Clinical trial NCT03412565
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC
Start date: 2018-04-26; Completion date: 2024-04-18
Enrollment: 265 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in participants with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.

Detailed description:
The hypothesis is that the addition of daratumumab administered SC to standard MM regimens will improve responses compared to response data observed in completed phase 3 studies without daratumumab. Disease evaluations will include measurements of myeloma proteins, bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin. Safety will be measured by adverse events, laboratory test results, electrocardiogram (ECGs), vital sign measurements, physical examination findings, SC injection-site assessments, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status score. Study will consist of 3 phases (screening, treatment and follow-up) and duration of study is approximately 3 years.

Arms: arm 1: Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. arm 2: Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. arm 3: Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study. arm 4: Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m\^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study.
Interventions: intervention 1: Daratumumab intervention 2: Bortezomib intervention 3: Lenalidomide intervention 4: Dexamethasone intervention 5: Melphalan intervention 6: Prednisone intervention 7: Carfilzomib
Intervention descriptions: intervention 1: Daratumumab will be administered at a dose of 1800 mg by SC injection in Cycles 1 to 4 in D-VRd cohort and until documented progression of disease, unacceptable toxicity, or end of study for D-VMP, D-Rd and D-Kd cohorts. intervention 2: Bortezomib will be administered as 1.3 mg/m\^2 SC injection in Cycles 1 to 4 in D-VRd cohort and in Cycles 1 to 9 in D-VMP cohort. intervention 3: Lenalidomide will be administered as 25 mg capsule orally in Cycles 1 to 4 in D-VRd cohort and in all Cycles until documented progression of disease, unacceptable toxicity, or end of study in D-Rd cohort. intervention 4: Dexamethasone will be administered as 20 mg orally or intravenously in Cycles 1 to 4 in D-VRd cohort; 40 mg orally or intravenously in all cycles and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Rd and D-Kd cohort. intervention 5: Melphalan will be administered as 9 mg/m\^2 orally in Cycles 1 to 9. intervention 6: Prednisone will be administered as 60 mg/m\^2 orally in cycles 1 to 9. intervention 7: Carfilzomib will be administered as 20 mg/m\^2 IV on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study in D-Kd cohort.

Protocol documents:
Prot_002.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 10 March 2022
Janssen Research & Development *
Clinical Protocol
A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination
with Standard Multiple Myeloma Treatment Regimens
Protocol 54767414MMY2040; Phase 2
AMENDMENT 6
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 Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; 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.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR
Part 312).
EudraCT NUMBER: 2017-004203-41
Status: 
Approved
Date: 
10 March 2022
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-ERI-147474836, 9.0
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.
NCT03412565


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Clinical Protocol 54767414MMY2040 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 10 March 2022
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 24
TIME AND EVENTS SCHEDULES............................................................................................................ 27
ABBREVIATIONS...................................................................................................................................... 51
1. 
INTRODUCTION................................................................................................................................ 54
1.1. 
Clinical Studies............................................................................................................................... 54
1.1.1. 
Combination Therapy Studies: Summary of the Results from Studies MMY3003,
MMY3004, MMY3007, and MMY1001 ....................................................................................... 55
1.1.2. 
Study 54767414MMY1004......................................................................................................... 56
1.1.2.1. 
Preliminary Data from Study MMY1004 Part 1 ....................................................................... 56
1.1.2.2. 
Preliminary Data from Study MMY1004 Part 2 ....................................................................... 57
1.2. 
Recombinant Human Hyaluronidase (rHuPH20)........................................................................... 59
1.2.1. 
Clinical Studies ........................................................................................................................... 59
1.3. 
Overall Rationale for the Study...................................................................................................... 60
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 60
2.1. 
Objectives and Endpoints .............................................................................................................. 60
2.1.1. 
Objectives................................................................................................................................... 60
2.1.2. 
Endpoints.................................................................................................................................... 61
2.2. 
Hypothesis ..................................................................................................................................... 61
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 62
3.1. 
Overview of Study Design.............................................................................................................. 62
3.2. 
Study Design Rationale.................................................................................................................. 64
4. 
SUBJECT POPULATION.................................................................................................................. 65
4.1. 
Inclusion Criteria ............................................................................................................................ 66
4.2. 
Exclusion Criteria ........................................................................................................................... 69
4.3. 
Prohibitions and Restrictions ......................................................................................................... 73
5. 
TREATMENT ALLOCATION AND BLINDING................................................................................. 74
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 74
6.1. 
Treatment Schedule and Administration for each Cohort.............................................................. 74
6.1.1. 
D-VRd Cohort ............................................................................................................................. 74
6.1.2. 
D-VMP Cohort ............................................................................................................................ 75
6.1.3. 
D-Rd Cohort................................................................................................................................ 76
6.1.4. 
D-Kd Cohort................................................................................................................................ 76
6.2. 
Study Drug Preparation.................................................................................................................. 78
6.2.1. 
Dara SC Preparation .................................................................................................................. 78
6.3. 
Study Drug Delivery....................................................................................................................... 78
6.3.1. 
Dara SC Delivery........................................................................................................................ 78
6.4. 
Guidelines for Prevention and Management of Infusion-related Reactions .................................. 78
6.4.1. 
Prevention of Infusion-related Reactions due to Daratumumab Injections ................................ 78
6.4.1.1. 
Pre-administration Medication................................................................................................. 78
6.4.1.2. 
Post-administration Medication ............................................................................................... 79
6.4.2. 
Management of Infusion-related Reactions................................................................................ 80
6.5. 
Dose Delays and Dose Modification of Daratumumab.................................................................. 81


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6.5.1. 
Daratumumab Toxicity Management.......................................................................................... 81
6.5.2. 
Daratumumab Interruption or Missed Doses.............................................................................. 83
6.6. 
Bortezomib, Melphalan, Lenalidomide, Carfilzomib, and Prednisone ........................................... 84
6.6.1. 
Dose Calculation of Bortezomib, Melphalan, Carfilzomib, and Prednisone............................... 84
6.7. 
Dose Reductions of Bortezomib, Lenalidomide, Melphalan, Carfilzomib, Dexamethasone,
and Prednisone.............................................................................................................................. 84
6.7.1. 
Dose Modification Guidelines for Bortezomib, Melphalan, and Prednisone-related
Toxicities (D-VMP cohort only)................................................................................................... 86
6.7.2. 
Dose Modification Guidelines for Dexamethasone .................................................................... 86
6.7.3. 
Bortezomib Toxicity .................................................................................................................... 87
6.7.3.1. 
Hematologic Toxicity of Bortezomib........................................................................................ 87
6.7.3.2. 
Neurologic Toxicity Bortezomib............................................................................................... 88
6.7.3.3. 
Other Grade 3 or 4 Non-Hematologic Toxicities Bortezomib.................................................. 88
6.7.4. 
Lenalidomide Toxicity................................................................................................................. 88
6.7.4.1. 
Deep Vein Thrombosis and Pulmonary Embolism.................................................................. 88
6.7.4.2. 
Thrombocytopenia................................................................................................................... 88
6.7.4.3. 
Neutropenia ............................................................................................................................. 89
6.7.4.4. 
Renal Impairment .................................................................................................................... 89
6.7.4.5. 
Other Grade 3 or 4 Non-Hematologic Adverse Events........................................................... 89
6.7.5. 
Carfilzomib Toxicity..................................................................................................................... 90
6.7.5.1. 
Hematologic Toxicity of Carfilzomib ........................................................................................ 90
6.7.5.2. 
Management of Peripheral Edema, Pulmonary Edema, Congestive Heart Failure................ 93
7. 
TREATMENT COMPLIANCE............................................................................................................ 93
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 93
8.1. 
Recommended Therapies.............................................................................................................. 93
8.1.1. 
Bisphosphonate Therapy............................................................................................................ 93
8.1.2. 
Therapy for Tumor Lysis Syndrome ........................................................................................... 94
8.1.3. 
Therapy for Pneumocystis carinii/jirovecii .................................................................................. 94
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 94
8.1.5. 
Prevention of Steroid Induced Gastritis...................................................................................... 94
8.1.6. 
Prevention of Deep Vein Thrombosis and Pulmonary Embolism............................................... 94
8.1.7. 
Management of Hepatitis B Virus Reactivation .......................................................................... 95
8.1.8. 
Infection Prophylaxis................................................................................................................... 95
8.2. 
Permitted Therapies....................................................................................................................... 95
8.3. 
Prohibited Therapies...................................................................................................................... 96
9. 
STUDY EVALUATIONS.................................................................................................................... 96
9.1. 
Study Procedures........................................................................................................................... 96
9.1.1. 
Overview..................................................................................................................................... 96
9.1.2. 
Screening Phase ........................................................................................................................ 97
9.1.3. 
Treatment Phase ........................................................................................................................ 98
9.1.4. 
Post-treatment Phase (Follow-Up)............................................................................................. 98
9.1.5. 
Final Analysis to End of Study.................................................................................................... 98
9.2. 
Efficacy Evaluations....................................................................................................................... 98
9.2.1. 
Evaluations ................................................................................................................................. 98
9.2.1.1. 
Response Categories.............................................................................................................. 98
9.2.1.2. 
Myeloma Protein Measurements in Serum and Urine .......................................................... 101
9.2.1.3. 
Serum Calcium Corrected for Albumin.................................................................................. 102
9.2.1.4. 
β2-microglobulin and Albumin............................................................................................... 102
9.2.1.5. 
Bone Marrow Examination .................................................................................................... 102
9.2.1.6. 
Minimal Residual Disease Assessment ................................................................................ 103
9.2.1.7. 
Assessment of Lytic Disease................................................................................................. 103
9.2.1.8. 
Documentation of Extramedullary Plasmacytomas............................................................... 103
9.3. 
Pharmacokinetics and Immunogenicity ....................................................................................... 104
9.3.1. 
Evaluations ............................................................................................................................... 104
9.3.2. 
Analytical Procedures............................................................................................................... 104


JNJ-54767414  (daratumumab)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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9.3.3. 
Pharmacokinetic Parameters ................................................................................................... 105
9.3.4. 
Immunogenicity Assessments.................................................................................................. 105
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 106
9.5. 
Biomarkers................................................................................................................................... 106
9.6. 
Safety Evaluations ....................................................................................................................... 107
9.7. 
Sample Collection and Handling.................................................................................................. 111
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL
FROM THE STUDY......................................................................................................................... 111
10.1. 
Completion ................................................................................................................................... 111
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study ................................................. 111
10.3. 
Withdrawal From the Use of Research Samples......................................................................... 114
11.
STATISTICAL METHODS............................................................................................................... 114
11.1. 
Subject Information ...................................................................................................................... 114
11.2. 
Sample Size Determination ......................................................................................................... 114
11.3. 
Efficacy Analyses......................................................................................................................... 115
11.4. 
Pharmacokinetic Analyses........................................................................................................... 116
11.5. 
Immunogenicity Analyses ............................................................................................................ 117
11.6. 
Pharmacodynamic Analyses, and Biomarker Analyses .............................................................. 117
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 117
11.8. 
Safety Analyses ........................................................................................................................... 117
11.9. 
Study Evaluation Team................................................................................................................ 118
12.
ADVERSE EVENT REPORTING .................................................................................................... 119
12.1. 
Definitions .................................................................................................................................... 119
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 119
12.1.2. 
Attribution Definitions................................................................................................................ 120
12.1.3. 
Severity Criteria ........................................................................................................................ 121
12.2. 
Special Reporting Situations........................................................................................................ 121
12.3. 
Procedures................................................................................................................................... 121
12.3.1. 
All Adverse Events.................................................................................................................... 121
12.3.2. 
Serious Adverse Events ........................................................................................................... 123
12.3.3. 
Pregnancy................................................................................................................................. 124
12.4. 
Contacting Sponsor Regarding Safety......................................................................................... 124
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 124
13.1. 
Procedures................................................................................................................................... 125
13.2. 
Contacting Sponsor Regarding Product Quality.......................................................................... 125
14.
STUDY DRUG INFORMATION....................................................................................................... 125
14.1. 
Physical Description of the Study Drug........................................................................................ 125
14.2. 
Packaging .................................................................................................................................... 125
14.3. 
Labeling........................................................................................................................................ 125
14.4. 
Preparation, Handling, and Storage............................................................................................. 125
14.4.1. 
Dara SC Formulation................................................................................................................ 125
14.5. 
Drug Accountability...................................................................................................................... 126
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 127
16.
ETHICAL ASPECTS....................................................................................................................... 127
16.1. 
Study-Specific Design Considerations......................................................................................... 127
16.2. 
Regulatory Ethics Compliance..................................................................................................... 128
16.2.1. 
Investigator Responsibilities..................................................................................................... 128
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 129
16.2.3. 
Informed Consent Form............................................................................................................ 130
16.2.4. 
Privacy of Personal Data .......................................................................................................... 131
16.2.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 132


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2040 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 10 March 2022
16.2.6. 
Country Selection ..................................................................................................................... 132
17. ADMINISTRATIVE REQUIREMENTS............................................................................................ 132
17.1. 
Protocol Amendments.................................................................................................................. 132
17.2. 
Regulatory Documentation .......................................................................................................... 133
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 133
17.2.2. 
Required Prestudy Documentation........................................................................................... 133
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 134
17.4. 
Source Documentation................................................................................................................. 134
17.5. 
Case Report Form Completion .................................................................................................... 135
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 135
17.7. 
Record Retention ......................................................................................................................... 136
17.8. 
Monitoring .................................................................................................................................... 136
17.9. 
Study Completion/Termination..................................................................................................... 137
17.9.1. 
End of Data Collection and End of Study................................................................................. 137
17.9.2. 
Study Termination..................................................................................................................... 138
17.10. On-Site Audits.............................................................................................................................. 138
17.11. Use of Information and Publication .............................................................................................. 138
REFERENCES.......................................................................................................................................... 140
ATTACHMENTS....................................................................................................................................... 142
Attachment 1: 
International Myeloma Working Group Diagnostic Criteria.......................................... 142
Attachment 2: 
Eastern Cooperative Oncology Group Performance Status Grade............................. 143
Attachment 3: 
Modified Diet in Renal Disease Formula ..................................................................... 144
Attachment 4: 
Serum Calcium Corrected for Albumin ........................................................................ 145
Attachment 5: 
Conversion Table for Glucocorticosteroid Dose .......................................................... 146
Attachment 6: 
Asthma Guidelines....................................................................................................... 147
Attachment 7: 
New York Heart Association (NYHA) Functional Classification................................... 149
Attachment 8: 
Antihistamines That May Be Used Pre-dose............................................................... 150
Attachment 9: 
Body Surface Area Nomogram.................................................................................... 151
Attachment 10: 
Interpretation of The SEBIA Hydrashift 2/4 Daratumumab IFE Interference Test....... 152
Attachment 11: 
Anticipated Events ....................................................................................................... 153
Attachment 12: 
Inhibitors and Inducers of CYP3A................................................................................ 154
Attachment 13: 
Contraceptive (and Barrier) Guidance and Collection of Pregnancy Information........ 156
Attachment 14: 
Lenalidomide Global Pregnancy Prevention Plan ....................................................... 159
Attachment 15: 
Continuation of Treatment After Clinical Cutoff for the Final Analysis (End of the
Data Collection)............................................................................................................................ 168
INVESTIGATOR AGREEMENT............................................................................................................... 170


