques, central, remote, and on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature
and location of all source documents will be identified to ensure that all sources of original data
required to complete the eCRF 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.


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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
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.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
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.


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STUDY AND SITE CLOSURE
Study 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
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 intervention development


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10.5. Appendix 5: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
medicinal (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 Conference 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 AEs under
Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious Adverse
Events Information, for time of last adverse event recording).
Serious Adverse Event
An SAE event 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 intervention 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).
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 intervention than the
underlying disease, the clinical signs or symptoms of progression and the possibility that the
study intervention is enhancing disease progression, should be reported per the usual reporting
requirements
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 daratumumab, the expectedness of an AE will be
determined by whether or not it is listed in the IB. For Kd, the expectedness of an AE will be
determined by whether or not it is listed in the package insert/summary of product
characteristics.
Adverse Event Associated With the Use of the Intervention
An AE is considered associated with the use of the intervention if the attribution is possible,
probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An AE that is not related to the use of the study intervention.
The following attributions are considered “Not Related”:
Not Related
An adverse event that is not related to the use of the intervention.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant
drug(s), concomitant disease(s), or the relationship in time suggests that a causal
relationship is unlikely.
Related
An AE that is related to the use of the study intervention.


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The following attributions are considered “Related”:
Possible
An adverse event that might be due to the use of the intervention. An alternative
explanation, eg, concomitant drug(s), concomitant disease(s), is inconclusive. The
relationship in time is reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the intervention. The relationship in time
is suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, eg,
concomitant drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably
explained by an alternative explanation, eg, concomitant drug(s), concomitant disease(s).
The relationship in time is very suggestive (eg, it is confirmed by dechallenge and
rechallenge).
SEVERITY CRITERIA
The severity assessment for an AE or SAE should be completed using the NCI CTCAE
Version 4.03.
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may
require expedited reporting or safety evaluation include, but are not limited to:
Overdose of a sponsor study intervention
Suspected abuse/misuse of a sponsor study intervention
Accidental or occupational exposure to a sponsor study intervention
Medication error involving a sponsor product (with or without participant/patient exposure to the
sponsor study intervention, eg, name confusion)
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.


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PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. 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"). Investigators must record in the eCRF 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 indicating the following:
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 staff only)
Site number
Participant number
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in 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 intervention 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)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a participant's participation in a study must be reported as an SAE, except
hospitalizations for the following:


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If the participant has not experienced a significant medical event but is hospitalized overnight
only for observation following injection of study intervention, then the hospitalization should not
be reported as a SAE.
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 eCRF).
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.
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 5).
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
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, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of participants,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 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.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the
sponsor according to the SAE reporting timelines (refer to Section 8.3.1, Time Period and
Frequency for Collecting Adverse Event and Serious Adverse Event Information). A sample of
the suspected product should be maintained for further investigation if requested by the sponsor.


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Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.


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10.6. Appendix 6: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.4 and Appendix 5.
Female participants:
Women of childbearing potential must commit to either abstain continuously from heterosexual
sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one
highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth
control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and
one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or
cervical cap). A reduction in the effectiveness of oral contraceptives during carfilzomib
treatment cannot be excluded. In addition, because of the increased risk of venous
thromboembolic events associated with carfilzomib, women should avoid the use of hormonal
contraceptives that are associated with a risk of thrombosis during treatment with carfilzomib.
Women of childbearing potential who are using oral contraceptives or a hormonal method of
contraception that is associated with a risk of thrombosis should switch to an alternative method
of highly effective contraception. Contraception must begin with study treatment initiation and
continue for 3 months after discontinuing study treatment. Reliable contraception is indicated
even where there has been a history of infertility, unless due to hysterectomy.
Male participants:
Male participants who are sexually active with women of childbearing potential or with pregnant
women must always use a latex or synthetic condom during the study and for 3 months after
discontinuing study treatment (even after a successful vasectomy).
Definitions
Woman of Childbearing Potential
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 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 measurement is insufficient.


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If there is a question about menopausal status in women on HRT, the woman will be required to
use one of the non-estrogen-containing hormonal highly effective contraceptive methods if she
wishes to continue HRT during the study.
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal
occlusion/ligation procedures, 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.
If reproductive status is questionable, additional evaluation should be considered.


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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.
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
Intrauterine device
Intrauterine hormone-releasing system
Bilateral tubal occlusion
Vasectomized partner
(Vasectomized partner is ahighly 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 intervention.
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
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 intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.7. Appendix 7:  Eastern Cooperative Oncology Group Performance Status
Score
Grade 
Eastern Cooperative Oncology Group Performance Status
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or
sedentary nature (eg, light house work, office work)
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more
than 50% of waking hours
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 
Dead
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair (Oken 198219).


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10.8. Appendix 8: Modified Diet in Renal Disease Formula
For creatinine in mg/dL, the estimated glomerular filtration rate (e-GFR) for the MDRD formula
is:
e-GFR (MDRD) mL/min per 1.73m2  175 × [serum creatinine (mg/dL)] 1.154  × [age] 0.203 ×
[1.212 if black] × [0.742 if female]
For creatinine in µmol/L, the e-GFR for the MDRD formulas is:
e-GFR (MDRD) mL/min per 1.73m2  175 x [serum creatinine (µmol/L)/88.4] 1.154 × [age]
0.203 × [1.212 if black] × [0.742 if female]
Source: Levey 200613


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10.9. Appendix 9: Serum Calcium Corrected for Albumin
If calcium is expressed in mg/dL and albumin is expressed in g/dL:
Corrected calcium (mg/dL) 
serum calcium (mg/dL) + 0.8 × (4 - serum albumin [g/dL])
If calcium is expressed in mmol/L and albumin is expressed in g/L:
Corrected calcium (mmol/L) 
serum calcium (mmol/L) + 0.02 × (40 - serum albumin [g/L])
(Burtis 19983)


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10.10. Appendix 10: Conversion Table for Glucocorticosteroid Dose
Glucocorticoid  
Approximate Equivalent 
Dose (mg)
Half-life (Biologic) hours
Intermediate-Acting
Methylprednisolone 
4 
18-36
Prednisolone 
5 
18-36
Prednisone 
5 
18-36
Triamcinolone 
4 
18-36
Long-Acting
Betamethasone 
0.6 –0.75 
36-54
Dexamethasone 
0.75 
36-54


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10.11. Appendix 11: Asthma Guidelines
Components of Severity  
ClassificationofAsthmaSeverity
Intermittent 
Persistent
Mild 
Moderate 
Severe
0 4 
yrs
5 11 yrs 
12 + yrs 
0 4yrs 
5 11 yrs 12 + yrs 
0 4yrs 
5 11 yrs 
12 + yrs 
0 4yrs 
5 11 yrs 
12 + yrs
Impairment 
Normal
FEV1/FVC: 
8 19yr 85% 
20 39yr 
80% 
40 59yr 
75% 
60 80yr 
70% 
Symptoms 
≤2 days/week  
≥2 days/week but not daily  
Daily  
Throughout the day
Nighttime 
awakenings 
0 
≤2x/month
1 2x/ 
month  
3 4x/month  
3 4x/ 
month  
>1x/week but not 
nightly  
>1x/
month  
Often 7x/week
SABA use for
symptom control
(not prevention
of EIB)
≤2 days/week  
≤2 days/week but not daily
>2 days/
week but
not daily, 
and
not more
than 1x
on
any day
Daily  
Several time per day
Interference with
normal activity  
None 
Minor limitation  
Some limitation  
Extremely limited
Lung function
FEV1 
FEV1/FVC 
N/A  
Normal FEV1 
between 
exacerbations
>80% 
>85% 
Normal FEV1 
between 
exacerbations 
>80%
Normal
N/A  
>80% 
>80% 
>80%
Normal 
N/A  
60 80% 
75 80% 
60 80%
Reduced
5% 
N/A
<60%
<75% 
<60%
Reduced
5%
Risk  
Exacerbations 
requiring oral 
systemic 
corticosteroids 
0 1/year 
≥2 exacerbations in  
6months requiring 
oral steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day and 
risk factors for 
persistent asthma 
≥2/year 
Relative 
annual 
risk may  
be related
to FEV1. 
≥2/year 
Relative 
annual 
risk may  
be related 
to FEV1. 
≥2 exacerbations 
in 6months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day and 
risk factors for 
persistent asthma 
≥2/year 
Relative 
annual 
risk may  
be related 
to FEV1. 
≥2/year 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥2 exacerbations 
in
6months 
requiring oral 
steroids or >4 
wheezing 
episodes/ 
1 year lasting >1 
day and risk
factors for
persistent asthma
≥2/year 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥2/year
Relative
annual
risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for participants in any severity category.


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Components of Severity
ClassificationofAsthmaSeverity
Intermittent 
Persistent
Mild 
Moderate 
Severe
0 4
yrs
5 11 yrs 
12 + yrs 
0 4yrs 
5 11 yrs 12 + yrs 
0 4yrs 
5 11 yrs 
12 + yrs 
0 4yrs 
5 11 yrs 
12 + yrs
Recommended Step for
InitiatingTreatment
Step 1 
Step 2 
Step 3and 
consider short 
course of oral 
steroids 
Step 3: 
medium  
dose ICS  
and 
consider 
short 
course of 
oral 
steroids 
Step 3and 
consider 
short 
course of 
oral 
steroids 
Step 3and 
consider short 
course of oral 
steroids 
Step 3: 
medium 
dose ICS  
OR Step 4 
and 
consider 
short course 
of oral
steroids
Step 4or
5 and
consider
short
course
of oral
steroids
In 2 6weeks, evaluate level of asthmacontrol that is achieved.
0 4years: If no clear benefit is observed in 4 6weeks, stop treatment and consider alternate diagnosis or
adjusting therapy. 5 11 and 12+ years: adjust therapy accordingly.