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2040 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 10 March 2022
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Time and Events Schedule –Overview for the D-VRd Cohort................................................. 27
Table 2: 
Time and Events Schedule - Pharmacokinetic/Immunogenicity Sample Collection
Times (D-VRd Cohort).............................................................................................................. 32
Table 3: 
Time and Events Schedule –Overview for the D-VMP Cohort................................................ 33
Table 4: 
Time and Events Schedule for Study Treatment (D-VMP Treatment Phase, Cycles 1
to 9)........................................................................................................................................... 37
Table 5: 
Time and Events Schedule - Pharmacokinetic/Immunogenicity Sample Collection
Times (D-VMP Cohort)............................................................................................................. 38
Table 6: 
Time and Events Schedule –Overview for the D-Rd Cohort................................................... 39
Table 7: 
Time and Events Schedule - Pharmacokinetic/Immunogenicity Sample Collection
Times (D-Rd Cohort)................................................................................................................. 43
Table 8: 
Time and Events Schedule –Overview for the D-Kd Cohort ................................................... 44
Table 9: 
Time and Events Schedule - Pharmacokinetic/Immunogenicity Sample Collection
Times (D-Kd Cohort)................................................................................................................. 50
Table 10: Treatment Schedule and Dosing (D-VRd Cohort).................................................................... 74
Table 11: Treatment Schedule and Dosing (D-VMP Cohort)................................................................... 75
Table 12: Treatment Schedule and Dosing (D-Rd Cohort) ...................................................................... 76
Table 13: Treatment Schedule and Dosing (D-Kd Cohort)....................................................................... 77
Table 14: Daratumumab-Related Toxicity Management (D-VRd Cohort)................................................ 82
Table 15: Daratumumab-Related Toxicity Management (D-VMP Cohort)............................................... 82
Table 16: Daratumumab-Related Toxicity Management (D-Rd Cohort or D-Kd Cohort)......................... 82
Table 17: Dose Reduction for Bortezomib................................................................................................ 84
Table 18: Dose Reduction for Lenalidomide............................................................................................. 84
Table 19: Dose Reduction for Melphalan ................................................................................................. 85
Table 20: Dose Reduction for Carfilzomib................................................................................................ 85
Table 21: Dose Reduction for Prednisone................................................................................................ 85
Table 22: Dose Reduction for Dexamethasone........................................................................................ 86
Table 23: Dose Modification Guidelines for Bortezomib, Melphalan, and Prednisone............................. 86
Table 24: Dexamethasone Dose Modification.......................................................................................... 87
Table 25: Dose Modifications for Hematologic Toxicity............................................................................ 87
Table 26: Recommended Dose Modification for Bortezomib-related Neuropathic Pain or
Peripheral Sensory or Motor Neuropathy................................................................................. 88
Table 27: Lenalidomide Dose Adjustment for Thrombocytopenia............................................................ 88
Table 28: Lenalidomide Dose Adjustment for Neutropenia...................................................................... 89
Table 29: Lenalidomide Dose Adjustment for Renal Impairment............................................................. 89
Table 30: Carfilzomib Dose Modifications for Hematologic Toxicity......................................................... 90
Table 31: Carfilzomib Dose Modification Guidelines for Non-hematologic Toxicities .............................. 91
Table 32: International Uniform Response Criteria Consensus Recommendations .............................. 100
Table 33: Bone Marrow Testing.............................................................................................................. 102
Table 34: Hypothesis and Power Table.................................................................................................. 115
FIGURES
Figure 1: Schematic Overview of the Phase 2 Study Design .................................................................. 63


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2040 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 10 March 2022
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol 
20 December 2017
Amendment 1 
06 June 2018
Amendment 2 
12 October 2018
Amendment 3 
31 January 2019
Amendment 4 
28 January 2020
Amendment 5 
30 September 2020
Amendment 6 
10 March 2022
Amendments below are listed beginning with the most recent amendment.
Amendment 6 (10 March 2022)
The overall reason for the amendment: The overall reason for the amendment is to update the definition of the
end of study. This amendment also incorporated changes made in the country-specific amendment for France in
response to feedback received from the French Regulatory Agency (Agence nationale de sécurité du medicament et
des produits de santé [ANSM]), who requested to add further guidance on testing for hepatitis B in subjects with
unknown serology status.
Applicable Section(s) 
Description of Change(s)
Rationale: To update the definition of the end of study so that the study may continue beyond June 2022.
Synopsis: Dosage and 
Administration; 3.1:
Overview of Study
Design; 9.1.5: Final
Analysis to End of
Study; 17.9.1: End of
Data Collection and
End of Study
End of study definition was updated so that the study may continue beyond June 2022.
Rationale: To add the text for hepatitis B serology testing of any subject with unknown hepatitis B serology and
monitoring and managing of hepatitis B virus (HBV) reactivation in response to a request from ANSM.
9.6: Safety 
Evaluations; 
Attachment 15:
Continuation of
Treatment After
Clinical Cutoff for the
Final Analysis (End
of the Data
Collection)
Information detailing the conduct of HBV serology testing was added for subjects with
unknown status of hepatitis B serologic status.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2040 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 10 March 2022
Amendment 5 (30 September 2020)
The overall reason for the amendment: The overall reason for the amendment is to define when the clinical
cutoff for the final analysis will occur which marks the end of data collection, to define the end of study, and to
clarify access to study drugs for subjects who continue to receive study treatment after data collection has ended.
Applicable Sections 
Description of Changes
Rationale: To clarify when the clinical cutoff for the final analysis will occur at which time the data collection
will end.
Synopsis: Dosage and 
Administration; 3.1 
Overview of Study 
Design; 9.1.5 Final
Analysis to End of
Study; 17.9.1 End of
Data Collection and
End of Study
The data cutoff for the final analysis and the end of data collection will occur
approximately 10 months after the last subject is enrolled in the D-Kd cohort.
Subsequently, the clinical database will be locked for the final analysis.
3.1 Overview of Study 
Design  
Text was updated to clarify that the data from the end of the data collection through the
end of study will be reported in a Clinical Study Report (CSR) addendum.
9.1.4 Post-treatment 
Phase (Follow-Up) 
Information regarding end of study was moved to Section 9.1.5 (a new section as of
this amendment).
17.5 Case Report Form 
Completion; 17.9.1 
End of Data Collection
and End of Study
Text updated to clarify that data collection in the electronic case report form (eCRF)
will not be performed after the database is closed for the final analysis.
Rationale: To define the end of study.
9.1.5 Final Analysis to 
End of Study (new
section)
End of study was defined.
9.6 Safety Evaluations 
Text was added to indicate that after the data collection has ended, only serious adverse
events will be collected.
12.3.3 Pregnancy  
It was clarified that pregnancy reporting will continue until the end of study.
17.9.1 End of Data 
Collection and End of
Study 
Section heading was updated to “End of Data Collection and End of Study”.
End of study was defined.
Rationale: To clarify the access to study drugs and to describe the study procedures for subjects who continue to
receive study drugs after the data collection has ended.
Synopsis: Dosage and 
Administration; 3.1 
Overview of Study 
Design; 9.1.1
Overview; 17.9.1 End
of Data Collection and
End of Study
Text added to indicate that subjects who are benefiting from study treatment can continue
receiving the study drugs after the end of the data collection until the study drugs are
commercially available, available from another source, or until study completion.


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Time and Events 
Schedules Table 1, 
Table 3, Table 4, Table 
5, Table 6, Table 7,
Table 8, and Table 9;
3.1 Overview of Study
Design; 9.1.1
Overview; 9.1.5 Final
Analysis to End of
Study; 9.6 Safety
Evaluations; 10.2
Discontinuation of
Study
Treatment/Withdrawal
from the Study; 12.3.2
Serious Adverse
Events; 12.3.3
Pregnancy; 17.5 Case
Report Form
Completion; 17.9.1
End of Data Collection
and End of Study
Reference to Attachment 15 was added to provide a description of respective study
procedures for subjects who continue to receive study drugs after the data collection has
ended.
9.1.4 Post-treatment 
Phase (Follow-Up) 
Information regarding access to study drugs for subjects who continue to receive study
treatment was moved to Section 9.1.5 (a new section as of this amendment).
9.1.5 Final Analysis to 
End of Study (new 
section) 
New section was added to include information that subjects benefiting from study
treatment can continue receiving the study drugs after the end of data collection until the
study drugs are commercially available, available from another source (eg, via a dedicated
long-term extension study), or until study completion.
10.1 Completion  
Text was updated to indicate that subjects can transition into receiving study drugs
(including, but not limited to, daratumumab SC) which are commercially available or
available from another source.
Attachment 15: 
Continuation of 
Treatment After
Clinical Cutoff for the
Final Analysis (End of
the Data Collection)
Attachment 15 (new):  provides the study procedures for the subjects who will continue
receiving study drugs after the data collection ends.
Rationale: Data for the experience survey will no longer be collected.
3.1 Overview of Study 
Design  
The text regarding experience survey was deleted because data collection will not be
occurring.
Rationale: Text in the protocol was clarified.
10.2 Discontinuation of 
Study 
Treatment/Withdrawal
from the Study
Clarified that documentation of progressive disease (PD) status in interactive web
response system (IWRS) is not required after end of data collection.
12.1.1 Adverse Event 
Definitions and 
Classifications
Text was added to clarify the definition of medically important events. The following text
was added: Examples of such medical events include second primary malignancy.
Rationale: Text was added to describe daratumumab approvals in the United States (US) and European Union (EU).


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1. Introduction  
Text was added to clarify the most updated approval status of daratumumab IV and SC
for all indications. Text reflecting the old approval status was deleted.
References 
References for recent Summary of Product Characteristics (SmPC) and United States
Package Insert (USPI) were added.
Rationale: Template-related changes were made.
Confidentiality 
Statement;
Running Footer
Updated the confidentiality statement and running footer based on the current template.
Rationale: Minor errors were noted.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes were made. List of abbreviations was
updated.
Amendment 4 (28 January 2020)
The overall reason for the amendment: The overall reason for the amendment is to clarify the timing of the
primary analysis for the daratumumab subcutaneous (SC), carfilzomib and dexamethasone (D-Kd) cohort and the
end of study. In addition, this amendment includes updated text to align with the daratumumab program standard
language for anticipated events and pregnancy/contraception.
Applicable Section(s) 
Description of Change(s)
Rationale: To clarify the timing of the primary analysis for the D-Kd cohort and the end of study.
3.1. Overview of 
Study Design; 11.3. 
Efficacy Analyses 
The following text was added: ‘The cutoff for the primary analysis for the D-Kd cohort
will occur at least 6 months after approximately the 60th  subject is enrolled in the D-Kd
cohort.’
3.1. Overview of 
Study Design; 9.1.4. 
Post-treatment Phase
(Follow-Up)
Clarification was added that the study will end approximately 18 months after the last
subject is enrolled in the D-Kd cohort.
Rationale: To clarify contraception requirements and pregnancies in partners of male subjects, which align with
daratumumab program standard language, and to include lenalidomide- and carfilzomib-specific contraception
guidance.
4.1. Inclusion Criteria 
Criterion #8: Modified to describe the timeline for use of contraception for women and
insist on use of one highly effective form of contraception along with one additional
effective contraceptive method. Also edited text regarding male contraception
requirement.
Criterion #8: Added cross-reference to Attachment 13.
Criterion #9: Deleted text ‘men must agree not to donate sperm for the purposes of
assisted reproduction’ and added text ‘male subjects of reproductive potential must not
donate semen or sperm during the study, during dose interruptions, or for 3 months after
the last dose of any study drug.
4.3. Prohibitions and 
Restrictions; 9.6.
Safety Evaluations;
12.3.3. Pregnancy;
Attachment 13:
Contraceptive (and
Barrier) Guidance and
Added cross-reference to Attachment 14.


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Applicable Section(s) 
Description of Change(s)
Collection of
Pregnancy
Information
Attachment 13: 
Contraceptive (and 
Barrier) Guidance and 
Collection of
Pregnancy
Information
Attachment 13 (new): added to provide clarification of definitions and contraceptive
guidance and collection of pregnancy information in studies which use daratumumab
and are specific for lenalidomide and carfilzomib.
Attachment 14: 
Lenalidomide Global 
Pregnancy Prevention
Plan
Attachment 14 (new): added to include the lenalidomide global pregnancy prevention
plan.
9.6. Safety 
Evaluations; 12.3.3. 
Pregnancy  
Additional text regarding the pregnancy reporting requirements and pregnancy
prevention plan for lenalidomide, and pregnancies in partners of male subjects was
added.
10.2. Discontinuation 
of Study 
Treatment/Withdrawal 
from the Study  
Text was added to specify that if a positive pregnancy test occurred in a subject enrolled
in lenalidomide containing cohort, lenalidomide was to be discontinued immediately or
if it occurred in the partner of a male subject enrolled in lenalidomide containing cohort
investigator was to be informed immediately.
Rationale: To clarify the timing of dexamethasone administration in relation to carfilzomib administration.
6.1.4. D-Kd Cohort; 
6.4.1.1
Pre-administration
Medication
Added text ‘When carfilzomib is given first’.
6.1.4. D-Kd Cohort 
Deleted ‘will’ and added ‘should’ for administration of carfilzomib followed by
daratumumab SC when both are given on the same day.
Table 13 Treatment 
Schedule and Dosing 
(D-Kd Cohort); 6.1.4.
D-Kd Cohort
Deleted ‘will’ and added ‘should’ for administration of half dose of dexamethasone
before and after administration of daratumumab.
Rationale: Modified the list of anticipated events to remove any events that are known adverse drug reactions of
daratumumab. Clarification that after unblinding of aggregate safety data by the sponsor’s study team, there is no
need for independent Safety Assessment Committee (SAC) review of anticipated events. Additional clarification
of the reporting responsibilities for anticipated events to Health Authorities and Institutional Review Boards
(IRB)/Independent Ethics Committees (IEC). Changed name of committee to be in alignment with company
procedures.
Attachment 11: 
Anticipated Events 
Anemia, neutropenia, and thrombocytopenia were deleted from the anticipated events
list.
The review and reporting requirements for anticipated events were clarified.
Revised “Anticipated Event Review Committee” to “Safety Assessment Committee”.
Rationale: To eliminate the possibility of inconsistency between the National Cancer Institute-Common
Terminology Criteria for Adverse Events (NCI-CTCAE) version number referenced in the protocol and the
standard AE grade descriptions outlined in the protocol.