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Components of 
Control 
Classification of Asthma Control
Well Controlled 
Not Well Controlled 
Very Poorly Controlled
0 4 yrs 
5 11 yrs 
12 + yrs 
0 4 yrs 
5 11 yrs 
12 + yrs 
0 4 yrs 
5 11 yrs 
12 + yrs
Symptoms 
≤2 days/week but not more
than once on each day
≤2 days/ week
>2 days/week or multiple
times on ≤2 days/week
>2 days/ week  
Throughout the day
Impairment
Nighttime
awakenings
≤1x/month  
≤2x/month  
>1x/month  
≥2x/month  
1 3x/week  
>1x/week  
≥2x/week  
≥4x/week
Interference with
normal activity
None 
Some limitation  
Extremely limited
SABA use for symptom
control (not prevention of 
EIB)
≤2 days/week  
>2 days/week  
Several times per day
Lung function
FEV1 or peak flow  
FEV1/FVC 
N/A  
>80% 
>80% 
>80% 
N/A  
60 80% 
75 80% 
60 80% 
N/A  
<60% 
<75%
<60%
Validated questionnaires 
ATAQ, ACQ, ACT  
0 
≤0.75 
≥20 
1 2 
≥1.5 
16 19 
3 4
N/A
≤15
Risk
Exacerbations requiring
oral systemic
corticosteroids
0 1/year 
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/
Progressive loss of lung
function
Evaluation requires long term follow up
Recommended Action for
Treatment
• Maintain current step
• Regular follow up every 1 6 months
• Consider step down if well controlled for at least
3 months
Step up 1 step 
Step up at least 1
step
• Step up1
step
• Reevaluate
in 2 6
weeks
• For side
effects,
consider
alternative
treatment
options
• Considershortcourse of oral
steroids
• Stepup1 2 steps
• Consider
short course
oforal
steroids
• Stepup1 2
steps
• Reevaluate
in 2 weeks
• For side
effects,
consider
alternative
treatment
options
• Before step up:
Review adherence to medication, inhaler
technique, and environmental control. If
alternative treatment was used,
discontinue it and use preferred treatment
for that step.
• Reevaluate the level of asthma control
in 2-6weeks to achieve control.
0 4 years: Ifno clear benefit is observed in
4 6 weeks, consider alternative diagnoses
or adjusting therapy.
5 11 years: Adjust therapy accordingly.
• For side effects, consider alternative
treatment options.
• Before step up:
Review adherence to medication,
inhaler technique, and
environmental control. If alternative
treatment was used, discontinue it
and use preferred treatment for that
step.
• Reevaluate the level of asthma
control in 2-6weeks to achieve
control.
0 4 years: Ifno clear benefit is
observed in
4 6 weeks, consider alternative
diagnoses or adjusting therapy.
5 11 years: Adjust therapy
accordingly.
• Forside effects, consider
alternative treatment options.


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10.12. Appendix 12: New York Heart Association Functional Classification
NYHA 
Class
Symptoms
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity (eg, shortness of
breath when walking or climbing stairs).
II 
Mild symptoms (mild shortness of breath or angina) and slight limitation during ordinary activity.
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity (eg, walking
short distances [20–100 m]).
Comfortable only at rest.
IV  
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.


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10.13. Appendix 13: Antihistamines That May Be Used Predose
The following antihistamines may be used predose, before Dara-SC injection (including, but not
limited to):
Diphenhydramine
Cetirizine
Fexofenadine
Loratadine
Clemastine
Dexchlorpheniramine
Promethazine*
* The IV use of promethazine should be avoided.


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10.14. Appendix 14: Body Surface Area Calculation
BSA should be calculated using the Mosteller Formula (shown below); however, the DuBois
Formula can be used as an alternative.


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10.15. Appendix 15: Interpretation of the SEBIA Hydrashift 2/4 Daratumumab
Immunofixation Electrophoresis Interference Test
Background: Clinical response assessment in myeloma relies on serum protein electrophoresis
(SPEP) and immunofixation electrophoresis (IFE). As daratumumab is a monoclonal IgG kappa
antibody, the SPEP and IFE can be positive for daratumumab at the serum levels anticipated
during this protocol.
Implementation: To mitigate this interference, the sponsor will use the SEBIA Hydrashift 2/4
Daratumumab IFE Interference test. Samples will be sent automatically to the central laboratory
if daratumumab interference is suspected.
Interpretation of results: The results will be available to the investigator via the central
laboratory interface and will be reported as follows:
DARAHydra Impress1:  result defined as “DARA detected”, “DARA not detected”, OR “DARA
indeterminate”
DARAHydra Impress2:  result defined as “M-protein not detected” OR the specific protein
detected (ie, “IgG,k” or “IgA”)
DARAHydra Impress3: result defined as “M-protein not detected” OR the specific protein
detected (ie, “IgG,k” or “IgA”)
If Impress1 result is “DARA detected” and Impress2 and 3 results are “M-protein not detected”,
the patient may be in complete response (CR) if the other criteria for CR (including negative
bone marrow aspirate/biopsy) are achieved.
If Impress1 result is “DARA not detected” or “DARA indeterminate”, the patient is still positive
for underlying (endogenous) monoclonal protein and Impress2 and 3 can inform as to the type of
endogenous protein still present.  Therefore, this patient is not in a complete response (CR),
because the CR response criteria requires a negative SPEP and serum IFE.
If Impress1 result is “DARA detected” but there is also protein present and reported by Impress2
or 3, the patient is still positive for underlying (endogenous) monoclonal protein and Impress2
and 3 can inform as to the type of endogenous protein still present.  Therefore, this patient is not
in a complete response (CR), because the CR response criteria requires a negative SPEP and
serum IFE.




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10.17. Appendix 17: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located directly
before the Table of Contents (TOC). A summary of previous amendment is provided below.
Amendment 1 (14 October 2019)
Overall Rationale for the Amendment: The overall rationale for the amendment is to include the
language clarifying the need for contraception for all participants to continue for 3 months after the end of
study treatment as well as the caution for women who are at high risk for thrombosis to use other means
of birth control other than hormonal birth control which carries the highest risk of thrombosis.
Section number 
and Name
Description of Change 
Brief Rationale
5.1. Inclusion
Criteria
(Criterion 8);
10.6. Appendix 6,
Contraceptive and
Barrier Guidance
and Collection of
Pregnancy
Information
Changed language to eliminate requirement for
4 weeks of contraception prior to starting study
treatment.
Added requirement to continue contraception until
3 months after end of treatment for men and
women.
Revisions made to align with a
daratumumab-wide program
change in language to other
protocols.
Added this requirement to align
with current labelling of
daratumumab.
5.1. Inclusion
Criteria
(Criterion 8);
10.6. Appendix 6,
Contraceptive and
Barrier Guidance
and Collection of
Pregnancy
Information
Added recommendation for women with an
increased risk of thrombosis to avoid hormonal
contraception as carfilzomib also increases risk of
venous thromboembolic events.
Added this recommendation to
align with current labelling of
carfilzomib.
1.3. Schedule of
Activities (Table 1),
Physical
examination row;
8.2.1. Physical
Examination
Text was modified to clarify timing and description
of physical examination requirements.
Physical examination is required at
each treatment visit.
1.3. Schedule of
Activities (Table 1),
Urine or serum
Pregnancy test row
8. Study
Assessments and
Procedures
Decreased frequency of pregnancy testing to
Screening and Cycle 1 Day 1 during the study.
Added requirement for a pregnancy test at
End-of-Treatment (EOT) visit.
Decreased the total blood volume collected during
the study.
High frequency of pregnancy
testing is not necessary as none of
the drugs in this study are known to
be teratogenic.
Given drug half-lives a pregnancy
test will be required to confirm that
women of childbearing potential
are not pregnant 4 weeks post
therapy.
The decrease in the number of
pregnancy tests has resulted in less
blood being collected.


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Section number
and Name
Description of Change 
Brief Rationale
1.3. Schedule of
Activities (Table 1)
1.3. Schedule of
Activities (Table 3)
8.1.5. Bone Marrow
Examination
Additional language was added to Footnote e: “If
local FISH testing is unavailable, this may be
performed centrally upon approval of the sponsor.”
Same text was added for Footnote a.
Additional language was added: “If cytogenetic
analysis is not available locally, this may be done
centrally with agreement of the sponsor. The
following FISH probes should be used for
cytogenetic analysis:”
Certain sites could not perform
local fluorescence in situ
hybridization (FISH) testing, so a
provision was made for central
testing with approval of the
sponsor.
1.3. Schedule of
Activities (Table 1),
SPEP and SIFE, 24-
hour UPEP and
UIFE row
8.1.2. Myeloma
Protein
Measurements in
Serum and Urine
Footnote f was added: “Blood samples for SPEP
and SIFE must be collected on the same day that
24-hour urine samples for UPEP and UIFE starts or
stops.”
Subsequent footnotes were re-lettered.
Same text was added for blood samples to this
section.
Clarification was needed to ensure
accurate timing for specimen
collections.
Section 1.3.
Schedule of
Activities (Table 1)
8.2.10.
Transthoracic
Echocardiogram or
Multiple-Gated
Acquisition Scan
10.1. Appendix 1,
Abbreviations
Footnote b had new text added: “A trans-
esophageal echocardiogram (TEE) will be an
acceptable alternative to TTE or MUGA if
performed as part of standard of care.” which was
included as a possible modality to evaluate cardiac
function.
Abbreviation for TEE added to Schedule of
Activities abbreviation table.
Same text was added for TEEs to this section.
Abbreviation for TEE added to abbreviation table.
Allowing TEEs already performed
as part of standard of care will
reduce unnecessary procedures.
2.1.3. Daratumumab
IV
Updated the list of current approved daratumumab
indications in the United States (US).
The indication list for daratumumab
IV use in adult multiple myeloma
patients was updated to be current
with the date of this amendment.
2.2. Study Rationale Wording was clarified to indicate that the Kd
schedule proposed in this study is Food and Drug
Administration (FDA) approved.
Clarification was requested to avoid
the potential implication that this
regimen is approved in Europe.


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Section number
and Name
Description of Change 
Brief Rationale
4.1. Overall Design
6.6. Intervention 
After the End of the 
Study  
Revised language to indicate that participants
benefiting from study treatment will be able to
continue receiving Dara-SC and carfilzomib after
the end of the study.
Revised language to indicate that participants
benefiting from study treatment will be able to
continue receiving both study drugs and indicated
the source of the study drugs after the study ends.
Clarification that participants will
be able to receive both study drugs
after the study ends.
Clarification that participants will
be able to receive both study drugs
and indicated the source of the
study drugs after the study ends.
5. Study Population  
Wording was changed to indicate that screening for
eligible participants will be performed within
28 days before randomization.
Timeframe for screening period
being based on randomization date
was made to maintain consistency
within the protocol.
5.1. Inclusion
Criteria (Criterion 4)
Added sentence “Participants must have
progressed from or be refractory to their last line of
treatment.”
Added sentence to clarify
relapse/refractory disease
requirement (participants must be
relapse/refractory to last line of
treatment.
5.1. Inclusion
Criteria (Criterion
10);
7.2. Discontinuation
of Study
Intervention;
8.3. Adverse Events
and Serious Adverse
Events;
8.3.4. Pregnancy;
10.4. Appendix 4,
Regulatory, Ethical,
and Study Oversight
Considerations
Removed references to a participant’s legally
acceptable representative.
In Section 10.4. changes occur in Informed
Consent Process, Data Protection Section.
The study does not provide for a
legally acceptable representative to
provide consent for participants to
join this study.
5.2. Exclusion
Criteria (Criterion 8,
Criterion 12)
Clarified that investigational treatment washout
period is measured by date of randomization for
this study.
Previously references were made to
randomization date and date of first
dose of daratumumab; clarification
was needed to specify the date of
reference is the date of
randomization.
6.1. Study
Interventions
Administered
(Table 4)
Footnote a was added to the table. Table was
clarified to indicate that Cycle 1 Day 1 dose of
dexamethasone is given as a split dose on Cycle 1
Day 1 and Cycle 1 Day 2.
Table text was updated to align
with protocol text.
6.1.2.1.
Dexamethasone: 
Dosage
Adjustments,
Dosage
Discontinuation
Added information that “Note that the dose
modifications above are suggested, but physician
discretion and clinical judgment should prevail.”
Information added to align with
other daratumumab protocols to
allow for the clinical judgement of
investigators regarding steroid dose
reductions and modifications.
6.5. Concomitant
Therapy
Revised timeframe to begin from the signing of the
ICF for recording of prestudy therapies at
screening.
Clarification of the timing of
prestudy medications to be
recorded.


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Section number
and Name
Description of Change 
Brief Rationale
6.5.1.2. Prevention
of Steroid Induced
Gastritis
Revised language to indicate that medications to 
prevent gastritis are strongly recommended. 
Clarification to allow for clinical
judgement in the administration of
medications for treatment to
prevent gastritis.
6.5.2.1.
Bisphosphonate
Therapy
Revised language to indicate that it is preferred that 
investigators use the same route of bisphosphonate 
therapy for all participants at their sites. 
To avoid protocol deviations, it is
preferred and not required that
investigators follow the same
procedure for administration of
bisphosphonate therapy at their
sites.
6.5.4. Prohibited
Therapies
Revised language to indicate that systemic 
corticosteroids other than those given as backbone 
therapy and for infusion-related reactions (IRRs) 
should be avoided. 
Clarification to allow for clinical
judgement in the administration of
steroids for treatment of potential
adverse events.
6.5.4. Prohibited
Therapies
Information was added to explain that when 
providing emergency radiotherapy, the 
“radiotherapy field must not include a measurable 
extramedullary plasmacytoma”.
Clarification to avoid radiation of
measurable disease that could be
used as part of response criteria.
8. Study
Assessments and
Procedures
In Study-Specific Materials, added IB for 
carfilzomib to list of items provided to the study 
sites. 
Added IB for carfilzomib for
completeness of items provided to
the study site.
9.5. Interim
Analysis
Added information on the futility analysis plan. 
Added information to provide
statistical guidance on futility
analysis.
9.5.1. Data Review
Committee
Added details on the meeting schedule of the Data 
Review Committee (DRC). 
Details of the meeting schedule for
the DRC were requested in the
protocol by the Bioresearch Quality
& Compliance (BRQC) Department
at Janssen.
10.2. Appendix 2,
Anticipated Events
Deleted the terms anemia, neutropenia, and 
thrombocytopenia from the anticipated events list. 
These hematological laboratory
adverse events are already listed as
Adverse Drug Reactions (ADRs)
for daratumumab. Therefore, they
should not be included on this list.
10.2. Appendix 2,
Anticipated Events
Revised language for expedited reporting of 
drug-related anticipated events to Health 
Authorities and IRBs/IECs. 
Revisions made to align with a
daratumumab-wide program
change in language to clarify
reporting responsibilities for
anticipated events to Health
Authorities and IRBs/IECs.
10.2. Appendix 2,
Anticipated Events
Added details specifying when the Safety 
Assessment Committee (SAC) reviews of 
pre-specified anticipated events may be terminated. 
Revisions made to align with a
daratumumab-wide program
change in language to other
protocols. Following unblinding of
aggregate safety data by the
sponsor’s study team, there is no
need for independent SAC review
of anticipated events.
10.1. Appendix 1,
Abbreviations;
10.2. Appendix 2,
Anticipated Events
Changed name of “Anticipated Event Review 
Committee” to “Safety Assessment Committee” 
Changed name of committee to be
in alignment with Janssen SOP
(21Dec2018) for “Identification,
Analysis, Assessment, and
Reporting of Anticipated Events”.


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Section number
and Name
Description of Change 
Brief Rationale
10.4. Appendix 4,
Regulatory, Ethical,
and Study Oversight
Considerations
Data Review Committee Structure Section:
Changed name of “Data Monitoring Committee” to
“Data Review Committee”
Changed name of committee for
alignment with other references in
the protocol as well as other
documents (eg, DRC Charter)
10.5. Appendix 5,
Adverse Events:
Definitions and
Procedures for
Recording,
Evaluating,
Follow-up, and
Reporting
Attribution Definitions Section:
Added definitions of attributions not related,
doubtful, possible, probable, very likely.
Added definitions which were
missing from the original protocol.
10.5. Appendix 5,
Adverse Events:
Definitions and
Procedures for
Recording,
Evaluating,
Follow-up, and
Reporting
Severity Criteria Section:
Eliminated definitions of severity criteria; retained
only reference to NCI CTCAE Version 4.03 as
source of definitions.
Revisions made to align with a
daratumumab-wide program
change in language to other
protocols.
Throughout the
protocol
Title Page
6.1.3.3.
Carfilzomib:  Dose
Reduction Levels
(Table 9)
9.4.2. Safety
Analyses
10.1. Appendix 1,
Abbreviations
10.1. Appendix 1,
Abbreviations
Appendix 3,
Clinical Laboratory
Tests
Minor grammatical, formatting, or spelling
changes were made.
Text in strikethrough has been deleted, text in bold
has been added:
Added "Janssen Biopharma Inc." to the
sponsorship statement
In footnote “a” deleted text for “on Cycle 1 Day 1
or Cycle 1 Day 2, the investigator”
In footnote “b” deleted text for “(ie, 15 mg/m2
Cycle 1 Day 1 and 2 and 52.5 mg/m2 Cycle 1
Day 8 and thereafter)
In Clinical Laboratory Tests, edited sentence
“Descriptive statistics will be calculated for
selected each laboratory analytes at baseline…”
Deleted and Trademarks from the title of this
section.
Added Data Review Committee (DRC)
White Blood Cell count –changed “CBC” to
“WBC”
Minor errors were noted
Added an additional Janssen
operating company to the list of
legal entities to comply with
protocol template updates.
Correction for a content error
(wrong day included for dose
reduction of carfilzomib).
Wording changed to comply with
protocol template updates.
Wording changed to comply with
protocol template updates.
Made corrections to protocol for
consistency throughout the
document.
Made corrections to protocol for
consistency throughout the
document.


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11. 
REFERENCES
1. 
Nooka AK, Joseph N, Boise LH, et al. Clinical Efficacy of Daratumumab, Pomalidomide and Dexamethasone
in Relapsed, Refractory Myeloma Patients: Utility of Retreatment with Daratumumab Among Refractory
Patients. Blood. 2016;128:492.
2. 
Alici E, Chrobok M, Lund J, et al. Re-challenging with anti-CD38 monotherapy in triple-refractory multiple
myeloma patients is afeasible and safe approach. Br J Haematol. 2016;174(3):473-477. doi:10.1111/bjh.13776.
Epub 2015 Oct 12. PubMed PMID: 26455823.
3. 
Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd Edition, Philadelphia; WB Saunders: 1998.
4. 
Chapuy CI, Aguad MD, Nicholson RT, et al. DARA-DTT Study Group* for the BEST Collaborative.
International validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with
blood compatibility testing. Transfusion. 2016;56:2964-2972.
5. 
Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with blood
compatibility testing. Transfusion. 2015;55:1545-1554.
6. 
de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal
antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840-
1848.
7. 
Dimopoulos MA, Moreau P, Palumbo A, et al. ENDEAVOR Investigators. Carfilzomib and dexamethasone
versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma
(ENDEAVOR): a randomised, Phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38. doi:
10.1016/S1470-2045(15)00464-7. Epub 2015 Dec 5. PubMed PMID: 26671818.
8. 
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma.
Leukemia 2006;20:1467–1473. Corrigenda/Erratum in: Leukemia. 2007;21:1134-1135.
9. 
Durie BG, Miguel JF, Blade J, et al. Clarification of the definition of complete response in multiple myeloma.
Leukemia. 2015;29(12):2416-2417.
10. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, Phase 2 study (EVOLUTION) of
combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated
multiple myeloma. Blood. 2012;119:4375-4382.
11. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response
and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-346.
12. Ladetto M, Brüggemann M, Monitillo L, et al. Next-generation sequencing and real-time quantitative PCR for
minimal residual disease detection in B-cell disorders. Leukemia. 2014;28(6):1299-1307. doi:
10.1038/leu.2013.375. Epub 2013 Dec 17.
13. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in
renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-254.
14. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal
residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079. DOI 10.1182/blood-2014-01-
550020.
15. Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients
with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised,
Phase 3 study. Lancet Oncol. 2018;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1. Epub 2018 Jun 1.
Erratum in: Lancet Oncol. 2018 Aug;19(8):e382. PubMed PMID: 29866475.
16. Moreau P, San Miguel J, Ludwig H, et al. Multiple Myeloma: ESMO Clinical Practice Guidelines for
Diagnosis, Treatment, and Follow-up. Ann Oncol. 2013;28(suppl4):1-5. Epub ahead of print:
doi:10.1093/annonc/mdt297.
17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines): Multiple Myeloma, version 2.2014. Fort Washington, PA: National Comprehensive Cancer
Network; 2013.


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18. Nijhof IS, Casneuf T, van Velzen J, et al. CD38 expression and complement inhibitors affect response and
resistance to daratumumab therapy in myeloma. Blood. 2016;128:959-970.
19. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology
Group. Am J Clin Oncol. 1982;5:649-655.
20. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor
activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311-
321.
21. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-4695.
22. San-Miguel J, Usmani SZ, Mateos M-V, et al. Subcutaneous daratumumab in patients with relapsed or
refractory multiple myeloma: Part 2 update of the open-label, multicenter, dose escalation phase 1b study
(PAVO). Poster PF555 presented at: The 23rd European Hematology Association (EHA) Annual Congress;
June 14-17, 2018; Stockholm, Sweden.
23. Usmani S, Ahmadi T, Ng Y, et al. Analysis of real-world data on overall survival in multiple myeloma patients
with ≥3 prior lines of therapy including a PI and an IMiD, or double refractory to a PI and an IMiD.
Oncologist. 2016;21:1355-1361.
24. Verelst SGR. PHAROS myeloma data comparison for registration file of daratumumab. Erasmus University
Medical Center, July 2015. Data on file.