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Applicable Section(s) 
Description of Change(s)
12.1.3. Severity 
Criteria 
Removed definitions of severity criteria as they are specified in NCI-CTCAE
Version 4.03.
Rationale: The definition of duration of response (DOR) was revised as subjects in the daratumumab SC in
combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) cohort received only 4 cycles of study
treatment and DOR was not calculated for this cohort.
2.1.2. Endpoints; 11.3. 
Efficacy Analyses 
The following text was removed ‘or very good partial response (VGPR) or better for D
VRd cohort’.
Deleted ‘D-VRd’.
Rationale: To maintain consistency in presentation of order of cohorts throughout the protocol.
Synopsis: Endpoints, 
Overview of Study 
Design, Statistical
Methods; 2.1.2.
Endpoints; 11.3.
Efficacy Analyses
Changed the order of ‘daratumumab SC in combination with bortezomib, melphalan,
and prednisone (D-VMP), D-Kd’ to ‘D-Kd, D-VMP’.
Rationale: To align the synopsis and body of the protocol with the Time and Event table.
Synopsis: 
Evaluations; 9.6. 
Safety Evaluations
Transthoracic echocardiogram (TTE) monitoring was added as a safety evaluation for
subjects in the D-Kd cohort.
Rationale: Comparisons for primary endpoints will not be performed, p-values are not applicable.
Synopsis: Statistical 
Methods; 11.3. 
Efficacy Analyses
Text regarding p-values for the hypothesis testing of primary endpoint for each cohort
was deleted.
Rationale: To maintain consistent text throughout the protocol.
3.2. Study Design 
Rationale 
Added text ‘>90% power for D-VRd, D-VMP, and daratumumab SC in combination
with lenalidomide and dexamethasone (D-Rd) cohorts and >80% power for the D-Kd
cohort’.
Rationale: To align with the Centers for Disease Control (CDC) definition of hepatitis B.
4.2. Exclusion Criteria Criterion #5: Modified the definition of subjects seropositive for hepatitis B.
Rationale: To align with daratumumab program standard language by clarifying the reasons for continued
observation on subsequent daratumumab injections and to clarify guidance regarding SC daratumumab injection.
6.3.1. Dara SC 
Delivery  
Deleted ‘will’ and added ‘should’ for administration of each dose of daratumumab SC
injection at alternating locations on the abdomen.
Additional text was added to keep the subjects with a higher risk of respiratory
complications, subject with infusion-related reaction (IRR) with first injection of study
drug, and subject with a decreased condition on day of dosing compared to prior dosing
day under observation and keep the dose of daratumumab constant throughout the
study.
6.4.1.1. 
Pre-administration 
Medication
The word ‘within’ was added to limit the duration of pre-administration medications
between 1 to 3 hours.
Additional clarification was added regarding pre-administration of antihistamine and
dexamethasone.


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Applicable Section(s) 
Description of Change(s)
Deleted words ‘mandatory and 1 to 3 hours ‘and maintained ‘3 hours’.
Rationale: To align with daratumumab program standard language.
4.3. Prohibitions and 
Restrictions 
Added text ‘during dose interruption’ to specify that subjects must not donate blood
during dose interruption.
6.4.2. Management of 
Infusion-related 
Reactions
Text was added requiring extra attention to be given to recruit staff trained in
daratumumab administration.
6.5. Dose Delays and 
Dose Modification of 
Daratumumab
Text was added to further clarify that it was mandatory to complete Day 1 of any cycle
and if it was missed it was to be considered a cycle delay.
6.5.2. Daratumumab 
Interruption or Missed 
Doses 
The following text was added: ‘Infusion-related reactions may occur upon re-initiation
of daratumumab after a prolonged delay in treatment. Investigators should consider the
applicable infusion reaction guidance provided in Section 6.4.2.’
8.1.4. Prophylaxis for 
Herpes Zoster 
Reactivation
Additional text was added regarding initiation of antiviral prophylaxis to prevent herpes
zoster reactivation.
8.1.8. Infection 
Prophylaxis (new 
section)
Text was added regarding prophylactic use of antibiotics for infection in subjects with
multiple myeloma.
8.3. Prohibited 
Therapies
Text was added clarifying the prohibited use of live attenuated vaccines.
10.2. Discontinuation 
of Study 
Treatment/Withdrawal 
from the Study
Text was added to clarify that subjects who discontinue treatment with any one
component of study treatment may continue to receive treatment with the other
components of study treatment.
Rationale: “Carfilzomib” was omitted in error.
6.5.1. Daratumumab 
Toxicity Management 
“Carfilzomib” was added to the list of background treatment where text describes
daratumumab toxicity management.
Rationale: Minor errors, editorial issues, or changes for clarity/consistency noted in the protocol were corrected.
1.2.1. Clinical 
Studies; 3.2. Study
Design Rationale; 8.3.
Prohibited Therapies;
9.6. Safety
Evaluations; 10.2.
Discontinuation of
Study
Treatment/Withdrawal
from the Study; 16.1.
Study-Specific Design
Considerations;
Attachment 6: Asthma
Guidelines;
Attachment 10:
Interpretation of The
Study-related use of the word ‘patient’ was changed to ‘subject’.


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Applicable Section(s) 
Description of Change(s)
SEBIA Hydrashift 2/4
Daratumumab IFE
Interference Test
1.2.1. Clinical Studies 
Changed word ‘infusion’ to ‘injection’.
6.1.1. D-VRd Cohort; 
6.4.1.1.
Pre-administration
Medication
Changed word ‘infusion’ to ‘administration’.
Table 8 Time and 
Events
Schedule - Overview
for the D-Kd Cohort
The use of the abbreviation ‘TTE’ (transthoracic echocardiogram) was added.
Abbreviations 
Removed ‘ARC’ (anticipated event review committee) and ‘IDMC’ (Independent Data
Monitoring Committee) and added ‘CD38’ (cluster of differentiation 38), ‘EOT’ (end of
treatment), ‘HRT’ (hormonal replacement therapy), ‘IMP’ (investigational medicinal
product), ‘NYHA’ (New York Heart Association), ‘SAC’ (Safety Assessment
Committee), and ‘TTE’ (transthoracic echocardiogram).
Table 23 Dose 
Modification 
Guidelines for 
Bortezomib,
Melphalan, and
Prednisone
The following abbreviation key was added for clarity: ‘VMP= bortezomib, melphalan,
and prednisone’ and ‘NCI-CTC= National Cancer Institute-Common Terminology
Criteria for Adverse Events’.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Status: Approved,  Date: 10 March 2022
Amendment 3(31 January 2019)
The overall reason for the amendment: The overall reason for the amendment is in response to identification of
a new important risk (hepatitis B virus [HBV] reactivation).
Applicable Section(s) 
Description of Change(s)
Rationale: The text for identification of HBV reactivation, testing, and management of subjects with the
potential for HBV reactivation was added in response to identification of a new important risk (HBV
reactivation).
Table 1: Time and Events 
Schedule - Overview for the D- 
VRd Cohort; Table 3: Time and 
Events Schedule - Overview for 
the D-VMP Cohort; Table 6: 
Time and Events Schedule - 
Overview for the D-Rd Cohort; 
Table 8: Time and Events 
Schedule - Overview for the 
D-Kd Cohort.
For HBV serology added a row and identified the timepoint at which HBV
serology would be conducted.
For HBV DNA test, changed the note from ‘Only for subjects with a known
history of positivity for antibodies to hepatitis B core antigen (Anti-HBc) or
antibodies to hepatitis B surface antigen (Anti-HBs)’ to ‘For subjects with
serologic evidence of resolved HBV infection (ie, positive Anti-HBs or
positive Anti-HBc) at Screening, HBV DNA testing by PCR must be
performed locally’ and identified when the HBV DNA test would be
conducted.
Section 4.2 Exclusion Criteria 
(Criterion # 5.1)
Clarified language to exclude subjects who are seropositive for hepatitis B.
Modified the following sentence: Subjects with resolved infection (ie,
subjects who are HBsAg negative but positive for Anti-HBc and/or Anti-
HBs) must be screened using real-time polymerase chain reaction (PCR)
measurement of HBV DNA levels.
Section 8.1.7 Management of 
Hepatitis B Virus Reactivation  
Added a new section for information for the management of HBV
reactivation.
Section 9.6 Safety Evaluations 
Added information detailing the conduct of HBV serology and updated
DNA tests.
References 
Deleted reference # 9 and renumbered other references.
Rationale: To correct the frequency of end of treatment (EOT) post-treatment visit in Time and Event Schedule
Tables 1 and 2 from 30 days to 4 weeks after the last dose of study drug.
Table 1: Time and Events 
Schedule –Overview for the D- 
VRd Cohort; Table 2: Time and
Events Schedule -
Pharmacokinetic/Immunogenicity
Sample Collection Times (D-
VRd Cohort)
Corrected the frequency of EOT post-treatment visit in the EOT column
heading from 30 days to 4 weeks after the last dose of study drug.
Rationale: To correct the days when pre-medications are administered and to coincide them with the days when
daratumumab is administered in Time and Event Schedule Table 8.
Table 8: Time and Events 
Schedule –Overview for the D- 
Kd Cohort
Removed the reference to the administration of pre-medications on Day 8 of
Cycles 3 to 6 and on Day 8 and Day 15 of Cycles 7+.
Rationale: To add the provision of conducting a study participant experience survey at the last study visit.


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Status: Approved,  Date: 10 March 2022
Applicable Section(s) 
Description of Change(s)
Section 3.1 Overview of Study 
Design  
Added a statement mentioning that at their last study visit, each study
participant will be invited to complete an independent ethics committee
(IEC)/institutional review board (IRB) approved experience survey, to share
his/her experiences as a volunteer in this study.
Rationale: To simplify the language for conducting the SEBIA Hydrashift 2/4 Daratumumab IFE Interference
test.
Attachment 10 Interpretation of 
The SEBIA Hydrashift 2/4
Daratumumab IFE Interference
test
The language for conducting the test was simplified.
Rationale: Minor errors were noted
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (12 October 2018)
The overall reason for the amendment: The overall reasons for the amendment is to add a cohort to explore the
efficacy and safety of daratumumab SC in combination with carfilzomib and dexamethasone.
Applicable Section(s) 
Description of Change(s)
Rationale: Information about the safety and efficacy of daratumumab for intravenous infusion (Dara IV) in
combination with carfilzomib and dexamethasone (D-Kd) was added.
1.1.1. Combination 
Therapy Studies
Information from Study 54767414MMY1001 was added.
Rationale: Study descriptions, design elements, treatment administration information and Time and Events
Schedules were updated to include information about the D-Kd cohort.
Time and Events 
Schedule, Table 8,
Table 9
Time and Events Schedules were added for the D-Kd cohort.
Synopsis, Secondary 
Objectives; 2.1.1.
Objectives
Added text to include evaluation of the D-Kd cohort for MRD negativity rate.
Synopsis, Primary 
Endpoints, Key 
Secondary Endpoints;
2.1.2. Endpoints
Added text to include evaluation ofthe D-Kd cohort for ORR, VGPR or better rate as
defined by the IMWG response criteria, DOR, and MRD negativity rate.
Synopsis, Overview of 
Study Design; 3.1. 
Overview of Study
Design
Added text for the inclusion of the D-Kd cohort in subjects in first relapse or refractory
MM after initial treatment with a lenalidomide-containing regimen.
Figure 1 
The schematic overview of the Phase 2 study design was updated to include the D-Kd
cohort.


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Applicable Section(s) 
Description of Change(s)
3.2. Study Design 
Rationale 
Included rationale for the inclusion ofthe D-Kd cohort; rationale for the inclusion of
D-Rd was updated to include the patient population for which D-Rd was approved,
namely patients with relapsed MM; rationale for the inclusion of D-VMP was updated to
denote the approval of daratumumab in combination with VMP for newly diagnosed
MM.
4.1. Inclusion Criteria 
Criterion #4.1.d. was added to provide criteria for inclusion in the D-Kd cohort for
relapsed or refractory disease; the requirements for inclusion of subjects in the D-Kd
cohort were added and included hemoglobin count (Criterion #6.1.a), platelet count
(Criterion #6.1.c), bilirubin values (Criterion #6.1.f), and estimated creatinine clearance
values (Criterion #6.1.g); included instruction for women of childbearing potential
(Criterion #7.1).
4.2. Exclusion Criteria 
Criterion #1.1: Denoted prior or concurrent exposure to lenalidomide instructions for the
D-Rd cohort only; added the following criterion for the D-Kd cohort: Subject has
previously received carfilzomib; included the D-Kd cohort to the exclusion criterion
regarding ASCT or allogeneic stem cell transplant.
Criterion #4.1: Added the following exclusion criterion for subjects in the D-Kd cohort:
Known infiltrative pulmonary disease or known pulmonary hypertension.
Criterion #8.1: Added clinically significant cardiac disease exclusion criteria for the
D-Kd cohort:  transthoracic echocardiogram showing left ventricular ejection fraction
(LVEF) <40% and uncontrolled hypertension, defined as an average systolic blood
pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment.
Criterion #9.1: Added: For D-Kd cohort only: allergy, hypersensitivity, or intolerance to
Captisol.
Criterion #17 was added.
4.3. Prohibitions and 
Restrictions
Denoted that the D-Kd cohort will be administered pregnancy test as clinically indicated.
Synopsis, Dosage and 
Administration  
The following text was added: Subjects in the D-Kd cohort will receive treatment in
28-day cycles. Treatment will consist of daratumumab SC 1800 mg weekly for Cycles 1
and 2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter for Cycles 7+.
Subjects will receive carfilzomib IV 20 mg/m2 on Cycle 1 Day 1. If tolerated, beginning
with the second dose of carfilzomib, the dose will be escalated to 70 mg/m2 on Cycle 1
Days 8 and 15. For Cycles 2+, carfilzomib IV 70mg/m2 will be given weekly on Days 1,
8, and 15 of each cycle.
6.1.4 D-Kd Cohort 
This section was added to include the treatment schedule and administration for the
D-Kd cohort


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Status: Approved,  Date: 10 March 2022
Applicable Section(s) 
Description of Change(s)
Synopsis, Overview of 
Study Design; 6.5.1.
Daratumumab Toxicity
Management; 6.5.2.
Daratumumab
Interruption or Missed
Doses; 8. Prestudy and
Concomitant Therapy;
9.1.3. Treatment Phase;
9.2.1.5. Bone Marrow
Examination, Table 33;
9.5. Biomarkers; 10.2.
Discontinuation of
Study
Treatment/Withdrawal
from the Study; 11.3
Efficacy Analysis; 16.1.
Study-Specific Design
Considerations
Instruction was added for the D-Kd cohort.
6.4.1.1. Pre- 
administration
Medication
Information about pre-administration of medications in the D-Kd cohort was added.
6.6. Bortezomib, 
Melphalan,
Lenalidomide,
Carfilzomib, and
Prednisone
Denoted that the sponsor may provide carfilzomib.
6.6.1. Dose Calculation 
of Bortezomib,
Melphalan,
Carfilzomib, and
Prednisone; 6.7. Dose
Reductions of
Bortezomib,
Lenalidomide,
Melphalan,
Carfilzomib,
Dexamethasone, and
Prednisone
Information on the dose calculation and dose reduction of carfilzomib was added.
6.7.5. Carfilzomib 
Toxicity; 6.7.5.1.
Hematologic Toxicity
of Carfilzomib; 6.7.5.2.
Hydration and Fluid
Monitoring; 6.7.5.3.
Management of
Peripheral Edema,
Pulmonary Edema,
Congestive Heart
Failure
These sections were added to inform on dose modifications for carfilzomib.
9.1.1. Overview  
Text was added to inform on the total blood volume for the D-Kd treatment group.