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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
 
03-Jun-2021 
14:52:32
(GMT)
Document Approval
PPD

SAP_001.pdf: 
1
Status: Pending approval, Date: September 26, 2019
Janssen Research & Development
Statistical Analysis Plan
A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in 
Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib 
and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been 
Previously Treated with Daratumumab Intravenous (Dara-IV) to Evaluate Daratumumab 
Retreatment
Protocol 54767414MMY2065; Phase 2
JNJ-54767414  (DARZALEX®)
Status:
Pending approval
Date:
September 26, 2019
Prepared by:
Janssen Research & Development, LLC; Janssen Research & Development, a division of 
Janssen Pharmaceutica NV)
Document No.:
EDMS-ERI-186576192; 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03871829


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Status: Pending approval, Date: September 26, 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.5.
Randomization and Blinding .......................................................................................................... 10
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 10
2.1.
Visit Windows................................................................................................................................. 10
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 11
2.3.
Analysis Sets.................................................................................................................................. 11
2.3.1.
Efficacy Analysis Set(s) .............................................................................................................. 11
2.3.2.
Safety Analysis Set..................................................................................................................... 11
2.3.3.
Pharmacokinetics (PK) Analysis Set .......................................................................................... 11
2.3.4.
Immunogenicity Analysis Set...................................................................................................... 11
2.3.5.
Pharmacodynamics Analysis Set ............................................................................................... 12
2.4.
Definition of Subgroups.................................................................................................................. 12
2.5.
Study Day and Relative Day .......................................................................................................... 13
2.6.
Baseline ......................................................................................................................................... 13
2.7.
Imputation Rules for Missing Date/Time........................................................................................ 13
2.7.1.
Adverse Event Onset/Resolution Date/Time.............................................................................. 13
2.7.2.
Concomitant Medication Start/End Date .................................................................................... 14
2.7.3.
Multiple Myeloma Diagnosis Date .............................................................................................. 15
2.7.4.
Prior Multiple Myeloma Therapy Start/End Date ........................................................................ 15
2.7.5.
Progressive Disease Date on Prior Multiple Myeloma Therapy................................................. 16
2.7.6.
Subsequent Antimyeloma Therapy Start Date ........................................................................... 16
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 17
4.
SUBJECT INFORMATION................................................................................................................ 18
4.1.
Demographics and Baseline Characteristics ................................................................................. 18
4.2.
Disposition Information................................................................................................................... 19
4.3.
Treatment Compliance................................................................................................................... 20
4.4.
Extent of Exposure......................................................................................................................... 20
4.5.
Protocol Deviations ........................................................................................................................ 20
4.6.
Prior and Concomitant Medications ............................................................................................... 21
4.6.1.
Prior Exposure to Multiple Myeloma Therapies.......................................................................... 21
4.6.2.
Refractory Disease ..................................................................................................................... 22
4.6.3.
Concomitant Medications ........................................................................................................... 22
4.7.
Subsequent Antimyeloma Therapy................................................................................................ 22
5.
EFFICACY ......................................................................................................................................... 23
5.1.
Analysis Specifications................................................................................................................... 23
5.1.1.
Level of Significance................................................................................................................... 23
5.1.2.
Data Handling Rules................................................................................................................... 23
5.2.
Primary Endpoint(s) ....................................................................................................................... 23


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5.2.1.
Definition..................................................................................................................................... 23
5.2.2.
Estimand..................................................................................................................................... 23
5.2.3.
Analysis Methods........................................................................................................................ 24
5.3.
Secondary Endpoints..................................................................................................................... 24
5.3.1.
ORR............................................................................................................................................ 24
5.3.1.1.
Definition.................................................................................................................................. 24
5.3.1.2.
Analysis Methods .................................................................................................................... 24
5.3.2.
CR or better ................................................................................................................................ 24
5.3.2.1.
Definition.................................................................................................................................. 24
5.3.2.2.
Analysis Methods .................................................................................................................... 25
5.3.3.
PFS............................................................................................................................................. 25
5.3.3.1.
Definition.................................................................................................................................. 25
5.3.3.2.
Analysis Methods .................................................................................................................... 26
5.3.4.
OS............................................................................................................................................... 26
5.3.4.1.
Definition.................................................................................................................................. 26
5.3.4.2.
Analysis Methods .................................................................................................................... 26
5.3.5.
MRD............................................................................................................................................ 27
5.3.5.1.
Definition.................................................................................................................................. 27
5.3.5.2.
Analysis Methods .................................................................................................................... 27
5.3.6.
Time to Subsequent Antimyeloma Treatment ............................................................................ 28
5.3.6.1.
Definition.................................................................................................................................. 28
5.3.6.2.
Analysis Methods .................................................................................................................... 28
5.4.
Other Endpoints ............................................................................................................................. 28
5.4.1.
Clinical benefit rate ..................................................................................................................... 28
5.4.1.1.
Analysis Methods .................................................................................................................... 28
5.4.2.
M-Protein Response................................................................................................................... 28
6.
SAFETY............................................................................................................................................. 29
6.1.
Adverse Events .............................................................................................................................. 29
6.2.
Adverse Events of Special Interest................................................................................................ 30
6.2.1.
Infections and infestations .......................................................................................................... 30
6.2.2.
Second Primary Malignancies .................................................................................................... 30
6.2.3.
Cardiac Events ........................................................................................................................... 31
6.3.
Clinical Laboratory Tests................................................................................................................ 31
6.4.
Vital Signs and Physical Examination Findings ............................................................................. 31
6.5.
Electrocardiogram.......................................................................................................................... 31
6.6.
Cardiac Assessment/Echocardiogram or MUGA........................................................................... 31
6.7.
Other Safety Parameters ............................................................................................................... 32
6.8.
ECOG Performance Score ............................................................................................................ 32
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 32
7.1.
Pharmacokinetics........................................................................................................................... 32
7.1.1.
Sampling Timepoints .................................................................................................................. 32
7.1.2.
Pharmacokinetic Parameters ..................................................................................................... 32
7.1.3.
Analysis Methods........................................................................................................................ 32
7.2.
Immune Response......................................................................................................................... 33
7.2.1.
Sampling Timepoints .................................................................................................................. 33
7.2.2.
Analysis Methods........................................................................................................................ 33
7.3.
Pharmacodynamics........................................................................................................................ 33
8.
BIOMARKERS................................................................................................................................... 33
8.1.
Minimal Residual Disease (MRD) .................................................................................................. 34
8.1.1.
Sampling Timepoints .................................................................................................................. 34
8.1.2.
Analysis Methods........................................................................................................................ 34
8.2.
Molecular Subtyping....................................................................................................................... 34
8.2.1.
Cytogenetic Risk Groups............................................................................................................ 34
8.2.2.
Molecular Risk Subgroup Analysis ............................................................................................. 34


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9.
MEDICAL RESOURCE UTILIAZTION.............................................................................................. 35
REFERENCES............................................................................................................................................ 36
LIST OF IN-TEXT TABLES
Table 1:
Subgroup Analyses for Efficacy and Safety Endpoints ............................................................ 12
Table 2:
Demographic Variables............................................................................................................. 18
Table 3:
Baseline Characteristics Variables ........................................................................................... 19
Table 4:
PFS Event and Censoring Method ........................................................................................... 25
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................... 9


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AMENDMENT HISTORY
ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
AUC
area under the curve
BMI
body mass index
BSA
body surface area
CBR
clinical benefit rate
CI
confidence interval
CL
total systemic clearance
Cmax
maximum concentration
CR
complete response
CRS
cytokine release syndrome
CrCL
creatinine clearance
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMC
Data Monitoring Committee
DOR
duration of response
DPS
Data Presentation Specifications
DRC
Data Review Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
F (%)
absolute SC bioavailability
FAS
full analysis set
FDA
Food and Drug Administration
FISH
fluorescence in situ hybridization
FLC
Free-light chain
IA
interim analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IMiD
Immunomodulatory drug
IMWG
International Myeloma Working Group
IQ
interquartile
IRR
infusion-related reaction
ISS
International Staging System
IVRS
interactive voice response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LVEF
left ventricular ejection fraction;
MedDRA
Medical Dictionary for Regulatory Activities
MR
minimal response 
MRD
minimal residual disease
NAb
neutralizing antibodies
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next generation sequencing
ORR
overall response rate
OS
overall survival


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PBMC
peripheral blood mononuclear cell
PD
progressive disease
PFS
Progression-free Survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PP
per protocol
PR
partial response
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCR
stringent complete response
SD
standard deviation
SPEP
serum protein electrophoresis
SMQs
standardized MedDRA queries
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
Tmax
time to maximum concentration
TTP
time to disease progression
TTR
time to response
UPEP
urine protein electrophoresis
US NCI
United States National Cancer Institute
V
volume distribution
VGPR
very good partial response
Vz
volume of distribution based on terminal phase
Vz/F
apparent volume of distribution based on terminal phase after extravascular administration
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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Status: Pending approval, Date: September 26, 2019
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of the analysis population(s), derived 
variables and statistical methods for Study 54767414 MMY2065. 
1.1.
Trial Objectives
The primary objective is to compare the efficacy (rate of very good partial response [VGPR] or 
better as best response as defined by the International Myeloma Working Group [IMWG] 
criteria) of Dara-SC in combination with carfilzomib-dexamethasone (DKd) with the efficacy of 
carfilzomib-dexamethasone (Kd) in participants with relapsed refractory multiple myeloma who 
were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab 
retreatment. The primary endpoint of this study is the rate of VGPR or better as defined by the 
IMWG criteria.
The secondary objectives of the study are:

To further characterize the efficacy (progression-free survival (PFS), overall survival (OS), 
overall response rate (ORR), rate of complete response (CR)/stringent complete response 
(sCR)) of Dara-SC in combination with Kd

To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD 
negativity status

To characterize the safety of Dara-SC in combination with Kd

To determine time to next treatment

To evaluate the pharmacokinetics (PK) of Dara-SC

To determine the immunogenicity of daratumumab and recombinant human hyaluronidase 
PH20
The secondary endpoints are:

ORR (rate of partial response, VGPR, CR, sCR)

Rate of CR/sCR

PFS 

OS

MRD negativity rate

Time to next treatment

Serum daratumumab concentrations

Prevalence and incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies


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1.2.
Trial Design
This is a Phase 2, open-label, randomized, multicenter study to determine the efficacy of DKd in 
adult participants with relapsed refractory multiple myeloma who had 1 or 2 prior line(s) of 
treatment including a line containing Dara-IV to evaluate daratumumab retreatment. Participants 
must have completed treatment with Dara-IV at least 3 months prior to randomization. The study 
will be conducted in 3 phases: Screening, Treatment, and Follow-Up. During the Treatment 
Phase, approximately 230 participants will be randomized in a 1:1 ratio to receive Kd or DKd, 
stratified 
by 
prior 
proteasome 
inhibitor 
exposure 
and 
daratumumab-free 
interval 
(3-6 months, >6 months). Participants in both arms will receive study intervention until 
confirmed progressive disease (PD), death, intolerable toxicity, start of a new treatment for 
multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Follow up 
of participants for disease progression and survival will continue during the Follow-up Phase. A 
schematic overview of the study is provided below.
The primary analysis will be conducted approximately 6 months after the last participant 
receives the initial dose of study intervention. An interim futility analysis will occur when 40% 
of participants are enrolled and treated for 6 months. If the Dkd treatment group is considered 
ineffective at the interim analysis, the study will be terminated. The end of study is no later than 
2 years after the last participant has received their initial dose of study intervention or when the 
sponsor decides to stop the study. A final analysis will occur at the end of the study to update 
PFS, overall survival, second primary malignancy and safety. 


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Figure 1:
Schematic Overview of the Study


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1.3.
Statistical Hypotheses for Trial Objectives
The statistical hypothesis for the primary objective is that Dara-SC in combination with Kd will 
have a higher VGPR or better rate as the best response than Kd in participants who have 
previously received 1 or 2 prior line(s) of therapy including Dara-IV. 
1.4.
Sample Size Justification
Based on Study MMY1001 study data, the rate of VGPR or better as the best response was 68% 
for DKd participants not previously treated with daratumumab. If VGPR or better rate is 
assumed to be 60% for DKd and 45% for Kd in the current study, 230 participants (assigned 1:1) 
are needed to detect an absolute 15% increase in VGPR or better rate with 70% power using a 
2-sided chi squared test at the 10% significance level.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be balanced 
by using randomly permuted blocks and will be stratified by prior protease inhibitor exposure 
and daratumumab-free interval (3-6 months, >6 months). The interactive web response system 
(IWRS) will assign a unique intervention code, which will dictate the intervention assignment 
and matching study intervention kit for the participant. The requestor must use his or her own 
user identification and personal identification number when contacting the IWRS and will then 
give the relevant participant details to uniquely identify the participant. As this is an open-label 
study, blinding procedures are not applicable. 
2.
GENERAL ANALYSIS DEFINITIONS
Study treatment refers to combinations of the individual medications dara-SC, carfilzomib, and 
dexamethasone. Study drug refers to individual medications within a study treatment.
2.1.
Visit Windows
Unless otherwise specified, data to be analyzed or listed over time will be presented by day and 
time point (as appropriate) that are recorded in the electronic case report form (eCRF).
For analyses of data by cycle, if data are collected by date (e.g., AE onset), the corresponding
study evaluations will be assigned to actual sequential cycles, which are derived from the study
treatment administration data. The start date of a particular cycle is defined as the date of the first
scheduled dose of any component of the study treatment, and the end date of a cycle is the start
date of the next cycle minus 1. For the last cycle, the end date is defined as the end of treatment
visit date or the minimum of last study treatment date plus 30 days and subsequent
antimyeloma therapy minus 1 day, if the end of treatment visit date is not available.


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In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal cycle
will be used to summarize data. However, due to possible cycle delays, assessment performed
in the same cycle may not be well aligned in time scale for different subjects. To address this,
by-week windowing rules may be applied in the overtime data summaries by study week.
2.2.
Pooling Algorithm for Analysis Centers
All participating centers in the study will be pooled together for analyses.
2.3.
Analysis Sets
2.3.1.
Efficacy Analysis Set(s)

The intent-to-treat (ITT) analysis set includes all subjects who were randomized in the study. 
Demographics, baseline characteristics, and efficacy endpoints will be primarily analyzed 
based on this analysis set.

The response-evaluable analysis set includes subjects who have a confirmed diagnosis of 
multiple myeloma and measurable disease at baseline or screening visit. In addition, subjects 
must have received at least one administration of study treatment and have adequate post-
baseline disease assessments. Measurable disease is defined as follows:
-
serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL for subjects with IgG type, or 
≥ 0.5 g/dL (≥ 5 g/L) for subjects with IgA, IgD, IgE, or IgM multiple myeloma or
-
urine M-protein level ≥200 mg/24 hours or
-
serum FLC multiple myeloma: involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) and 
abnormal serum immunoglobulin kappa lambda free light chain ratio
2.3.2.
Safety Analysis Set
The safety analysis set includes all subjects who received at least 1 dose of study treatment.
This analysis set will be used for safety summaries and listings.
2.3.3.
Pharmacokinetics (PK) Analysis Set
The PK analysis set includes all subjects who have received at least 1 dose of dara-SC and have 
at least 1 post-dose pharmacokinetic sample.
This analysis set will be used for all pharmacokinetics analyses.
2.3.4.
Immunogenicity Analysis Set
The immunogenicity analysis set for dara-SC includes all randomized subjects who have 
appropriate samples for detection of the antibodies.


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Immunogenicity-evaluable analysis set for anti-rHuPH20 antibodies is defined as all subjects 
who receive at least one dose of Dara-SC and have appropriate plasma samples for detection of 
antibodies to rHuPH20 (at least 1 sample after the start of the first dose of Dara-SC).
2.3.5.
Pharmacodynamics Analysis Set 
NA
2.4.
Definition of Subgroups
The following pre-specified subgroup (Table 1) analyses are to be performed for the primary 
efficacy endpoint, major secondary endpoints, and safety endpoints. Additional subgroup 
analyses may be performed for selected efficacy and/or safety endpoints.
Table 1:
Subgroup Analyses for Efficacy and Safety Endpoints
Subgroup
Definition
Analysis Type
daratumumab-free interval (derived)
3-6 months, >6 months
Efficacy(E)
prior proteasome inhibitor exposure
Yes, No
E
Sex
Male, Female
E, Safety(S)
Age
<65, ≥65 years
E, S
Race
White, Other
S
Weight

≤70 kg

>70 kg
E
Baseline renal function (baseline 
CrCl): 
•
<60 mL/min
•
60 to <90 mL/min
•
≥90 mL/min
Based on creatinine clearance (mL/min) 
values
S 
Region

Europe

Rest of the world
E
Baseline hepatic function 
Normal, Impaireda
E, S 
Number of prior lines of therapy 
1 line, >=2 lines  
E 
Prior IMiD 
Yes, No 
E 
Refractoryb to: 
       IMiD 
Yes, No 
E 
       last line of prior therapy 
Yes, No 
E 
Type of Multiple Myeloma 
IgG, Non-IgG 
E 
International Staging System (ISS)c
I, II, and III 
E 
cytogenetics risk group
positive for Del17P, t(4;14), t(14;16), or 
amplification 1q by FISH 
E 
ECOG performance score 
0, ≥1 
E 
Efficacy: efficacy (VGPR or better, ORR, CR/sCR, PFS, and  OS ); Safety: TEAE 
Keys: CrCL; ECOG; FISH; IMiD = Immunomodulatory agent;  
a Includes mild, moderate and severe. mild: (total bilirubin ≤ ULN and AST > ULN) or ULN < 
total bilirubin ≤ 1.5×ULN; moderate: 1.5×ULN < total bilirubin ≤ 3×ULN; severe: total 
bilirubin > 3×ULN
b Refractory disease in this study is defined as <25% reduction in M-protein or confirmed PD 
by IMWG criteria during previous treatment or =< 60 days after cessation of treatment.
c Baseline ISS will be derived based on the combination of serum β2-microglobulin and 
albumin


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2.5.
Study Day and Relative Day
Study Day 1 refers to the start of the first study treatment administration. All efficacy and safety 
assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥ date of Study Day 1

Visit date - Date of Study Day 1, if visit date < date of Study Day 1
There is no 'Day 0'
2.6.
Baseline 
Baseline measurement is defined as the last non-missing measurement prior to the start of the 
first study treatment administration (including time if time is available, with exception of
parameters associated with disease-related efficacy assessment such as SPEP, UPEP, kappa,
lambda, kappa/lambda ratio, serum calcium, and albumin).
2.7.
Imputation Rules for Missing Date/Time 
2.7.1.
Adverse Event Onset/Resolution Date/Time
Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the study treatment start

The day of study treatment start, if the month/year of the onset of AE is the same as 
month/year of the study treatment start date and month/year of the AE resolution date is 
different

The day of study treatment start or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the study treatment start date and 
month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the 
earliest of:

January 1 of the year of onset, as long as this date is on or after the study treatment start 
date

Month and day of the study treatment start date, if this date is the same year that the AE 
occurred

Last day of the year if the year of the AE onset is prior to the year of the study treatment 
start date,

The AE resolution date.


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
Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution or the day of the date of death, if the 
death occurred in that month.

If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.

Completely missing resolution dates will not be imputed.
AE onset/resolution dates with missing times will be imputed as follows:

A missing time of onset of an adverse event will be set to the earlier of:

00:01 as long as the onset date is after the study treatment start date

The time of the study treatment start if this is the same day the AE occurred.

The missing time of resolution of an adverse event will be set to 23:59.
If a missing time is associated with a partial or missing date, the date will be imputed first prior 
to imputing the time.
2.7.2.
Concomitant Medication Start/End Date
In case of partially missing dates, the imputation will be done as follows:

If the date is completely missing, no imputation will be performed.

Otherwise, the following rules will be applied to impute partially missing dates (start date, 
end date). 
o
If only the day is missing, the 15th day of the month will be used. 
o
If both the day and month are missing, the 30th of June will be used.

If the concomitant medication was taken prior to study start, and the imputed start date is 
after study treatment start date, further adjust the imputed start date as the day prior to study 
treatment start date; if the medication was taken after study start, and the imputed start date 
is prior to study treatment start date, further adjust the imputed start date as study treatment 
start date. Also adjust the imputed medication end date so that it is on or after study 
treatment start date.


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2.7.3.
Multiple Myeloma Diagnosis Date
For partial date of original multiple myeloma diagnosis, the following imputation rules will be 
applied:

If only day is missing,
o
if month and year of start of 1st line of prior multiple myeloma therapy are the same 
year and month of diagnosis, and day of start of the 1st line of prior multiple 
myeloma therapy is available, impute day with day of start of 1st line of prior 
multiple myeloma therapy
o
otherwise, impute day with 15

If both month and day are missing,
o
if year of diagnosis is the same as year of start of 1st line of prior multiple myeloma 
therapy, and month information is available for start of the 1st line of prior multiple 
myeloma therapy

impute month with month of start of 1st line of prior multiple myeloma 
therapy

if day of start of 1st line of prior multiple myeloma therapy is available, 
impute diagnosis day with day of start of 1st line of prior multiple myeloma 
therapy; otherwise, impute diagnosis day with 15
o
otherwise, impute with June 30

If year is missing, no imputation will be applied.
2.7.4.
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, 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 study treatment start date, further adjust the imputed 
start/end date as the day prior to study treatment start date.


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2.7.5.
Progressive Disease Date on Prior Multiple Myeloma Therapy
For partially missing progressive disease date on prior multiple myeloma therapy, the following 
imputation rules will be applied. If the date is completely missing, no imputation will be 
performed. Partially missing prior multiple myeloma therapy start/end dates will be imputed 
before imputing partially 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, 15th day 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 the imputed progressive disease date is before the prior multiple myeloma therapy start date, 
further adjust the imputed progressive disease date as the prior multiple myeloma therapy start 
date. If the imputed progressive disease date is later than first study treatment date -1, then 
further adjust the imputed progressive disease date as the first study treatment date - 1.
2.7.6.
Subsequent Antimyeloma Therapy Start Date
If no components of the start date are present, 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 last study treatment end date, then the month and day of 
last study treatment end date + 1 day will be used.

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 last study 
treatment end date, the day of last study treatment end date + 1 day is imputed. 