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Status: Approved,  Date: 10 March 2022
Applicable Section(s) 
Description of Change(s)
9.6 Safety Evaluations 
The following evaluation was added: Participants in the D-Kd cohort must have a
transthoracic echocardiogram according to the Time and Events Schedule (Table 8).
Two-dimensional transthoracic echocardiogram to assess left ventricular ejection
fraction for eligibility purposes will be assessed during screening and will serve as the
baseline echocardiogram.
11.2. Sample Size 
Determination 
The following text was added: … for the D-Kd cohort, the corresponding power is >80%
to test the null hypothesis that the ORR is at most 65%, against the alternative hypothesis
that the ORR is at least 80%.
11.2. Sample Size 
Determination, Table 34  
The Hypothesis and Power Table was updated to include information for the D-Kd
cohort.
3.1. Overview of Study 
Design; 11.3. Efficacy 
Analyses
Text was updated to denote that the timing of the analysis would be associated with
enrollment of the 60th  subject, not after the last subject was enrolled.
Following text was added: at the time of the primary analysis, the D-Kd cohort will not
be included in the analysis and will be analyzed in subsequent analyses after
approximately the 60th  subject is enrolled in the D Kd cohort.
Rationale: The windows were broadened for End of Treatment (EOT) visit and Follow Up (FUP) Post-Treatment
Visit at 8 weeks in the daratumumab SC, bortezomib, lenalidomide, and dexamethasone (D-VRd) arm to enable
flexibility for stem cell collection and autologous stem cell transplant (ASCT).
Time and Events 
Schedules Table 1, 
Table 2 
The EOT visit was changed from 30 days to 4 weeks; the EOT visit window was
changed from ±1wk to ±2wk and the FUP Post-Treatment visit at 8 weeks was changed
from ±1wk to -2wk/+4wk.
Rationale: Changes were made to provide consistency in visit windows between cycles.
Time and Events 
Schedules Table 3 
The visit window for Cycles 1 to 9 was changed to ±3d for consistency with the visit
window in Cycles 10+.
Time and Events 
Schedules Table 6 
The visit windows for Cycles 1 & 2 Day 1 and for Cycles 3 to 6 Day 1 were changed to
±3d for consistency with the visit window in Cycles 7+ Day 1.
Rationale: The assay to be used for the analysis of daratumumab interference on serum M-protein quantitation was
changed.
Attachment 10 
Information about the Daratumumab Interference Reflex Assay (DIRA) was replaced
with information about the SEBIA Hydrashift 2/4 Daratumumab IFE Interference test.
Rationale: Text was updated to include instruction on disease evaluations that should be collected for subjects who
discontinue treatment prior to PD.
10.2. Discontinuation of 
Study 
Treatment/Withdrawal 
from the Study  
The following text was added: For subjects who discontinue treatment prior to PD,
disease evaluations should continue every 28 days until the Follow-up Visit is
completed. For subjects in the D-VRd cohort, subsequent therapy will be collected
potentially after the End-of-Treatment Visits and best response after transplant will be
collected in the eCRF.
Rationale: To clarify that hepatitis serology testing will occur during screening.
9.6. Safety Evaluations, 
HBV-DNA Tests 
Text was added to clarify that subjects who have a history of hepatitis will undergo
hepatitis serology testing during screening.
Rationale: To clarify age of subjects who will receive a specified dexamethasone dose.
Section 6.1.3. D-Rd 
Cohort 
Clarified that dexamethasone will be administered at a dose of 20mg/week PO for
subjects ≥75 years or BMI <18.5, rather than >75 years.


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Applicable Section(s) 
Description of Change(s)
Rationale: To clarify the immunogenicity-evaluable analysis set.
11.1. Subject 
Information
Text was updated to clarify the immunogenicity-evaluable analysis set.
Rationale: Minor errors were noted.
Throughout the protocol Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (06 Jun 2018)
The overall reason for the amendment: To address Health Authority (HA) requests and to correct
administrative errors and inconsistencies in the original protocol.
Applicable Sections 
Description of Changes
Rationale: Provided rationale for why the sponsor considers that the combination therapy should not be
considered investigational medicinal products (IMPs).
3.2 Study Design Rationale 
Added text describing why the use of VMP, VRd, and Rd is
considered standard of care in the proposed study and why they
should not be considered IMPs.
Added clarification text for VRd bullet.
Rationale: Update the study’s inclusion criteria to: align with the lenalidomide and bortezomib Summary of
Product Characteristics (SmPCs); clarify and align with the text in the body of the protocol; and align with the
Clinical Trial Facilitation Group (CTFG) guidance to clarify the duration of contraceptive method use.
4.1 Inclusion Criteria 
Minor revisions to Criterion #4.1 for clarification purposes and
changed “investigator’s determination” to “investigator’s
evaluation”.
Revised Criterion #6.1 for platelet count (6c), total bilirubin (6f),
and corrected serum calcium (6h) for safety purposes.
Deletion in Criterion #7.1 to align with body text.
For Criterion #8.1, added that contraception must continue during
the study and for 3 months after receiving the last dose of
daratumumab.
Rationale: To update the study exclusion criteria to: remove erroneous, duplicative text; align with instructions
provided to the PI; and to align with the current protocol template and standard text across daratumumab protocols.
4.2 Exclusion Criteria 
Criterion #1.1, deleted bullet for receiving cumulative dose of
corticosteroids.
Criterion #2.1, revisions made to align with PI letter sent to the
sites.
Criterion #5.1, added clarification lead-in text of “known to be…”
with further clarification for hepatitis B bullet.
Criterion #6.1, added clarification lead-in text of “known to be…”
with further clarification for hepatitis C bullet.
Criterion #16 was added.
Rationale: To clarify the dosing instructions for the various components of the backbone regimen(s).


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Applicable Sections 
Description of Changes
Synopsis, Dosage and Administration  
Prednisone PO 60 mg/m2 on Days 1-4 2, 3 and 4 for Cycles 1 to 9.
and dexamethasone PO or IV at 20 mg weekly for Cycle 1, every
3 weeks for Cycles 2 to 9, and every 4 weeks for Cycles 10+.
6.1.1 D-VRd Cohort 
Added clarification text for administration of lenalidomide,
dexamethasone, and bortezomib. Also, deleted text to allow for
lenalidomide administration per local label for subjects outside of
the US.
6.1.2 D-VMP Cohort, Table 15 Treatment 
Schedule and Dosing (D-VMP-Cohort) 
“Prednisone” Dose for Cycle 1 and Cycles 2-9 corrected to “Days
1-4”, and “Dexamethasone” row deleted.
6.1.3 D-Rd Cohort, Table 16 Treatment 
Schedule and Dosing (D-Rd Cohort) 
Change made from “Days 1, 8, 15, 22” to “weekly” for “Cycles 1
and 2”, and footnote added at select timepoints for all cycles.
6.7 Dose Reductions of Bortezomib, 
Lenalidomide, Melphalan, Dexamethasone, 
and Prednisone, Table 17 Dose Reduction
for Prednisone
Changed starting dose, first dose reduction, and second dose
reduction from “…on Days 1-4” to “… on Days 2 to 4”.
6.1.2 D-VMP Cohort 
Paragraph added for melphalan and prednisone and for bortezomib
to give instructions on dose, administration, and timing of
administration.
6.1.3 D-Rd Cohort 
Deleted text to allow for lenalidomide administration per local
label for subjects outside of the US.
Revisions made for dexamethasone administration.
Rationale: Text revised for consistency to clarify the daratumumab route of administration.
6.4.1.1 Pre-administration Medication; 
6.5.1 Daratumumab Toxicity Management; 
8 Prestudy and Concomitant Therapy;
9.6 Safety Evaluations, Daratumumab
Interference with Indirect Antiglobulin Test
Results subsection;
12.3.2 Serious Adverse Events
Changed “infusion” to “administration” or “injection” as
applicable.
Rationale: Clarified text concerning continuation of study treatment when one component of the regimen is
discontinued due to toxicity.
6.5.2 Daratumumab Interruption or Missed 
Doses 
A daratumumab dose that is held for more than the permitted
time (Table 14 to Table 16) 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. If one of the components
of the standard myeloma therapy is discontinued due to
toxicity, the remaining components should continue as long
as no dose interruption rules have been met.
Rationale: Revised to align with current International Myeloma Working Group (IMWG) criteria.
Deleted all text for “clinical relapse” footnote, as it is not accepted by the sponsor.
9.2.1.1 Response Categories, Table 32 
International Uniform Response Criteria 
Consensus Recommendations 
For Minimal response (MR) row: removed bullet for “in subjects
with relapsed refractory myeloma…”.
Deleted all footnote text for “clinical relapse”.
Rationale: Revisions made to align with SAP and planned statistical analyses.


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Applicable Sections 
Description of Changes
11.1 Subject Information 
Deleted bullet for “All subjects enrolled analysis set” and revised
“Treated analysis set” to “All treated analysis set” and
accompanying text regarding the use and analysis set.
11.3 Efficacy Analyses (MRD Negativity 
Rate)
Deleted, “…or whole blood”.
11.5 Immunogenicity Analyses 
Text revised for immunogenicity analyses paragraph.
Rationale: To align with current template text and other recent amendments across the daratumumab compound.
10.2 Discontinuation of Study 
Treatment/Withdrawal from the Study  
Deleted text specifying “Relapse from CR is not considered as
disease progression.
Revised the text related to subjects withdrawing from the study.
12.1.1 Adverse Event Definitions and 
Classifications, Unlisted (Unexpected) 
Adverse Event/Reference Safety Information
subsection;
14.1 Physical Description of the Study Drug;
15 Study-Specific Materials
Added Japan-specific text for the bortezomib Investigator’s
Brochure and IP classification.
12.3.1 All Adverse Events 
Added text related to sponsor's responsibility for reporting
anticipated events.
12.3.2 Serious Adverse Events 
Added clarification text for expected disease progression.
12.3.3 Pregnancy  
Deleted text concerning unknown effects of study drug on sperm.
17.3 Subject Identification, Enrollment, and 
Screening Logs 
Added ‘(as allowed by local regulations)’ following 2 instances of
‘date of birth’.
17.11 Use of Information and Publication  
Changed the time for submitting study results for publication from
‘within 12 months of the availability of the final data (tables,
listings, graphs)’ to ‘within 18 months after study end date’.
Revised the text beginning ‘Authorship of publications...’
Rationale: To clarify the procedures, including timing, that need to be completed and to ensure consistency with
the text in the body of the protocol.
Time and Events Schedules Table 1 through 
Table 7
Miscellaneous edits throughout the Time and Events Schedules.
Rationale: Miscellaneous edits made for clarity and consistency across the protocol.
4.2 Exclusion Criteria 
Criterion #8.1 revised to remove text referring to National Cancer
Institute-Common Terminology Criteria for Adverse Events [NCI-
CTCAE, Version 4.03] Grade 2 or higher).
6.7.2 Dose Modification Guidelines for 
Dexamethasone 
Added, “PO”, as in, “The 20-mg IV or PO dose of
dexamethasone…”.
6.7.3.1 Hematologic Toxicity of Bortezomib 
Table 25 Dose Modifications for 
Hematologic Toxicity
“Thrombocytopenia Grade 3” row revised to add instructional text
on withholding bortezomib to align with local protocol revisions.


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Applicable Sections 
Description of Changes
8.3 Prohibited Therapies 
Revised text to, “…given as backbone therapy and IRRs…”, and
added text for inhibitors and inducers.
9.2.1.1 Response Categories; 
16.2.3 Informed Consent Form  
Since “survival status” was deleted from Time and Events Tables
1, 3, and 6, accompanying survival status text was also deleted in
body text.
For 9.2.1.1 only: Added missing bibliographic reference citation
for Kumar 2016, and changed “determine response” to “evaluate
response”.
9.2.1.5 Bone Marrow Examination, Table 33 
Bone Marrow Testing 
For “Screening” and “CR, sCR” rows: Added clarification text
concerning sample collection timing in the “Central Testing”
column.
11.8 Safety Analyses, Stem Cell Collection 
subsection
Changed “D-Rd arm only” to “D-VRd cohort only”
Attachment 8: Antihistamines That May Be 
Used Pre-dose
Revised text to remove reference to Dara-IV infusion.
Attachments 
In Attachment 3, corrected the e-GFR formula for creatinine in
µmol/L.
Added Attachment 12 for inhibitors and inducers.
Rationale: Minor errors were noted.
Throughout document 
Minor corrections for formatting, grammar, etc.


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SYNOPSIS
A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination with Standard
Multiple Myeloma Treatment Regimens
EudraCT NUMBER: 2017-004203-41
This is an open-label, international, multicenter study to demonstrate that daratumumab administered by
subcutaneous (SC) injection in combination with standard treatment regimens is safe and efficacious in
subjects with newly diagnosed multiple myeloma (MM) or in subjects with relapsed or refractory disease.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Primary Objective
 
To evaluate the clinical benefit of SC daratumumab administered in combination with standard MM
regimens in subjects with MM as measured by overall response rate (ORR) or very good partial
response (VGPR) or better rate.
Secondary Objectives
 
To evaluate safety and pharmacokinetics of SC administration of daratumumab in combination with
standard MM regimens
 
To evaluate additional clinical benefit of SC daratumumab administered in combination with
standard MM regimens in subjects with MM
 
To characterize the immunogenicity of daratumumab and rHuPH20 following SC administration
 
To evaluate minimal residual disease (MRD) negativity rate in the D-VMP (daratumumab SC in
combination with bortezomib, melphalan and prednisone), D-Rd (daratumumab SC in combination
with lenalidomide and dexamethasone), and D-Kd (daratumumab SC in combination with
carfilzomib and dexamethasone) cohorts
Endpoints
Primary Endpoints
 
ORR, defined as the proportion of subjects with a partial response or better as defined by the
International Myeloma Working Group (IMWG) response criteria (D-Kd, D-VMP, and D-Rd
cohorts)
 
VGPR or better rate, defined as the proportion of subjects with a VGPR or better rate as defined by
the IMWG response criteria (D-VRd cohort)
Key Secondary Endpoints
 
Serum concentrations of daratumumab
 
Rate of infusion-related reactions
 
VGPR or better rate as defined by the IMWG response criteria (D-Kd, D-VMP, and D-Rd
cohort), and ORR as defined by the IMWG response criteria (D-VRd cohort)
Hypothesis
The hypothesis is that the addition ofdaratumumab administered SC to standard MM regimens will
improve responses compared to response data observed in completed phase 3 studies without
daratumumab.