Otherwise, the first day of the month is imputed. 


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
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.
Note: * The first post-baseline progressive disease is based on investigator assessment (recording 
in disease progression CRF page). 
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
One interim futility analysis is planned.  The interim futility analysis will occur when 40% of 
participants are enrolled and treated for 6 months. The rate of VGPR or better will be the primary 
endpoint for the futility analysis. The criterion for futility is defined as: 
-
If the observed rate of VGPR or better in DKd group is no higher than the rate in the Kd 
group, than the null hypothesis (no treatment difference in rate of VGPR or better) will be 
accepted, and the study will may be terminated. 
-
Otherwise, the study will continue.
The criterion only serves as a statistical guidance. Assuming the rate in the Kd group is 45%, the 
probability of early termination is at least 53% if in fact the rate in the DKd group is no higher 
than 45% and is less than 8% if in fact the rate in the DKd group is at least 60%.  
In addition, the rate of VGPR or better will be compared between the treatment arms using the 
stratified Cochran-Mantel-Haenszel test. The stratification factors are prior PI exposure and 
daratumumab-free interval (3-6 months, >6 months) at randomization. The Mantel-Haenszel 
estimate of common odds ratio, along with its 2-sided 90% confidence interval, and the nominal 
p-value from the CMH test will be reported for descriptive purpose.  The rate of VGPR or better 
will also be summarized by the stratification factor. 
ORR and CR or better will be analyzed using the same method as the primary endpoint. Number 
and percentage of subjects in the response categories below (including not evaluable (NE)) will 
be tabulated by treatment group.  Summaries will be provided for other efficacy endpoints ( sCR, 
PR, SD, PD, and PFS).
Other details about the conduct of these analyses can be found in a stand-alone DRC Charter and 
SAP.


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4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by treatment group 
and overall. In addition, the distribution of subjects by region, and country will be presented 
unless otherwise noted.
4.1.
Demographics and Baseline Characteristics
Table 2 presents a list of the demographic variables that will be summarized by treatment group 
and overall for the ITT analysis set.  
Table 2:
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 Mass Index (BMI) (kg/m2)
Body Surface Area (BSA) (m2)
Categorical Variables
Age (<65, ≥65 years)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (male, female)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other, Not 
Reported)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
Baseline ECOG performance status (0, >=1)
Weight (≤70 kg, >70 kg)
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'


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Table 3 presents a list of the baseline characteristics variables that will be summarized by 
treatment group and overall for the ITT analysis sets.
Table 3:
Baseline Characteristics Variables
Continuous Variables
Summary Type
Time since initial multiple myeloma diagnosis (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Selected hematology laboratory analytes (hemoglobin, platelets, absolute 
lymphocyte count, lymphocyte, absolute neutrophil count)
Selected chemistry laboratory analytes (AST, ALT, Alkaline phosphatase, 
creatinine clearance, total bilirubin, corrected serum calcium)
Vital sign parameters (pulse, systolic blood pressure, diastolic blood 
pressure, temperature)
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 subjects 
in each category.
Type of measurable disease (Serum only, Serum and urine, Urine only, or 
Serum FLC)
ISS staging at screening by central laboratory assessment (I, II, III)
Number of lytic bone lesions (None, 1-3, 4-10, more than 10)
Presence of diffuse myeloma-related osteopenia
Number of extramedullary plasmacytomas [0, >=1]
Presence of evaluable bone marrow assessment (yes, no)
Bone marrow % plasma cells (<10, 10-30, >30-60, >60)
Bone marrow cellularity (hypercellular, normocellular, hypocellular, 
indeterminate) by biopsy or aspirate
Standard-risk and high-risk cytogenetic abnormalities (del17p, t(4;14), 
t(14;16), amplification 1q)
Baseline toxicity grade (1, 2, 3, 4) of selected hematology laboratory 
analytes 
Baseline toxicity grade (1, 2, 3, 4 of selected chemistry laboratory analytes 
Medical history collected at screening visit (by system organ class, 
preferred term)
ECG overall interpretation at baseline (normal, abnormal and clinically
significant, abnormal and not clinically significant, not evaluable)
Stratification factors (Prior PI exposure, dara-free interval)
4.2.
Disposition Information
The number of subjects in the following disposition categories will be summarized throughout 
the study by treatment group and overall:

Subjects randomized but not treated with study medication  

Subjects received study treatment

Subjects didn’t receive study treatment and the reasons

Subject ongoing 

Subjects completed the study treatment

Subjects discontinued study treatment

Reasons for discontinuation of study treatment

Subjects completed the study


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
Subjects discontinued the study participation prematurely 

Reasons for discontinuation of study
Listings of subjects will be provided for the following category:

Subjects who discontinued study treatment

Subjects who were randomized but never treated 

Subjects who terminated study participation prematurely 
4.3.
Treatment Compliance
No treatment compliance will be summarized.
4.4.
Extent of Exposure
The maximum number of treatment cycles received for each subject and exposure to each of the 
study treatments will be summarized by frequency and descriptive statistics.
Duration of study treatment, defined as the number of days from the date of the first
administration of study treatment to the date of the last administration of study treatment, will be
summarized.
The number (%) of subjects with a dose modification and reasons will be summarized by 
treatment group and cycle. 
The dose intensity, which is defined as the sum of total dose administered in all cycles divided
by the number of treatment cycles, will be calculated for each study drug and summarized
accordingly. Additionally, the dara-SC dose intensity will be summarized for cycles 1-2, cycles 
3-6, and cycles >=7.
The relative dose intensity (%) defined as the ratio of total dose actually received and total
planned dose (planned dose level times the number of administered infusions/medications) will
be calculated for each study treatment and summarized by treatment group using descriptive
statistics.
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations will be identified prior to database lock and the subjects with 
major protocol deviations will be summarized by category.


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
Developed withdrawal criteria but not withdrawn

Entered but did not satisfy the inclusion/exclusion criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
A list of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided.
4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (WHO-DD) (September 2017) version. Prior medications are defined as any 
therapy used before the day of first dose (partial or complete) of study treatment. Concomitant 
medications are defined as any therapy used on or after the same day as the first dose of study 
treatment, including those that started before and continue on after the first dose of study 
treatment.
4.6.1.
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 calculated and summarized by the following categories: 
1, 2, >2 through frequency and descriptive statistics. Additionally, the summary of prior systemic 
therapies will be presented by therapy class and therapy. Summaries will be provided for time 
since last Dara-IV exposure to randomization, and time since last proteasome inhibitor exposure 
to randomization.
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, and steroids class: dexamethasone and prednisone, among others. 
The number of subjects who had prior exposure to multiple therapy classes (e.g., PI + IMiD) or 
multiple therapies (e.g., bortezomib + lenalidomide) may be provided, if the number of subjects 
who exposed to those therapy classes or therapies is sufficient. 


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4.6.2.
Refractory Disease 
Relapsed disease is defined as an initial response to previous treatment, followed by confirmed 
PD by IMWG criteria >60 days after cessation of treatment.
Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG 
criteria during previous treatment or =<60 days after cessation of treatment.
Refractory status (yes, no) to a prior MM therapy class (i.e., PI/IMiD) or prior MM therapy 
(e.g., bortezomib, thalidomide, or Dara-IV) will be based on refractory status to each line of prior 
regimen, or each specific medication/therapy collected on prior systemic therapy CRF page. For 
each subject, refractory to each therapy class/therapy refers to refractory to his/her most recent 
therapy-containing line.
The number and percentage of subjects’ refractory status to PI, IMiD, or anti-CD38 antibody 
therapy class will be summarized by the following categories: none, PI only (PI-refractory but 
not IMiD- and anti-CD38 antibody-refractory), IMiD only (IMiD-refractory only but not PI- and 
anti-CD38 antibody-refractory), anti-CD38 antibody only (anti-CD38 antibody-refractory only 
but not PI- and IMiD-refractory), both PI and IMiD. Refractory to specific prior multiple 
myeloma therapy, such as bortezomib, carfilzomib, ixazomib, lenalidomide, pomalidomide, 
thalidomide, daratumumab or isatuximab, and the relevant combinations of the aforementioned 
therapies will be provided separately. 
The incidence of subjects who are refractory to their last line of therapy will be reported. 
4.6.3.
Concomitant Medications
Summaries of concomitant medications will be presented by therapeutic class, pharmacologic 
class, and drug name for each treatment group. The proportion of subjects who receive each 
concomitant medication will be summarized as well as the proportion of subjects who receive at 
least 1 concomitant medication. In addition, concomitant medications of special interest will be 
presented.  These include pre-infusion medication, post-infusion medication, growth factor use, 
and systemic steroids use. 
4.7.
Subsequent Antimyeloma Therapy 
The total number of subjects who received subsequent antimyeloma therapy will be reported for 
each treatment group. A summary of subsequent antimyeloma therapy will be presented by 
therapeutic class, pharmacologic class and drug name, coded using the WHO-DD 
(September 2017) version.
In addition, for subjects who received subsequent antimyeloma therapy, their best response to the 
first subsequent antimyeloma therapy will be summarized.


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5.
EFFICACY
Efficacy assessment will be performed by sponsor using a computerized algorithm, following the 
IMWG criteria. Detailed rules for response/PD assessment will be provided in a separate 
document. As a sensitivity analysis, investigator assessment of response and disease progression 
using the IMWG response criteria will also be summarized.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All statistical hypothesis tests will be based on 1-sided test at significance level of 0.05. All 
interval estimations will be reported using 2-sided 90% CI. 
5.1.2.
Data Handling Rules
5.2.
Primary Endpoint(s)
The primary efficacy endpoint is VGPR or better response rate according to the IMWG criteria.
5.2.1.
Definition
VGPR or better rate is defined as the proportion of subjects achieving VGPR, CR, or sCR in 
accordance with the IMWG criteria, during or after the study treatment but before the start of 
subsequent anti-myeloma therapy. 
5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components:
•
Population: subjects with relapsed refractory multiple myeloma who were previously 
exposed to daratumumab intravenous (Dara-IV);
•
Variable: VGPR or better response (see definition above);
•
Intercurrent events: Subsequent anti-myeloma treatment and treatment discontinuation;
•
Population-level summary: The Mantel-Haenszel estimate of common odds ratio for 
VGPR or better between the two treatment groups
Two strategies are used to account for the intercurrent events. 
•
Disease assessment after subsequent therapy will be ignored for a subject who started 
subsequent anti-myeloma therapy (while-on-treatment strategy). 
•
Treatment discontinuation will also be ignored (treatment policy strategy). 
Sensitivity and supplementary analysis for the primary endpoint rate of VGPR or better are 
described in the analysis methods below.


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5.2.3.
Analysis Methods
The response rate of VGPR or better will be calculated based on a computerized algorithm for 
each of the treatment group. The analysis of the response rate will be based on the 
ITT population. The corresponding 90% exact CI will be provided.
The rate of VGPR or better will be compared between the DKd group and the Kd group using 
the stratified Cochran-Mantel-Haenszel(CMH) test. The stratification
factors are prior 
PI exposure and daratumumab-free interval (3-6 months, >6 months) at randomization. The 
Mantel-Haenszel estimate of common odds ratio, along with its 2-sided 90% confidence interval 
and the p-value from the CMH test will be reported.
A sensitivity analysis, in which VGPR or better response is based on investigator assessment 
according to the IMWG response criteria, will be performed in a similar manner as described 
above. 
In addition, as a supplementary analysis, both the response rate based on the computer algorithm 
and the response rate based on the investigator assessment will be analyzed for the 
response-evaluable population.
5.3.
Secondary Endpoints
5.3.1.
ORR 
5.3.1.1.
Definition
Overall response rate (ORR) is defined as the proportion of subjects who achieve PR or better 
responses (i.e. PR, VGPR, CR, or sCR) based on the computerized algorithm, in accordance with 
the IMWG criteria, during or after the study treatment but before the start of subsequent 
anti-myeloma therapy.
5.3.1.2.
Analysis Methods
ORR will be calculated for the response-evaluable population and the ITT population.  ORR will 
be analyzed using the same mothed for the primary endpoint.
5.3.2.
CR or better 
5.3.2.1.
Definition
CR or better rate is defined as the proportion of subjects achieving CR or sCR based on the 
computerized algorithm, according to IMWG response criteria, during or after the study 
treatment prior to the start of subsequent antimyeloma therapy.  


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5.3.2.2.
Analysis Methods
The rate of CR or better will be analyzed using the same method for the primary endpoint.  
In addition to VGPR or better, ORR, and CR or better, summaries for the following response 
categories based on the computerize algorithm will be presented by treatment group: stringent 
complete response (sCR), complete response (CR), very good partial response (VGPR), Clinical 
benefit (including sCR, CR, VGPR, PR, and MR), partial response (PR), minimal response 
(MR), stable disease (SD), progressive disease (PD), and not evaluable (NE). The corresponding 
90% exact CI for each response category will be provided.
5.3.3.
PFS
5.3.3.1.
Definition
PFS is defined as the duration from the date of randomization to either progressive disease (PD) 
or death, whichever comes first. Disease progression will be determined according to the 
International Myeloma Working Group (IMWG) criteria 1, 2. Subjects who withdrew consent
from the study before disease progression will be censored at the last disease assessment.
Subjects who are lost to follow-up without PD will be censored at the last disease assessment.
Subjects who have not progressed and are still alive at the cutoff date for analysis will be
censored at the last disease assessment. Subjects without any post-baseline disease assessment
will be censored at the date of randomization. PFS survival is calculated in months as follows:
PFS = (date of PD/death or censoring – date of randomization + 1) / (365.25/12).
Determination of dates of PFS event and dates for censoring is summarized in Table 4 as
follows.
Table 4:
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* 

PFS event

Date of death

No postbaseline disease assessment

Censored

Date of randomization

Other, such as:
Withdrawal of consent to study 
participation 
Lost to follow-up

Censored

Date of last disease assessment 
prior to withdrawal of consent 
to study participation or lost to 
follow-up.  
*Subjects who died after consent withdrawal will be censored at the date of consent withdrawal for PFS analysis


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5.3.3.2.
Analysis Methods
PFS will be calculated based on the computer algorithm and analyzed based on the ITT analysis 
set. The Kaplan-Meier method will be used to estimate the distribution of overall PFS for each 
treatment group. The median PFS with 90% CI will be provided. In addition, the number and 
percentage of subjects who had a PFS event or were censored will be reported. The reasons for 
PFS censoring will be summarized accordingly. The Kaplan-Meier PFS curve will also be 
plotted by treatment group.
The treatment comparison of the distribution of overall PFS will be based on a stratified log-rank 
test. The p-value from a stratified log-rank test will be reported. Hazard ratio and its 90% 
confidence interval will be estimated based on a stratified Cox’s regression model with treatment 
as the sole explanatory variable. Stratification factors used in the analyses are prior PI exposure 
and daratumumab-free interval (3-6 months, >6 months) at randomization. 
In addition, PFS rate at 12, 18 and 24 months with 90% CI will be estimated by Kaplan-Meier 
method and reported for each treatment group.
A sensitivity analysis of PFS, in which progressive disease is based on investigator assessment 
according to the IMWG response criteria, may be performed in a similar manner as described 
above.
5.3.4.
OS
5.3.4.1.
Definition
Overall survival (OS) is defined as the time from the date of randomization to the date of the 
subject’s death due to any cause. Subjects who are lost to follow-up will be censored at the time 
of lost to follow-up. Subjects who died after consent withdrawal will be considered as having an 
OS event. If the subject is alive at the cutoff date for the analysis or the survival status is 
unknown, then the subject’s data will be censored at the date the subject 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. Overall survival is 
calculated in months as follows: 
OS = (date of death or censoring – date of randomization + 1) / (365.25/12).
5.3.4.2.
Analysis Methods
The OS will be analyzed using the same method for the PFS.


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5.3.5.
MRD
Bone marrow aspirates will be collected for MRD central testing (NGS) at time of suspected 
CR/sCR and for participants who achieve CR, have not progressed, and remain on the study, 
additional bone marrow aspirate will be obtained at 12, 18, and 24 months post Cycle 1 Day 1 
(±1 month). For this study, three threshold values <10-6, <10-5, and <10-4, will be used to 
evaluate MRD negativity status and its predictive value for PFS. The MRD data will be analyzed 
when sufficient data is available.
5.3.5.1.
Definition
MRD negativity rate, defined as the proportion of subjects who have MRD negative status at 10-5
by bone marrow aspirate after the date of randomization and prior to progressive disease (PD) or 
subsequent anti-myeloma therapy. MRD positive subjects include subjects of which all tested 
samples were found to be MRD positive or ambiguous. Subjects with missing or unevaluable 
MRD status will be considered as MRD positive. Subjects who have achieved MRD negative 
status on or after PD or switch to subsequent anti-myeloma therapy before PD, will not be 
considered MRD negative in the analysis.
Durable MRD negativity rate is defined as the proportion of subjects who have achieved 
MRD negative status at 10-5 at 2 bone marrow aspirate examinations that are a minimum of 
1 year apart, without any examination showing MRD positive status in between.
5.3.5.2.
Analysis Methods
For this study, threshold value of 10-5 will be used for the primary MRD negativity analysis.  
Other threshold values 10-4 and 10-6 may also be explored.
The overall MRD negativity rate will be calculated for each treatment group based on the 
ITT analysis set. The corresponding 90% exact CI will be provided. Reasons for missing or 
unevaluable MRD status will be tabulated by treatment group.
The stratified Cochran Mantel Haenszel (CMH) estimate of odds ratio and its 90% confidence 
interval and p-value from Fisher’s exact test will be used to test if the MRD negativity rate is the 
same between the two treatment groups. Stratification factors used in the analysis are prior 
PI exposure and daratumumab-free interval (3-6 months, >6 months).
Durable MRD-negative rate at 10-5 will be similarly. MRD rate at <10-6 and <10-4 will be 
summarized as well.


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5.3.6.
Time to Subsequent Antimyeloma Treatment
5.3.6.1.
Definition
Time to subsequent antimyeloma treatment is defined as the time from randomization to the start 
of subsequent antimyeloma treatment. Death due to PD without the start of any subsequent 
therapy will be considered as event. Subjects who withdrew consent to study or are lost to 
follow-up or die due to causes other than PD will be censored at the date of death or the last date 
known to be alive.
5.3.6.2.
Analysis Methods
Analysis of time to subsequent antimyeloma treatment will be based on the ITT population. The 
Kaplan-Meier method will be used to estimate the distribution of time to subsequent 
antimyeloma treatment for the ITT population. Median time to subsequent antimyeloma 
treatment with 90% CI will be tabulated for each treatment group. In addition, A Kaplan-Meier 
curve for time to subsequent antimyeloma treatment will be plotted. The hazards ratio and its 
90% CI will be obtained through a stratified Cox’s regression model with treatment as the sole 
explanatory variable. Treatment comparison will be made using log-rank test stratified by 
randomization factor.
5.4.
Other Endpoints 
5.4.1.
Clinical benefit rate
Clinical benefit rate is defined as the proportion of subjects with best response of MR or better 
(including sCR, CR, VGPR, PR, and MR) based on the computerized algorithm, in accordance 
with the IMWG criteria, during or after the study treatment but before the start of subsequent 
anti-myeloma therapy.
5.4.1.1.
Analysis Methods
The corresponding 90% exact CI for clinical benefit rate will be provided for the ITT population.   
For durable MRD negativity rate, the 90% exact CI will be provided by treatment group for 
subjects who have achieved MRD negative status.  
In addition, summaries for the following response categories based on the computerize algorithm 
will be presented by treatment group for the ITT population: stringent complete response (sCR), 
complete response (CR), very good partial response (VGPR), partial response (PR), minimal 
response (MR), stable disease (SD), progressive disease (PD), and not evaluable (NE). The 
corresponding 90% exact CI for each response category will be provided.
5.4.2.
M-Protein Response
Best M-protein response in serum and urine and best response in serum dFLC will be 
summarized for response-evaluable set. 


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6.
SAFETY
All safety analyses will be based on the safety analysis set based on actual treatment received, 
unless otherwise specified.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
Version (20.0). 
Any AE occurring at or after the initial administration of study treatment through the day of last 
dose plus 30 days or prior to the start of subsequent antimyeloma therapy, whichever is earlier, 
or the follow-up AE (linked to an existing TEAE) with onset date and time beyond 30 days after 
the last dose of study treatment but prior to the start of subsequent therapy is considered to be 
treatment emergent. If the event occurs on the day of the initial administration of study 
treatment, and either event time or time of administration are missing, then the event will be 
assumed to be treatment emergent. If the event date is recorded as partial or completely missing, 
then the event will be considered as treatment emergent unless it is known to be prior to the first 
administration of study treatment based on partial onset date or resolution date. If the event is
considered drug-related (very likely, probably, or possibly related) regardless of the start date
of the event; or the event that is present at baseline but worsens in toxicity grade or is 
subsequently considered drug-related by the investigator, then this event will be assumed to be 
treatment emergent.
All reported treatment-emergent adverse events will be included in the analysis.  For each 
adverse event, the number and percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by treatment group. In addition, comparisons between treatment 
groups will be provided if appropriate.
Summary tables will be provided for:

TEAEs by overall and subgroup (age, sex, race, renal abnormality, hepatic abnormality)

Toxicity Grade 3 or 4 TEAEs

Serious TEAEs (SAEs)

Study drug-related TEAEs and Serious TEAEs

TEAEs leading to discontinuation of study treatment

TEAEs by severity, toxicity grade

TEAEs by relationship to study drug


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
TEAEs leading to treatment interruption/treatment modification

TEAEs with outcome of death

Daratumumab infusion related reactions (DKd arm only)