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OVERVIEW OF STUDY DESIGN
This study will investigate the efficacy and safety of daratumumab administered SC (Dara SC) in
combination with bortezomib, lenalidomide, and dexamethasone (VRd) in subjects with newly diagnosed
MM who are transplant eligible; or in combination with bortezomib, melphalan, and prednisone (VMP) in
subjects with newly diagnosed MM who are ineligible for transplant; or in combination with lenalidomide
and dexamethasone (Rd) in subjects with relapsed or refractory MM or in combination with carfilzomib
and dexamethasone (D-Kd) in subjects in first relapse or refractory MM after initial treatment with a
lenalidomide-containing regimen. Approximately 60 subjects will be treated per cohort. Subjects enrolled
in the daratumumab-VRd cohort (D-VRd) will be treated for 4 cycles and will be evaluated for a VGPR
or better rate. Hematopoietic stem cell collection and autologous transplant will be performed off
protocol. Subjects enrolled in the D-Kd, D-VMP, and D-Rd cohorts will be evaluated for ORR and will
be treated until disease progression. A study evaluation team will evaluate safety during this study.
SUBJECT POPULATION
Key eligibility criteria: 18 years of age; documented secretory MM based on IMWG criteria, and an
Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1, or 2. Additional criteria
are defined for each treatment cohort (D-VRd, D-VMP, D-Kd, and D-Rd).
DOSAGE AND ADMINISTRATION
Subjects in the D-VRd cohort will receive treatment in 21-day cycles for a maximum of 4 cycles.
Treatment will consist of daratumumab SC 1800 mg weekly for Cycles 1 to 3 and on Day 1 of Cycle 4;
bortezomib SC 1.3 mg/m2 on Days 1, 4, 8 and 11 of each cycle; lenalidomide orally (PO) at 25 mg on
Days 1 to 14 of each cycle; and dexamethasone PO or intravenously (IV) 20 mg on Days 1, 2, 8, 9, 15 and
16 of each cycle.
Subjects in the D-VMP cohort will receive treatment in 42-day cycles for Cycles 1 to 9 and then 28-day
cycles thereafter. Treatment will consist of daratumumab SC 1800 mg weekly for Cycle 1, every 3 weeks
for Cycles 2 to 9 and every 4 weeks thereafter; bortezomib SC 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29
and 32 for Cycle 1, and Days 1, 8, 22 and 29 for Cycles 2 to 9; melphalan PO 9 mg/m2on Days 1-4 for
Cycles 1 to 9; prednisone PO 60 mg/m2 on Days 1-4 for Cycles 1 to 9.
Subjects in the D-Kd cohort will receive treatment in 28-day cycles. Treatment will consist of
daratumumab SC 1800 mg weekly for Cycles 1 and 2, every 2 weeks for Cycles 3-6, and every 4 weeks
thereafter for Cycles 7+. Subjects will receive carfilzomib IV 20 mg/m2 on Cycle 1 Day 1. If tolerated,
beginning with the second dose of carfilzomib, the dose will be escalated to 70 mg/m2 on Cycle 1 Days 8
and 15. For Cycles 2+, carfilzomib IV 70mg/m2 will be given weekly on Days 1, 8, and 15 of each cycle.
Subjects in the D-Rd cohort will receive treatment in 28-day cycles. Treatment will consist of
daratumumab SC 1800 mg weekly for Cycles 1 and 2, every 2 weeks for Cycles 3 to 6 and every 4 weeks
thereafter; lenalidomide PO 25 mg on Days 1 to 21 of each cycle; and dexamethasone PO or IV 40 mg
weekly for each cycle.
The data cutoff for the final analysis and the end of data collection will occur approximately 10
months after the last subject is enrolled in the D-Kd cohort. Subsequently, the clinical database
will be locked for the final analysis.
Subjects benefiting from study treatment can continue receiving the study drugs after the end of data
collection until the study drugs are commercially available, available from another source (eg. via a
dedicated long-term extension study), or until study completion.


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The end of study will occur when all subjects who are still receiving study treatment after the clinical
cutoff date of the final analysis have discontinued daratumumab treatment, or when all subjects have
access through another source such as commercial availability, continued access through a dedicated
long-term extension study, or a patient access program, or by June 2024, if the prior 2 criteria are not met
first.
EVALUATIONS
Assessment of disease will be conducted in accordance with the IMWG response criteria. Disease
evaluations will include: measurements of myeloma proteins, bone marrow examinations, skeletal
surveys and other imaging studies, and serum calcium corrected for albumin. Blood samples will be
drawn from all subjects to characterize the pharmacokinetics of daratumumab and to assess for the
generation of antibodies to daratumumab and to rHuPH20. Biomarkers will also be assessed. Safety
evaluations include adverse event monitoring, physical examinations, electrocardiograms, transthoracic
echocardiograms (TTE) for D-Kd cohort only, SC injection site evaluations, clinical laboratory
parameters (hematology and chemistry), vital sign measurements, and ECOG performance status.
STATISTICAL METHODS
Response and progressive disease will be analyzed and reported using a computerized algorithm based on
the central laboratory results (unless otherwise specified). The primary efficacy endpoints of ORR (D-Kd,
D-VMP, and D-Rd cohorts) or VGPR or better rate (D-VRd cohort), along with their two-sided 90%
exact confidence interval, will be calculated for each treatment cohort. No formal comparisons between
these treatment cohorts will be performed.


















































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ABBREVIATIONS
Anti-HBc 
antibodies to hepatitis B core antigen
Anti-HBs 
antibodies to hepatitis B surface antigen
ASCT  
autologous stem cell transplant
BMI 
body mass index
CD38  
cluster of differentiation 38
CI 
confidence interval
Cmin  
minimum observed concentration
Cmax  
maximum observed concentration
COPD  
chronic obstructive pulmonary disease
CR  
complete response
CT  
computed tomography
Ctrough  
trough concentration
Dara-IV  
daratumumab for intravenous infusion
Dara-MD  
daratumumab and recombinant human hyaluronidase for subcutaneous injection: mix and
deliver
Dara SC  
daratumumab and recombinant human hyaluronidase for subcutaneous injection: co-formulated
DOR  
duration or response
DRd 
daratumumab-IV, lenalidomide, and dexamethasone
D-Kd 
daratumumab-SC, carfilzomib, and dexamethasone
D-Rd 
daratumumab SC, lenalidomide, and dexamethasone
DVd 
daratumumab-IV, bortezomib, and dexamethasone
D-VMP  
daratumumab SC, bortezomib, melphalan, and prednisone
D-VRd 
daratumumab SC, bortezomib, lenalidomide, and dexamethasone
ECG  
electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EOT  
end of treatment
EU  
European Union
FEV1 
forced expiratory volume in 1 second
FFPE 
formalin-fixed, paraffin-embedded
FOIA  
Freedom of Information Act
FLC  
free light chain
GCP  
good clinical practice
HBc 
hepatitis B core antigen
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HRT  
hormonal replacement therapy
IAT  
indirect antiglobulin test
ICF  
informed consent form
ICH  
International Council on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
IFE 
immunofixation electrophoresis
IgG  
immunoglobulin G
IMiD  
immunomodulatory drug
IMP  
investigational medicinal product


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IMWG  
International Myeloma Working Group
INR  
international normalized ratio
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
IRR  
infusion-related reaction
IV  
intravenous
IWRS  
interactive web response system
LMWH  
low molecular weight heparin
MDRD  
modification of diet in renal disease
MDSC  
myeloid-derived suppressor cell
MM  
multiple myeloma
M-protein  
monoclonal paraprotein
MRD  
minimal residual disease
MRI 
magnetic resonance imaging
NCI-CTCAE  
National Cancer Institute-Common Terminology Criteria for Adverse Events
NK  
natural killer
NYHA  
New York Heart Association
ORR  
overall response rate
OS  
overall survival
PCR  
polymerase chain reaction
PD 
progressive disease
PFS  
progression-free survival
PI 
proteasome inhibitor
PK 
pharmacokinetic
PO 
orally
PQC  
product quality complaint
PR 
partial response
RBC  
red blood cell
Rd 
lenalidomide and dexamethasone
REMS  
risk evaluation and mitigation strategy
rHuPH20 
recombinant human hyaluronidase
SAC  
Safety Assessment Committee
SC 
subcutaneous
sCR  
stringent complete response
SET  
study evaluation team
SIPPM  
Site Investigational Product and Procedures Manual
SmPC  
Summary of Product Characteristics
SPEP  
serum M-protein quantitation by electrophoresis
SPM  
secondary primary malignancy
SUSARs 
suspected unexpected serious adverse reaction
TEAE 
treatment-emergent adverse event
Tmax  
time to maximum observed concentration
TTE 
transthoracic echocardiogram
ULN  
upper limit of normal
UPEP  
urine M-protein quantitation by electrophoresis
US  
United States
Vd 
bortezomib and dexamethasone
VMP  
bortezomib, melphalan, and prednisone
VRd 
bortezomib, lenalidomide, and dexamethasone


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VGPR  
very good partial response


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1. 
INTRODUCTION
Daratumumab (JNJ-54767414) is a human immunoglobulin G (IgG) monoclonal antibody
(mAb) immunotherapy that binds with high affinity to cluster of differentiation 38 (CD38), a
transmembrane glycoprotein, expressed on tumor cells, and induces tumor cell death through
multiple mechanisms of action. These mechanisms of action include complement-dependent
cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular
phagocytosis, and direct cytotoxicity by induction of apoptosis by Fc gamma receptor mediated
crosslinking of tumor-bound monoclonal antibodies. Daratumumab treatment leads to the rapid
and sustained elimination of highly immunosuppressive subsets of CD38+ Tregs, CD38+
MDSCs, and CD38+ regulatory B cells (Bregs) (Krejcik 201615). The elimination of these
immunosuppressive cells, modulation of CD38 enzymatic activity and destruction of the
malignant myeloma cells is thought to lead to the clonal expansion of CD8+ and CD4+ T cells
(Chiu 20166). The multiple mechanisms of actions are hypothesized to lead to the minimal
residual disease (MRD) negative responses observed in some patients
The intravenous (IV) formulation of DARZALEX (daratumumab) is approved in a number of
countries worldwide for the treatment of multiple myeloma (MM). DARZALEX was initially
approved in the United States (US) and European Union(EU) as monotherapy for the treatment
of heavily pre-treated patients with relapsed and refractory multiple myeloma and since this time,
several indications have been approved for DARZALEX in combination with background
therapies for both relapsed/refractory and newly diagnosed multiple myeloma patients. Most
recently, the subcutaneous (SC) formulation of DARZALEX was approved in the US and EU
and provides several key benefits for patients and healthcare providers as it is a flat dose that
reduces the time taken to receive daratumumab treatment and reduces the incidence and severity
of infusion related reactions (IRRs) in comparison to the IV formulation. For more details about
current approved indications, please refer to Summary of Product Characteristics (SmPC 20208)
and United States Package Insert (USPI 20209).
Recombinant human hyaluronidase (rHuPH20) is the active ingredient of Hylenex® recombinant
(hyaluronidase human injection), which was approved for use in the US in December 2005.
rHuPH20 is also approved in combination with protein therapeutics for SC administration, such
as HyQvia (Immune globulin infusion 10% [human] with rHuPH20) in the US and EU, as well
as anticancer medications such as Herceptin® SC (trastuzumab) in the EU and MabThera® SC
(rituximab) in the EU and the US.
For the most comprehensive nonclinical and clinical information regarding daratumumab and
rHuPH20, refer to the latest version of the Investigator’s Brochures for daratumumab and
rHuPH2013. 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.
1.1. 
Clinical Studies
For the results of the single agent IV daratumumab studies refer to the daratumumab
Investigator's Brochure13.


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1.1.1. 
Combination Therapy Studies: Summary of the Results from
Studies MMY3003, MMY3004, MMY3007, and MMY1001
The US and EU approval of daratumumab for the treatment of patients with MM who have
received at least 1 prior therapy was based on the results of the phase 3
Study 54767414MMY3003 (hereafter referred to as Study MMY3003) and Study MMY3004 as
well as the Phase 1 Study 54767414MMY1001, all of which examined the safety and efficacy of
daratumumab for intravenous infusion (Dara-IV) in combination with other therapies in the
treatment of relapsed MM. The results from the 3 studies are summarized below along with the
interim results of the phase 3 combination Study 54767414MMY3007 comparing daratumumab
SC, bortezomib, melphalan, and prednisone (D-VMP) to daratumumab SC, bortezomib,
melphalan, and prednisone (VMP) in newly diagnosed MM:
 
In Study MMY3003, subjects with MM received Dara-IV in combination with lenalidomide
and dexamethasone (DRd). At the time of the first interim analysis, treatment with DRd
resulted in a 63% reduction in the risk of disease progression or death compared to the
combination of lenalidomide and dexamethasone (Rd). The median progression-free
survival (PFS) was not reached in the daratumumab group; median PFS was 18.4 months in
the Rd group. The overall response rates (ORRs) were 93% for the DRd group and 76% for
Rd group.
 
In Study MMY3004, subjects with MM received Dara-IV in combination with bortezomib
and dexamethasone (DVd). At the time of the first interim analysis, treatment with DVd
showed a 61% reduction in the risk for disease progression or death compared to the
combination of bortezomib and dexamethasone (Vd). The median PFS was not estimable in
the DVd group; median PFS was 7.2 months, in the Vd group. The ORRs were 83% for the
DVd group and 63% for the Vd group.
 
In Study MMY3007, subjects with MM received Dara-IV in combination with bortezomib,
melphalan and dexamethasone (D-VMP). At the time of the first interim analysis, treatment
with D-VMP showed a 50% reduction in the risk for disease progression or death compared
to the combination of bortezomib, melphalan and dexamethasone (VMP). The median PFS
was not reached for the D-VMP group and was 18.1 months for the VMP group. The ORRs
were 91% for the D-VMP group and 75% for the VMP group.
 
In Study MMY1001, subjects with MM received Dara-IV in combination with carfilzomib
(70 mg/m2 weekly) and dexamethasone (D-Kd).  As of the clinical cutoff date of 12 Oct
2017, 85 subjects were treated with D-Kd which resulted in a 12-month PFS rate of 71%.
The median PFS was not reached. The ORR was 86% (Lonial 201721).


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Adverse events of special interest from these studies include:
 
Neutropenia in combinations of daratumumab with lenalidomide, pomalidomide, or
melphalan; thrombocytopenia combinations of daratumumab with bortezomib or melphalan.
 
A higher incidence of all-grade infections. However, the incidence of life-threatening and
fatal infections was low and generally balanced between the 2 treatment arms.
 
An increased risk of secondary primary malignancy (SPM).
The incidence of study drug discontinuation and deaths in these studies was low. For further
details and the most up-to-date information about combination therapy studies, refer to the
daratumumab Investigator's Brochure.
1.1.2. 
Study 54767414MMY1004
Study 54767414MMY1004 (hereafter referred to as Study MMY1004) is an ongoing,
open-label, 2-part phase 1b study to assess the safety and pharmacokinetics (PK) of SC
daratumumab in subjects with relapsed or refractory multiple myeloma who have received
2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug
(IMiD). In Part 1, subjects (n 53) received the mix and deliver formulation of subcutaneous
daratumumab (Dara-MD), and in Part 2, subjects (n 25) are receiving daratumumab co-
formulated (Dara SC) with rHuPH20. Enrollment in both parts of the study has been completed.
1.1.2.1. 
Preliminary Data from Study MMY1004 Part 1
Dara-MD is a solution that requires mixing of the daratumumab drug product with rHuPH20
prior to delivery. In Part 1 of Study MMY1004, Dara-MD was administered subcutaneously
according to the same schedule as the approved IV daratumumab regimen, ie, once weekly in
Cycles 1 and 2, every 2 weeks in Cycles 3 to 6, and then every 4 weeks in subsequent cycles
until disease progression or unacceptable toxicity. Subjects were enrolled in sequential cohorts at
1200 mg (n 8 subjects) and 1800 mg (n 45 subjects).
After a median treatment duration of 2.6 months for the 1200 mg cohort and 5.4 months for the
1800 mg cohort (clinical cutoff 03 Aug 2017), the key safety findings were:
 
The incidence of all-grade IRRs was 13% and 24% in the 1200 mg and 1800 mg Dara-MD
cohorts, respectively. In comparison, among subjects treated in single-agent or combination
studies with IV daratumumab, IRRs were reported in 48% of subjects.
 
Across both cohorts, all but 1 infusion-related reaction (IRR) were mostly Grade 1 or 2.
One subject (2%) in the 1200 mg Dara-MD cohort developed a Grade 3 IRR of dyspnea
compared to 6% on daratumumab IV monotherapy studies.
 
All IRRs developed within 6 hours of the start of the Dara-MD infusion and did not
result in treatment discontinuation.


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 
The most frequently reported treatment-emergent adverse events (TEAEs) (20% of all
subjects) were upper respiratory tract infection, thrombocytopenia and insomnia (38% each)
and pyrexia, fatigue, anemia, diarrhea, vomiting, headache, and cough (25% each) for the
1200 mg cohort. For the 1800 mg cohort TEAEs were anemia (33%), diarrhea, upper
respiratory tract infection (22% each), pyrexia (27%), fatigue and asthenia (20% each).
 
Grade 3 or 4 TEAEs were reported in 63% and 49% of subjects in the 1200 mg and 1800 mg
cohorts, respectively. In studies of IV daratumumab, Grade 3 or 4 TEAEs were reported in
56% of subjects.
 
Serious TEAEs were reported in 50% and 31% of subjects in the 1200 mg and 1800 mg
cohorts, respectively compared to 34% on Dara-IV monotherapy studies.
 
One subject in the 1800 mg cohort died due to a TEAE of depressed level of consciousness;
this event occurred 20 days after last dose of Dara-MD and was considered by the
investigator to be unrelated to study drug and related to progression of disease.
At the time of the clinical cutoff (03 Aug 2017), 53 subjects (8 subjects in the 1200 mg Dara-MD
cohort and 45 subjects in the 1800 mg Dara-MD cohort) were evaluable for efficacy, which was
defined as having C3D1 disease evaluation or demonstrated disease progression. In the 1200 mg
Dara-MD cohort, the ORR was 25% (95% confidence interval (CI): 3%-65%) and 2 subjects
achieved partial responses (PRs): one 8 weeks and the other 20 weeks after initiation of
treatment. In the Dara-MD 1800 mg cohort, the ORR was 42% (compared to 31% for Dara-IV).
The rates of greater than or equal to very good partial response (VGPR) and complete response
(CR) were 20% and 9%, respectively (12% and 3% respectively for Dara-IV). The median time
to first response in the 1200 mg and 1800 mg cohorts was 3.4 months (range 1.8-4.9 months) and
1 month (range 0.9-10.2 months), respectively, which is in line with what was observed for
Dara-IV.
Preliminary Pharmacokinetic Data
Preliminary PK data following Dara-MD administration show a slower absorption with a later
Tmax  (approximately 72 h post-infusion) compared with IV administration. Preliminary analyses
indicate the bioavailability of Dara-MD is approximately 77% when administered
subcutaneously. Please refer to Section 1.1.2.2, Preliminary Data from Study MMY1004 Part 2,
for detailed results for Dara SC.
1.1.2.2. 
Preliminary Data from Study MMY1004 Part 2
The final SC daratumumab, Dara SC, which will be used in Study MMY2040 is a co-formulated
drug product intended for a fixed-dose administration, containing rHuPH20 and daratumumab in
a single vial. Part 2 of Study MMY1004 is a phase 1b, non-randomized, open-label study to
evaluate Dara SC (referred to in the MMY1004 protocol as Dara-CF) administered
subcutaneously to subjects with multiple myeloma who have received at least 2 prior lines of
therapy, including a PI and an IMiD, and have measurable disease. Based on the results from
Part 1 of the study, the 1800 mg dose was selected for Part 2.


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After a median treatment duration of 2.3 months (clinical cutoff date of 03 Aug 2017), key safety
findings for the 25 subjects who have received at least 1 dose of 1800 mg Dara SC are as
follows:
 
IRRs (all grades) was reported in 8% of subjects. All IRRs (chills, dyspnea, and allergic
rhinitis) were Grade 1 or 2.
 
Injection site reactions were reported in 2 subjects: 1 subject had a Grade 1 injection site
discoloration/injection site induration (although no measurable induration was reported in
this subject), and 1 subject had a Grade 1 erythema. A Grade 1 hematoma was reported for a
third subject after the clinical cutoff.
 
The most frequently reported TEAEs (3 [12%] subjects) were lymphopenia (32%);
thrombocytopenia, pyrexia, fatigue, asthenia, back pain, nausea, headache, insomnia
(16% each); and leukopenia, anemia, chills, and diarrhea (12% each).
 
Grade 3 or 4 TEAEs were reported in 36% of subjects.
 
Serious TEAEs were reported in 2 subjects (8%). The serious TEAEs were pyrexia,
asthenia, fatigue, hyponatremia, febrile neutropenia, leukopenia, and thrombocytopenia; and
all were Grade 3 or 4 except for pyrexia.
 
No subject discontinued treatment or died due to a TEAE.
Preliminary Pharmacokinetic Data
As of the clinical cutoff date, 20 subjects had reached Cycle 3 Day 1 (C3D1). Of those,
18 subjects had received all scheduled doses of study drug in cycles 1 and 2 and had provided a
pre-dose PK sample on C3D1 and were therefore considered evaluable for the PK endpoint.
The primary PK endpoint of C3D1 trough concentration (Ctrough) mean value was 904.42 µg/mL
for the Dara SC cohort (n 18) compared with 754.62 µg/mL for the 1800 mg Dara-MD cohorts
(n 38), 617.17 µg/mL in Study GEN501 Part 2 (n 27), and 573.49 µg/mL in Study MMY2002
(n 73). The median C3D1 Ctrough  values for Dara SC are similar to the 1800 mg Dara-MD
formulations (798.9 and 795.5 µg/mL, respectively) and slightly higher than the 16 mg/kg IV
median values from Studies MMY2002 and GEN501 (559.6 and 713.9 µg/mL, respectively).
The range of C3D1 Ctrough  observations for the SC cohort is within the range observed following
16 mg/kg IV dosing and the variability appeared to be similar for the Dara SC and 16 mg/kg IV
cohorts.
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 914.9 µg/mL
observed after the C3D1 (9th) dose for Dara-IV in Study MMY2002. The C3D1 Cmax  was
selected for this comparison as the Cmax  was not captured following the last weekly (8th) dose in
Study MMY2002. The observed Cmax  values from the Dara SC cohort is within the range
observed for Dara-MD and daratumumab 16 mg/kg IV.


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1.2. 
Recombinant Human Hyaluronidase (rHuPH20)
Recombinant human hyaluronidase (rHuPH20) is a recombinantly expressed version of
hyaluronidase synthesized in Chinese Hamster Ovary cells that have been transfected with a
plasmid containing the DNA sequence encoding human PH20 hyaluronidase. rHuPH20 acts
locally and transiently within the SC space to increase the tissue dispersion and absorption of
other injected drugs and fluids. rHuPH20 cleaves the repeating disaccharide subunits
(N-acetyl-D-glucosamine and D-glucuronic acid) of hyaluronan, a polymeric, gel-like
glycosaminoglycan (mucopolysaccharide) that limits the movement of fluids and other
molecules in the SC tissue. rHuPH20 de-polymerizes the gel-like hyaluronan, resulting in
decreased resistance to fluid flow and a transient increase in permeability of the local SC tissue.
The co-formulated preparation (Dara SC) currently under study in Part 2 of Study MMY1004
has a daratumumab concentration of 120 mg/mL and rHuPH20 at a concentration of 2000 U/mL.
The injection volume for daratumumab 1800 mg with Dara SC is approximately 15 mL, which
contains 30,000 U rHuPH20.
1.2.1. 
Clinical Studies
When rHuPH20 doses of 10,000 and 30,000 U were administered IV to humans, the mean
maximum concentration achieved was 2.5 and 6.8 U/mL, respectively. The half-life of plasma
enzymatic activity was 3.7 and 5.6 minutes for the respective doses. It is expected that SC doses
in the range of 30,000 to 45,000 U will result in levels of rHuPH20 in plasma that are well below
limits of quantitation (approximately 0.3 U/mL).
In Part 1 of Study MMY1004, the concentration of rHuPH20 was 500 U/mL, which is
approximately equivalent to rHuPH20 30,000 U for a 60-mL infusion of 1200 mg of
daratumumab, and rHuPH20 45,000 U for a 90-mL infusion of 1800 mg of daratumumab. In
Part 2, a flat-dosed, fixed co-formulated drug product containing rHuPH20 drug substance
(2000 U/mL) and Generation 2 (Gen 2) daratumumab drug substance (120 mg/mL) in a single
vial (Dara SC) was used. Previous clinical studies have demonstrated that SC injection of up to
96,000 U of rHuPH20 is tolerable (Halozyme data on file). Currently marketed anticancer
therapeutic antibodies have achieved bioavailability of 71% (rituximab) to 87% (trastuzumab)
with co-administration of <30,000 U of rHuPH20.
Phase 1 trials of rituximab SC administration in subjects with follicular lymphoma and
trastuzumab SC in healthy volunteers and subjects with early breast cancer using rHuPH20 have
demonstrated substantially shorter administration times, comparable tolerability, and comparable
PK compared with IV (Shpilberg 201330). More gradual absorption was observed with
trastuzumab SC administration, with maximum observed concentrations approximately  2-fold
lower for SC versus IV, and the time to maximum concentration was 4 to 6 days with SC
administration versus 3 hours with IV administration (Wynne 201331). However, the trough
concentrations occurring with SC delivery are generally the same or higher as compared to IV
(Bittner 20122), and clinical efficacy of the 2 routes of administration is comparable
(Ismael 201214). In a 2-stage phase 1b study with rituximab, the fixed dose of rituximab 1400 mg


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SC was confirmed to have non-inferior observed serum concentrations immediately prior to the
next administration (Ctrough) relative to rituximab 375 mg/m2 IV, with a comparable safety
profile. Local administration-related reactions, mostly mild to moderate in severity, occurred
more frequently after SC administration (Salar 201429). These findings were confirmed in a
randomized phase 3 study (Davies 20147).
1.3. 
Overall Rationale for the Study
A co-formulated product of daratumumab and rHuPH20 allows for the SC administration of
daratumumab in 3 to 5 minutes compared to 4 to 7 hours for an IV infusion of daratumumab.
Results from the phase 1 monotherapy study (MMY1004) suggest a reduction of IRRs and
efficacy that is similar to what is observed with daratumumab IV monotherapy. This is an open-
label, international, multicenter, phase 2 study to demonstrate that daratumumab administered by
SC injection in combination with standard treatment regimens is safe and efficacious in subjects
with newly diagnosed MM or in subjects with relapsed or refractory disease.
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1. 
Objectives and Endpoints
2.1.1. 
Objectives
Primary Objective
 
To evaluate the clinical benefit of SC daratumumab administered in combination with
standard MM regimens in subjects with MM as measured by ORR or VGPR or better rate.
Secondary Objectives
 
To evaluate safety and PK of SC administration of daratumumab in combination with
standard MM regimens
 
To evaluate additional clinical benefit of SC daratumumab administered in combination with
standard MM regimens in subjects with MM
 
To characterize the immunogenicity of daratumumab and rHuPH20 following
SC administration
 
To evaluate minimal residual disease (MRD) negativity rate in the D-VMP (daratumumab
SC in combination with bortezomib, melphalan, and prednisone), D-Kd (daratumumab SC
in combination with carfilzomib and dexamethasone), and D-Rd (daratumumab SC in
combination with lenalidomide and dexamethasone) cohorts.


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2.1.2. 
Endpoints
Primary Endpoint
 
ORR, defined as the proportion of subjects with a partial response or better as defined by the
International Myeloma Working Group (IMWG) response criteria (D-Kd, D-VMP, and
D-Rd cohorts)
 
VGPR or better rate, defined as the proportion of subjects with a VGPR or better rate as
defined by the IMWG response criteria (D-VRd cohort)
Secondary Endpoints
 
Serum concentrations of daratumumab
 
Rate of IRRs
 
VGPR or better rate as defined by the IMWG response criteria (D-Kd, D-VMP, and D-Rd
cohort), and ORR as defined by the IMWG response criteria (D-VRd cohort)
 
CR or better rate, as defined by the IMWG response criteria
 
Duration of response (DOR), defined as the time from the date of initial documented
response (PR or better for D-Kd, D-VMP, and D-Rd cohorts) to the date of first documented
evidence of progressive disease or death due to PD
 
Incidence of anti-drug antibodies against daratumumab or rHuPH20
 
Minimal residual disease (MRD) negativity rate in the D-Kd, D-VMP, and D-Rd cohorts.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2. 
Hypothesis
The hypothesis is that the addition ofdaratumumab administered SC to standard MM regimens
will improve responses compared to response data observed in completed phase 3 studies
without daratumumab.