Daratumumab injection site related reactions (DKd arm only)

Time to onset of infusion related reactions
In addition to the summary tables, listings will be provided for subjects who:

Had TEAEs

Had Serious TEAEs

Had TEAEs leading to discontinuation of study drug/termination of study participation

TEAE with outcome of death

Had infusion related reactions or injection site related reactions

Had TEAE grade 3 or higher
Deaths will be displayed by actual treatment received. Frequencies for the following parameters 
will be included in the summary table:

Number of subjects who died

Primary Cause of death

Relationship to study treatment (yes/no)
Summary table will also be presented for subjects who died within 30 days of last study
treatment dose and within 60 days of first study treatment dose, respectively.
A listing of subjects who died will be provided.
6.2.
Adverse Events of Special Interest
6.2.1.
Infections and infestations
Infections and infestations refer to adverse events with MedDRA SOC of infections and 
infestations. A summary of number of subjects with 1 or more toxicity Grade 3 or 4 
treatment-emergent infections and infestations by MedDRA preferred term and relationship to 
treatment will be provided. In addition, incidences of Grade 3 or 4 treatment-emergent infections 
and infestation will be summarized by MedDRA preferred term and treatment cycle. A summary 
of treatment-emergent opportunistic infections and a listing of treatment-emergent 
HBV reactivation will be provided as well.
6.2.2.
Second Primary Malignancies
A listing of subjects who reported second primary malignancies during the study will be 
provided. The listing will include subject ID, treatment group, diagnosis, stud day of diagnosis, 
recurrence of a prior existing malignancy (yes, no) and initial diagnosis date etc. collected in new 


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malignancies CRF page. In addition, prior exposure to multiple myeloma therapies, treatment 
related to second primary malignancy, cumulative study treatment exposure, and subject survival 
status information will also be presented in the listing.
6.2.3.
Cardiac Events 
Treatment-emergent cardiac events refer to events identified by cardiac arrhythmias (SMQ), 
cardiac failure (SMQ), and ischemic heart disease (SMQ). A summary of number of subjects 
with 1 or more toxicity Grade 3 or 4 treatment-emergent cardiac events by MedDRA SMQ, 
preferred term and relationship to treatment will be provided. In addition, incidences of Grade 3 
or 4 treatment-emergent cardiac events will be summarized by MedDRA SMQ, preferred term 
and treatment cycle.
6.3.
Clinical Laboratory Tests
All clinical laboratory tests will be displayed for the subjects included in the safety analysis set.
Descriptive statistics will be presented for all chemistry and hematology tests at scheduled time 
points.
Change/percent change from baseline will be summarized for chemistry and hematology tests 
and displayed by treatment group. 
Applicable laboratory results will be graded according to NCI-CTCAE version [5.0].
The worst toxicity grade in hematology and chemistry during the treatment will be summarized
by treatment group and toxicity grade.
Shift summaries from baseline laboratory value to the worst on-treatment grade in chemistry and 
hematology tests with NCI-CTCAE, version [5.0] will be presented.
6.4.
Vital Signs and Physical Examination Findings
Post baseline vital signs and physical examination findings were collected only as clinically 
indicated and therefore will not be summarized.
6.5.
Electrocardiogram
The interpretation of the ECGs (normal, abnormal, clinically significant abnormal) as determined 
by a qualified physician (investigator or qualified designee) will be displayed by the number and 
percentage of subjects in each of the categories. Summary of the findings and shift from baseline 
to end of the treatment will be provided.
6.6.
Cardiac Assessment/Echocardiogram or MUGA
The interpretation of the cardiac assessment (normal, abnormal, clinically significant abnormal) 
will be displayed by the number and percentage of subjects in each of the categories. Summary 
of the findings and shift from baseline to end of the treatment will be provided. Change from 
baseline in LVEF will be summarized over time.


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6.7.
Other Safety Parameters
6.8.
ECOG Performance Score
ECOG performance status evaluates the effect of the disease status on the activities of daily 
living will be assessed at screening visit and post-baseline time points. Descriptive statistics will 
be used to summarize ECOG performance status at baseline, scheduled post-baseline timepoints 
(including change from baseline), worst score during post injection period (including change 
from baseline) for each treatment group. Shift table from baseline to worst score during the post 
injection period may be provided.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Descriptive statistics (e.g., number of observations, mean, SD, median, and range) will be
used to summarize pharmacokinetics data. For in-text tables, mean (SD) and N will be provided.
In addition, coefficient variation (%CV) and geometric mean might be provided in the 
pharmacokinetic concentration summary.
7.1.
Pharmacokinetics
7.1.1.
Sampling Timepoints
For subjects assigned to the Kd group, blood samples to assess serum concentration of 
daratumumab will be obtained at Day 1 of Cycles 1 and 3.  For subjects assigned to DKd, samples 
to assess serum concentration of dara-SC will be obtained at Day 1 of Cycles 1, 3, and 7, and 
Post-Treatment Week 8. On a daratumumab dosing day, blood samples need to be collected 
before (up to 2 hours but not after) the start of drug administration. 
7.1.2.
Pharmacokinetic Parameters
Descriptive statistics will be used to summarize pharmacokinetic parameters. The
pharmacokinetic parameters that will be estimated include observed trough concentrations by 
visit and treatment.
7.1.3.
Analysis Methods
Pharmacokinetic data from subjects in the pharmacokinetic analysis set will be presented at each 
sampling timepoint. All serum concentrations below the lowest quantifiable concentration or 
missing data will be labeled as such in the concentration data presentation. Concentrations below 
the lowest quantifiable concentration will be treated as zero in the summary statistics. Data from 
subjects outside the prespecified visit window will be reported, but not included in the summary 
statistics. All subjects and samples excluded from the analysis will be clearly documented in 
the data presentation specification.
Descriptive statistics will be used to summarize dara-SC serum concentrations at
each
sampling time point. Line plot of mean (±SD) daratumumab serum trough concentrations over 
time will be provided.


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7.2.
Immune Response
7.2.1.
Sampling Timepoints
For subjects in the Kd group, samples to assess the generation of antibodies to daratumumab 
(immunogenicity) will be obtained from all subjects in the Kd group at Cycle 1 Day 1.  For 
subjects in the DKd group, samples for daratumumab immunogenicity assessments will be 
obtained at Day 1 of Cycles 1 and 7 predose and at Week 8 after the end of the study treatment.  
For the rHuPH20 immunogenicity assessments, plasma samples will be obtained at Day 1 of 
Cycles 1 and 7 predose and at Week 8 after the end of the study treatment for subjects in the DKd 
group.
In addition, when an IRR occurs associated with the second or later daratumumab administration, 
2 separate blood samples should be obtained, if possible, for determination of serum 
anti-daratumumab
antibodies (and associated serum daratumumab concentration) and 
anti-rHuPH20 antibodies
7.2.2.
Analysis Methods
The incidence of anti-daratumumab antibodies will be summarized by treatment group for all 
subjects who have appropriate samples for detection of the antibodies. The incidence of 
anti-rHuPH20 antibodies will be summarized for all subjects who receive at least one dose of 
Dara-SC and have appropriate plasma samples for detection of antibodies to rHuPH20 (at least 1 
sample after the start of the first dose of Dara-SC). In addition, subjects who are positive for 
anti-daratumumab antibodies or anti rHuPH20 antibodies will be listed. 
7.3.
Pharmacodynamics
If sufficient data are available, other pharmacokinetic/pharmacodynamic (PK/PD) modeling may 
be performed, including exploring the relationship between serum concentrations of dara-SC and 
clinical efficacy/safety endpoints. If PK/PD analysis is conducted, details and results of the 
analysis will be presented in a separate report.
8.
BIOMARKERS
Biomarker studies are designed to identify markers predictive of response (or resistance) to the 
study drug. 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.
Minimal residual disease (MRD) will be assessed for all subjects who achieve a CR/sCR. 
Molecular subtyping will be done through next generation sequencing (NGS) to evaluate
response rates in risk-stratified multiple myeloma subpopulations.


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8.1.
Minimal Residual Disease (MRD)
Bone marrow aspirates will be collected at baseline from all subjects, as well as on treatment in
those subjects who attain or suspect to have a CR/sCR to monitor MRD. MRD will be
monitored using ClonoSEQ Assay 2.0 on bone marrow aspirate.
8.1.1.
Sampling Timepoints
For all subjects, a fresh bone marrow aspirate will be obtained at baseline, as well as on 
treatment for subjects who were suspected to have a CR/sCR, at the time of the suspected 
CR/sCR, and 3 landmark time points: 12, 18, and 24 months (within the window of  +/- 1 month)
after first dose of study treatment.   
8.1.2.
Analysis Methods
Details on MRD negativity rate analyses are described in efficacy section. 
In addition, exploratory landmark analyses may be conducted to correlate MRD negativity 
results (as either binary or continuous values) with responses (CR or better rate) or long-term
clinical endpoints such as PFS. Subgroup analysis of PFS by MRD negativity status may also be 
performed. Similar analysis may be performed for subjects who achieved CR or better.
8.2.
Molecular Subtyping
8.2.1.
Cytogenetic Risk Groups 
A portion of the bone marrow aspirate samples collected will be utilized for 
translocation/mutation/genomic analysis to assess whether specific molecular subtypes having 
chromosomal aberrations del17p, t(4;14), t(14;16), and optionally Amplification 1q are 
responsive to dara-SC treatment.
8.2.2.
Molecular Risk Subgroup Analysis
To determine if the study drug will lead to improved clinical responses in standard as well as 
high-risk molecular subgroups, the following exploratory analysis may be conducted by using 
the similar analysis methods specified in efficacy section.

To evaluate VGPR or better, ORR, and PFS for subjects in high-risk molecular subgroup 
and subjects with the specific molecular subtypes.

To evaluate MRD negativity rate for subjects in standard-risk and high-risk molecular 
subgroups.

To evaluate PFS and OS for subjects in high-risk molecular subgroup and subjects with 
specific molecular subtyping.
Subgroup exploratory analysis of VGPR, ORR, and PFS by molecular risk within treatment 
group, as well as between molecular subgroups across treatment group may be conducted.


JNJ-54767414  (DARZALEX®)
Statistical Analysis Plan 54767414MMY2065
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Status: Pending approval, Date: September 26, 2019
9.
MEDICAL RESOURCE UTILIAZTION
Medical resource utilization will be descriptively summarized by treatment group. Frequencies 
of hospitalization, outpatient visits, type of hospitalization or outpatient visit, reasons for 
hospitalization or outpatient visit, durations of hospitalization or outpatient visit, types of adverse 
events if involved, blood product transfusions, antibiotic use, and other concomitant medication 
will be calculated and tabulated


JNJ-54767414  (DARZALEX®)
Statistical Analysis Plan 54767414MMY2065
36
Status: Pending approval, Date: September 26, 2019
REFERENCES
1.
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response 
and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346.
2.
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-4695.