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3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a multicenter, open-label, phase 2 study to investigate the efficacy and safety of Dara SC
in combination with bortezomib, lenalidomide, and dexamethasone (VRd) in subjects with newly
diagnosed MM who are transplant eligible; or in combination with bortezomib, melphalan, and
prednisone (VMP) in subjects with newly diagnosed MM who are ineligible for transplant; or in
combination with lenalidomide and dexamethasone (Rd) in subjects with relapsed or refractory
MM, or in combination with carfilzomib and dexamethasone (Kd) in subjects in subjects in first
relapse or refractory MM after initial treatment with a lenalidomide-containing regimen.
Approximately 60 subjects will be treated in each cohort. Subjects enrolled in the daratumumab,
bortezomib, lenalidomide, and dexamethasone cohort (D-VRd) will be treated for 4 cycles and
will be evaluated for a VGPR or better rate thereafter. Hematopoietic stem cell collection and
autologous transplant will be performed off protocol. Subjects enrolled in the D-VMP, D-Kd, and
D-Rd cohorts will be treated until disease progression. A diagram of the study design is provided
in Figure 1.
The data cutoff for the primary analysis for the study will occur at least 6 months after
approximately the 60th  subject is enrolled in the last treatment cohort (D-VRd, D-VMP, or
D-Rd). All available data at the time of this data cutoff will be included in the Clinical Study
Report. The cutoff for the primary analysis for the D-Kd cohort will occur at least 6 months after
approximately the 60th  subject is enrolled in the D-Kd cohort. The data cutoff for the final
analysis and the end of data collection will occur approximately 10 months after the last subject
is enrolled in the D-Kd cohort. Subsequently, the clinical database will be locked for the final
analysis (see Attachment 15).
Subjects benefiting from study treatment can continue receiving the study drugs after the end of
data collection. The end of study  will occur when all subjects who are still receiving study
treatment after the clinical cutoff date of the final analysis have discontinued daratumumab
treatment, or when all subjects have access through another source such as commercial
availability, continued access through a dedicated long-term extension study, or a patient access
program, or by June 2024, if the prior 2 criteria are not met first. An addendum to the Clinical
Study Report will be generated and describe safety data, including serious adverse events and
pregnancy reporting, from the end of data collection through the end of study.
A study evaluation team (SET) consisting of the participating investigators the sponsor’s medical
monitor, the sponsor’s clinical pharmacologist (if PK data are being evaluated), the sponsor’s
statistician the sponsor’s safety officer, and the sponsor’s study manager will evaluate safety data
after at least 6 toxicity-evaluable subjects complete Cycle 1 in each cohort. Additional data
reviews by the SET can be scheduled as needed to support decisions on dose selection or
schedule modification. The SET reviews and dose selection decisions will be documented in
writing in the Trial Master File.




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3.2. 
Study Design Rationale
Study MMY2040 will test Dara SC (1800 mg) in combination with the regimens that have been
evaluated in several completed or ongoing daratumumab IV Phase 3 studies, for which
indications are already approved or are anticipated. The regimens include: Dara SC in
combination with bortezomib, lenalidomide and dexamethasone (D-VRd) in newly diagnosed
subjects with MM who are eligible for transplant; in combination with bortezomib, melphalan
and prednisone (D-VMP) in newly diagnosed subjects with MM who are ineligible for
transplant; and in combination with lenalidomide and dexamethasone (D-Rd) in subjects with
relapsed or refractory MM, or in combination with carfilzomib and dexamethasone (D-Kd) in
MM subjects who had lenalidomide-containing frontline treatment and are relapse or refractory
to lenalidomide.
The 
4 
drug 
combinations 
bortezomib/melphalan/prednisone 
(VMP),
lenalidomide/dexamethasone 
(Rd), 
carfilzomib/dexamethasone 
(Kd), 
and
bortezomib/lenalidomide/dexamethasone (VRd) are all established myeloma regimens.  Per the
Summary of Product Characteristics (SmPC), bortezomib is indicated in combination with
melphalan and prednisone (VMP) for adult subjects with previously untreated multiple myeloma
who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation. It
is also indicated in combination with an IMiD and dexamethasone as the induction treatment for
adult subjects with previously untreated multiple myeloma who are eligible for high-dose
chemotherapy with hematopoietic stem cell transplant. Both the European Myeloma Network
(Engelhardt 201411) and the National Comprehensive Cancer Network recommend VRd as an
induction therapy for transplant-eligible subjects. Per the SmPC, lenalidomide is indicated in
combination with dexamethasone in adult subjects with previously treated multiple myeloma
who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
The sponsor considers the use of VMP, VRd, Kd, and Rd in the aforementioned indications as
standard of care. In the proposed study, the 4 combination regimens are used according to their
indications/recommendations in combination with Dara SC. The sponsor therefore believes the
combination therapies VMP, VRd, Kd, and Rd should also be considered standard of care in the
proposed study and should not be considered IMPs.
The rationale for selecting the 4 combination regimens is as follows:
 
To evaluate 3 classes of myeloma drugs, (IMiDs, proteasome inhibitors [PIs], alkylators)
and their combinations.
 
To evaluate daratumumab in combination with standard regimen in the 3 major segments of
the MM disease spectrum (newly diagnosed transplant eligible MM, newly diagnosed
transplant ineligible MM, and relapsed MM).
 
D-Rd (1+ lines) is the regimen that was evaluated in Study MMY3003, which led to the
approval of daratumumab IV in combination with Rd in subjects with relapsed MM.
 
D-VMP (frontline) is the regimen evaluated in Study MMY3007, which led to the approval
of daratumumab in combination with VMP for subjects with newly diagnosed MM.


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 
VRd (frontline) is an emerging SOC regimen commonly used as induction for newly
diagnosed transplant eligible subjects with MM and D-VRd is the experimental arm in the
ongoing Study MMY2004.
 
Kd is an approved regimen in the United States and Europe for subjects with
relapsed/refractory MM who have received 1-3 lines of therapy. Carfilzomib 70 mg/m2
weekly dose is an approved dose schedule in the United States. The combination of
Dara-IV+Kd was evaluated as a single arm and was effective in Study MMY1001.
Study MMY2040 will include 60 subjects/cohort which will provide >90% power for D-VRd,
D-VMP, D-Rd cohorts and >80% power for the D-Kd cohort to reject the null hypotheses for
each treatment combination.
Rationale for PK, Immunogenicity, and Biomarker Evaluations
Data obtained from the current study will provide information about the PK profile of
daratumumab by SC delivery in subjects with MM in these combinations. If sufficient data are
available, then population PK analysis of concentration-time data for daratumumab will be
performed and reported separately.
Immunogenicity to daratumumab or rHuPH20 is possible. Therefore, samples to determine the
presence of antibodies to daratumumab (immunogenicity) and samples to determine the presence
of antibodies to rHuPH20 (immunogenicity) will be collected from all subjects.
Biomarkers collected in this study may provide information about daratumumab’s mechanism of
action of these novel combinations. Samples may be used for immunophenotyping, which would
include analysis of specific subsets of immune cells, such as cytotoxic T cells, regulatory T cells,
and activated natural killer (NK) cells. Refer to Section 9.5, Biomarkers for details of the
biomarker analyses.
4. 
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before administration of the
study drug. The inclusion and exclusion criteria for enrolling subjects in this study are described
in the following 2 subsections. If there is a question about the inclusion or exclusion criteria
below, the investigator must consult with the appropriate sponsor representative and resolve any
issues before enrolling a subject in the study. Waivers are not allowed. For a discussion of the
statistical considerations of subject selection, refer to Section 11.2, Sample Size Determination.


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4.1. 
Inclusion Criteria
Each potential subject must satisfy all the following criteria to be enrolled in the study:
1. 
18 years of age (or the legal age of consent if it is higher than 18 years of age in the
jurisdiction in which the study is taking place)
2. 
Multiple myeloma diagnosed according to the IMWG diagnostic criteria (refer to
Attachment 1) (Rajkumar 201428)
3. 
Measurable, secretory disease as defined by any of the following:
 
Serum M-protein level 1.0 g/dL; or
 
Urine M-protein level 200 mg/24 hours; or
 
Light chain MM, for subjects without measurable disease in the serum or
urine: serum Ig free light chain (FLC) 10 mg/dL and abnormal FLC ratio
4. 
4.1 
Criterion modified per Amendment 1 and Amendment 2:
Meets one of the sets of the following criteria:
a. For inclusion into the D-VRd cohort for newly diagnosed disease:
 
Newly diagnosed MM by IMWG criteria and eligible/planned for high-
dose therapy and autologous stem cell transplant (ASCT)
b. For inclusion into the D-VMP cohort:
 
Newly diagnosed and previously untreated MM by IMWG criteria and not
considered a candidate for high-dose chemotherapy with ASCT due to:
 
Being age 65 years, or
 
In subjects <65 years: presence of important comorbid condition(s)
will make stem cell transplant intolerable for the subject. Sponsor
review of these comorbid conditions and approval is required before
the first dose of study treatment.
c. For inclusion into the D-Rd cohort for relapsed or refractory disease:
 
Relapsed disease is defined as progression of disease after an initial
response to previous treatment, more than 60 days after cessation of
treatment
 
Refractory disease is defined as either <25% reduction in M-protein or
confirmed progressive disease (PD) by IMWG criteria during previous
treatment or 60 days after cessation of treatment
 
Subject must have received at least 1 prior line of therapy for MM
 
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


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dexamethasone 40 mg/day for 4 days) would not be considered prior
lines of therapy.
 
Subjects must have progressed from or be refractory to their last line of
treatment
 
Subject must have achieved a response (PR or better based on
investigator’s evaluation of response by the IMWG criteria) to at least 1
prior treatment regimen
d. For inclusion in the D-Kd cohort for relapsed or refractory disease:
 
Subject must have received only 1 prior line of therapy for MM which
included at least 2 consecutive cycles of lenalidomide therapy
 
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
 
Subject must have achieved a response (PR or better based on
investigator’s evaluation of response by the IMWG criteria) to the first
treatment regimen
 
Subject must have progressed from or be refractory to the first line of
treatment as defined below:
 Relapsed disease is defined as progression of disease after an initial
response to previous treatment, more than 60 days after cessation of
treatment
 Refractory disease is defined as confirmed PD by IMWG criteria
during previous treatment or 60 days after cessation of treatment
(primary refractory patients are not eligible)
5. 
Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0, 1, or 2
(refer to Attachment 2).
6. 
Criterion Modified per Amendment 1 and Amendment 2
6.1 
Pretreatment clinical laboratory values during the Screening Phase (all cohorts):
a) hemoglobin 7.5 g/dL (mmol/L); D-Kd cohort 8.0 g/dL (without prior red
blood cell [RBC] transfusion within 7 days before the laboratory test;
recombinant human erythropoietin use is permitted);
b) absolute neutrophil count 1.0 × 109/L (prior growth factor support is
permitted);
c) platelet count for D-Rd, D-Kd, and D-VRd cohorts: >75 × 109/L for subjects in
whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet
count >50 × 109/L (transfusions are not permitted within 7 days of testing to
achieve this minimum platelet count); for the D-VMP cohort: platelet count


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70 x 109/L for subjects in whom <50% of bone marrow nucleated cells are
plasma cells; otherwise platelet count >50 × 109/L (transfusions are not
permitted within 7 days of testing to achieve this minimum platelet count;
d) aspartate aminotransferase 2.5 × upper limit of normal (ULN);
e) alanine aminotransferase 2.5 × ULN;
f) For the D-Rd cohort: total bilirubin 2.0 × ULN; except in subjects with
congenital bilirubinemia, such as Gilbert syndrome (in which case direct
bilirubin 2.0 × ULN is required); for the, D-Kd, D-VMP, and D-VRd cohorts:
total bilirubin 1.5 × ULN; except in subjects with congenital bilirubinemia,
such as Gilbert syndrome (in which case direct bilirubin 1.5 × ULN is
required);
g) estimated creatinine clearance mL/min (D-VMP cohort) or 30
mL/min (for D-VRd and D-Rd cohorts); or ≥20 mL/min (D-Kd
cohort) (refer to Attachment 3)
h) corrected serum calcium 13.5 mg/dL (3.4 mmol/L) or free ionized calcium
6.5 mg/dL (1.6 mmol/L) (refer to Attachment 4)
7.
7.1
Criterion modified per Amendment 1 and Amendment 2:
D-VRd and D-Rd cohorts: A woman of childbearing potential must have 2 negative
serum or urine pregnancy tests at screening, the first within 10 to 14 days prior to dosing
and the second within 24 hours prior to dosing.
D-VMP and D-Kd cohorts: A woman of childbearing potential must have a negative
serum or urine pregnancy test at screening within 14 days prior to dosing.
8. 
8.1. 
8.2. 
Criterion modified per Amendment 1:
Criterion modified per Amendment 4:
Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse, or to use 2 methods of reliable birth control
simultaneously during the Treatment Period, during any dose interruptions, and for
3 months after the last dose of any component of study treatment. This birth control
method must include 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 with confirmation of procedure), and one
additional effective contraceptive method (male latex or synthetic condom, diaphragm,
or cervical cap). Contraception must begin 4 weeks prior to dosing and continue for
3 months after discontinuation of study treatment. Reliable contraception is indicated
even where there has been a history of infertility, unless due to hysterectomy or bilateral
oophorectomy (See Attachment 13 for further details).
Male subjects who are sexually active with women of childbearing potential must


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always use a latex or synthetic condom during the study and for 3 months after
discontinuing study treatment (even after a successful vasectomy).
9. 
9.1. 
Criterion modified per Amendment 4:
During the study, during dose interruptions, and for 3 months after receiving the last
dose of any component of the study treatment, a female subject must agree not to donate
eggs (ova, oocytes) and male subjects of reproductive potential must not donate semen
or sperm during the study, during dose interruptions, or for 3 months after the last dose
of any study drug.
10. 
Each subject (or their legally acceptable representative) must sign an informed consent
form (ICF) indicating that he or she understands the purpose of and procedures required
for the study and are willing to participate in the study. Subjects must be willing and
able to adhere to the prohibitions and restrictions specified in this protocol.
4.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study:
1. 
Criterion modified per Amendment 1 and Amendment 2:
1.1 
Prior or concurrent exposure to any of the following:
 
Daratumumab or other anti-CD38 therapies
 
Approved or investigational treatments for MM (including but not limited to
conventional chemotherapies, IMiDs, or PIs) within 2 weeks of Cycle 1 Day 1
 
Maximum of 40 mg dexamethasone (or equivalent) daily for a maximum of 4 days
up to 21 days prior to the 1st dose
 
Investigational drug (including investigational vaccines) or an invasive
investigational medical device within 4 weeks or 5 half-lives (whichever is longer)
before Cycle 1 Day 1, or is currently enrolled in another investigational study
 
ASCT within 12 weeks before the date of administration of study treatment, or
allogeneic stem cell transplant (regardless of timing) for the D-Rd and D-Kd
cohorts
 
For D-Rd cohort, only: Refractory to lenalidomide, (ie, subjects who had
progression of disease while receiving lenalidomide therapy or within 60 days of
ending lenalidomide therapy) or who are intolerant to lenalidomide
(ie, discontinued due to any drug-related adverse event) while on lenalidomide
treatment are not eligible for the lenalidomide-containing cohorts
 
For D-Kd cohort, only: Subject has previously received carfilzomib


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2. 
Criterion modified per Amendment 1:
2.1 
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.
3. 
Exhibits clinical signs of meningeal involvement of MM.
4. 
4.1 
Criterion modified per Amendment 2:
Either of the following:
 
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 subjects suspected of having COPD and subjects must be excluded if
FEV1 is <50% of predicted normal
 
Moderate or severe persistent asthma, or a history of asthma within the last 2 years,
or currently has uncontrolled asthma of any classification (refer to Attachment 6).
(Subjects who currently have controlled intermittent asthma or controlled mild
persistent asthma are allowed to participate in the study).
For D-Kd cohort: Known infiltrative pulmonary disease or known pulmonary
hypertension.
5. 
Criterion modified per Amendment 1.
5.1. 
5.2. 
5.3. 
Criterion modified per Amendment 3.
Criterion modified per Amendment 4:
Any of the following:
 
Known to be seropositive for human immunodeficiency virus (HIV);
 
Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg
negative with antibodies to total hepatitis B core antigen [Anti-HBc] with or
without the presence of hepatitis B surface antibody [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:
Subjects 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.
6. 
Criterion modified per Amendment 1:


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6.1 
Known to be seropositive for hepatitis C (Anti-HCV antibody positive or HCV-RNA
quantitation positive), except in the setting of a sustained virologic response [SVR],
defined as aviremia at least 12 weeks after completion of antiviral therapy).
7. 
Concurrent medical or psychiatric condition or disease (eg, active systemic infection,
uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to
interfere with the study procedures or results, or that in the opinion of the investigator,
would constitute a hazard for participating in this study.
8. 
Criterion modified per Amendment 1 and Amendment 2:
8.1 
Clinically significant cardiac disease, including:
 
myocardial infarction within 6 months before Cycle 1 Day  1, or an unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable
angina, congestive heart failure, New York Heart Association Class III-IV) (refer to
Attachment 7);
 
uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG)
abnormalities; or screening 12-lead ECG showing a baseline QT interval as
corrected by Fridericia’s formula (QTc) >470 msec.
 
For D-Kd cohort only:
 
Transthoracic echocardiogram (TTE) showing left ventricular ejection fraction
(LVEF) <40%;
 
Uncontrolled hypertension, defined as an average systolic blood pressure
>159 mmHg or diastolic >99 mmHg despite optimal treatment
9. 
Criterion modified per Amendment 2
9.1 
Allergies, hypersensitivity, or intolerance to any of the study drugs, hyaluronidase,
monoclonal antibodies, human proteins, or their excipients (refer to daratumumab
Investigator’s Brochure and rHuPH20 Investigator’s Brochure) or known sensitivity to
mammalian-derived products.
For D-Kd cohort only: allergy, hypersensitivity, or intolerance to Captisol.
10. 
Plasma cell leukemia, Waldenström’s macroglobulinemia, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
changes), or amyloidosis.
11. 
Unable to comply with the study protocol (eg, because of alcoholism, drug dependency,
or psychological disorder) or the subject has any condition for which, in the opinion of
the investigator, participation would not be in the best interest of the subject
(eg, compromise their well-being) or that could prevent, limit, or confound the protocol-
specified assessments.


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12. 
Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or
within 3 months after the last dose of any study drug.
13. 
Plans to father a child while enrolled in this study or within 3 months after the last dose
of any study drug.
14. 
Major surgery within 2 weeks before administration of study treatment, or has not fully
recovered from surgery, or has surgery planned during the time the subject is expected
to participate in the study or within 2 weeks after the last dose of study drug
administration. Kyphoplasty or vertebroplasty are not considered major surgery. Note:
Subjects 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 subject in the study.
15. 
Plasmapheresis within 28 days before Cycle 1 Day 1
16. 
For D-VRd and D-VMP cohorts: Received a strong CYP3A4 inducer within 5 half-lives
prior to randomization (Indiana University 201612) (Attachment 12).
For D-VMP arm: neuropathy or neuropathic pain Grade 2 or higher, as defined by the
National Cancer Institute-Common Terminology Criteria for Adverse Events
(NCI-CTCAE) Version 4.03.
17. 
Criterion added per Amendment 2:
17.1 
For D-VMP cohort: Neuropathy or neuropathic pain Grade 2 or higher, as defined by
the NCI-CTCAE Version 4.03.
For D-Kd cohort: Neuropathy or neuropathic pain Grade 3 or higher, as defined by the
NCI-CTCAE Version 4.03.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a subject's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study drug is given such
that he or she no longer meets all eligibility criteria, then the subject should be excluded from
participation in the study. Section 17.4, Source Documentation, describes the required
documentation to support meeting the enrollment criteria.
Subjects who fail to meet the inclusion and exclusion criteria (ie, screen failures) may be
rescreened once if their condition changes. Rescreening must be discussed with and approved by
the sponsor on a case-by-case basis. Subjects who are determined to be eligible for the study
after rescreening must sign a new ICF and then will be assigned a new screening number.


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4.3. 
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and
restrictions during the course of the study to be eligible for participation:
1. 
Refer to Section 8 Prestudy and Concomitant Therapy for details regarding prohibited
and restricted therapy during the study.
2. 
Typically, IV contrast is NOT used in computed tomography (CT) scanning of subjects
with secretory MM because of the risk to the kidney. If administration of IV contrast is
necessary, then adequate precautions including hydration are indicated.
3. 
Subjects must not donate blood during therapy, during dose interruptions, and for at
least 4 weeks following discontinuation of lenalidomide.
4. 
Subjects in the D-VRd and D-Rd cohorts: Due to the embryo-fetal risk of lenalidomide,
all subjects must adhere to the local lenalidomide Risk Evaluation and Mitigation
Strategy (REMS) program (when lenalidomide is supplied locally), or the Lenalidomide
Global Pregnancy Prevention Plan (when lenalidomide is supplied centrally and no local
lenalidomide REMS program exists). (See Attachment 14 for further details).
5. 
In the D-VRd and D-Rd cohorts: During the Treatment Phase, pregnancy tests are
required weekly during Cycle 1 and then monthly in subsequent cycles in women with
regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. A
pregnancy test is also required at the End-of-Treatment Visit. Additional pregnancy tests
may be required, as specified in the local lenalidomide REMS program (where
lenalidomide is supplied locally) or the Lenalidomide Global Pregnancy Prevention Plan
(where lenalidomide is supplied centrally and no local lenalidomide REMS program
exists).
6. 
In the D-VMP and D-Kd cohorts: During the Treatment Phase, pregnancy tests will be
administered as clinically indicated.


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5. 
TREATMENT ALLOCATION AND BLINDING
Each subject will be assigned into the treatment group for which he or she is eligible and will
receive a unique subject number.
6. 
DOSAGE AND ADMINISTRATION
Detailed information on the composition of the study drug is in the Site Investigational Product
and Procedures Manual (SIPPM), and the Investigational Product Preparation Instructions (IPPI).
6.1. 
Treatment Schedule and Administration for each Cohort
6.1.1. 
D-VRd Cohort
The Treatment Phase will consist of 4 cycles of approximately 21 days. Subjects will receive
pre-and 
post-administration 
medications 
for 
prevention 
of IRRs 
(Section 6.4.1.1,
Pre-administration Medication). Subjects in the D-VRd cohort will continue to receive the study
drugs for a maximum of 4 cycles (see Table 10), if disease progression, unacceptable toxicity, or
other reasons listed in Section 10.2 (Discontinuation of Study Treatment/Withdrawal from the
Study) occur then the subject will discontinue treatment before the 4 cycles are completed.
Table 10: 
Treatment Schedule and Dosing (D-VRd Cohort)
Drug, Route of administration 
Dose, Cycles 1 3 (21 day cycles) 
Dose, Cycle 4 (21 day cycles)
Daratumumab, SC 
1800 mg on Days 1, 8, 15 
1800 mg on Day 1
Bortezomib, SC  
1.3 mg/m2 on Days 1, 4, 8, 11 
1.3 mg/m2 on Days 1, 4, 8, 11
Lenalidomide, PO  
25 mg on Days 1 14 
25 mg on Days 1 14
Dexamethasone, IV or PO  
20 mg on Days 1, 2, 8, 9, 15, 16 
20 mg on Days 1, 2, 8, 9, 15, 16
D VRd=Dara SC, bortezomib, lenalidomide, and dexamethasone; PO=orally, IV=intravenous, SC=subcutaneous
Lenalidomide will be administered to subjects in the D-VRd cohort at a dose of 25 mg orally
(PO) daily on Days 1 through 14 of each 21-day cycle for subjects with creatinine clearance
>60 mL/min. For subjects with creatinine clearance between 30 and 60 mL/min, the dose is
10 mg every 24 hours. Creatinine clearance should be recalculated at the beginning of every
cycle. Once the creatinine clearance is >60 mL/min during the course of the treatment,
lenalidomide can be increased to 25 mg. On daratumumab treatment days, lenalidomide should
be administered either prior to or, preferably, at the same time as the pre-administration
medications. If a daily lenalidomide dose is missed, it may be taken if <12 hours have elapsed
since the time that it should have been taken. If the next dose is scheduled to be taken within 12
hours, the missed lenalidomide dose should be skipped. Lenalidomide should be taken as a single
dose at the same time daily. Lenalidomide can be taken with or without food. Breaking or
dividing the lenalidomide capsule is strongly discouraged. Home administration of lenalidomide
should be documented by the subject in a diary (provided by the site).
Bortezomib must be administered after the daratumumab administration. Bortezomib dosing may
be delayed up to 48 hours, however subsequent doses must be adjusted to account for the delay.
Note that there should be at least 72 hours between doses of bortezomib. Skipped doses of
bortezomib will not be made up later in the cycle. Individual doses within a cycle have a ±1 day
window. For subjects with unacceptable toxicity at the local injection site of bortezomib despite
dose modifications or change in injection concentration, bortezomib can be administered


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intravenously as a 3 to 5 sec bolus injection. Please refer to local prescribing information for
further details on either SC or IV administration.
Dexamethasone will be administered at 20 mg weekly for subjects 75 years of age or
underweight (body mass index [BMI] <18.5). If dexamethasone is given on the daratumumab
dosing day, then this will serve as the pre-medication and no additional dexamethasone
administration will be needed. On daratumumab dosing days, the pre-administration medication
replaces the daily dose dexamethasone. Home administration of lenalidomide should be
documented by the subject in a diary (provided by the site).
6.1.2. 
D-VMP Cohort
The Treatment Phase will consist of 9 cycles of the VMP regimen (1 Cycle  6 weeks) with
daratumumab. Thereafter, subjects will receive daratumumab monotherapy in 28-day cycles and
will continue to receive study drugs until disease progression, unacceptable toxicity, or other
reasons as listed in Section 10.2 (Discontinuation of Study Treatment/Withdrawal from the
Study) (Table 11). Subjects will receive pre- and post-administration medications for prevention
of IRRs (Section 6.4.1.1).
Table 11: 
Treatment Schedule and Dosing (D-VMP Cohort)
Drug, Route of 
Administration  
Dose, Cycle 1 
(42 day cycles) 
Dose, Cycles 2 9 
(42 day cycles) 
Dose, Cycles 10+
(28 day cycles)
Daratumumab, SC  
1800 mg on Days 1, 8, 15, 22, 29, 36 
1800 mg on Days 1, 22 
1800 mg on Day 1
Bortezomib, SC 
1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 
32 
1.3 mg/m2 on Days 1, 8, 22,
29
Melphalan, PO  
9 mg/m2 on Days 1 4 
9 mg/m2 on Days 1 4
Prednisone, PO  
60 mg/ m2 on Days 1 4 
60 mg/ m2 on Days 1 4
D VMP=Dara SC, bortezomib, melphalan, and prednisone; PO=orally; SC=subcutaneous
Breaking or dividing melphalan or prednisone tablets is strongly discouraged; the total calculated
dose should be rounded to the closest dose that can be administered using the tablets available.
Prednisone tablets are to be taken with or immediately after a meal or snack, preferably in the
morning. Home administration of melphalan and prednisone should be documented by the
subject in a diary (provided by the site).
Prednisone will not be given on days that dexamethasone is given as pre-medication. Instead,
dexamethasone will serve as the treatment dose of corticosteroid for Day 1 of Cycles 1 through 9
as well as the required pre-medication prior to daratumumab administration. Prednisolone may
be substituted for prednisone in countries where prednisone is not available.
In exceptional circumstances, a subject may not tolerate sudden corticosteroid withdrawal at the
end of 4 days of prednisone treatment. In such an instance, a tapering regimen of prednisone
(30 mg/m2 on Day 5, 20 mg/m2 on Day 6, 10 mg/m2 on Day 7, then stop) can be prescribed to
the subject after sponsor review. Under no circumstances will melphalan administration be
prolonged beyond 4 days.
Bortezomib must be administered after the daratumumab administration. Bortezomib dosing may
be delayed up to 48 hours, however subsequent doses must be adjusted to account for the delay.
Note that there should be at least 72 hours between doses of bortezomib. Skipped doses of


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bortezomib will not be made up later in the cycle. Individual doses within a cycle have a ±1 day
window. For subjects with unacceptable toxicity at the local injection site of bortezomib despite
dose modifications or change in injection  concentration, bortezomib can be administered
intravenously as a 3 to 5 sec bolus injection. Please refer to local prescribing information for
further details on either SC or IV administration.
6.1.3. 
D-Rd Cohort
The Treatment Phase will consist of cycles of approximately 28 days and will continue to receive
study drugs until disease progression, unacceptable toxicity, or other reasons as listed in
Section 10.2 (Discontinuation of Study Treatment/Withdrawal from the Study) (Table 12).
Subjects will receive pre- and post-administration medications for prevention of IRRs
(Section 6.4.1.1).
Table 12: 
Treatment Schedule and Dosing (D-Rd Cohort)
Drug, Route of 
administration  
Cycles 1 & 2 
(28 day cycles) 
Cycles 36 
(28 day cycles) 
Cycles 7+
(28 day cycles)
Daratumumab, SC  
1800 mg on Days 1, 8, 15, 22 
1800 mg on Days 1 and 15 
1800 mg on Day 1
Lenalidomide, PO  
25 mg on Days 1 to 21 
25 mg on Days 1 to 21 
25 mg on Days 1 to 21
Dexamethasone, IV or PO 
40 mg on weekly* 
40 mg on Days 1*, 8, 15*, 22 
40 mg on Days 1*, 8, 15, 22
D Rd=Dara SC, lenalidomide, and dexamethasone; PO=orally, IV=intravenous, SC=subcutaneous
* During weeks when the subject receives an administration of daratumumab, half the dexamethasone dose will be given on the
day of administration (20 mg) and half the dose will be given via PO administration the day after the administration (20 mg).
Subjects older than 75 years or underweight who may be taking the 20 mg dose should receive the entire 20 mg prior to
daratumumab administration only.
Lenalidomide will be administered to subjects in the D-Rd cohort at a dose of 25 mg PO daily on
Days 1 through 21 of each 28-day cycle for subjects with creatinine clearance >60 mL/min. For
subjects with creatinine clearance between 30 and 60 mL/min, the dose is 10 mg every 24 hours.
Creatinine clearance should be recalculated at the beginning of every cycle. Once the creatinine
clearance is >60 mL/min during the course of the treatment, lenalidomide can be increased to
25 mg.
Dexamethasone (or equivalent in accordance with local standards; see Attachment 5 for
conversion table) will be administered at a total dose of 40 mg weekly. For subjects 75 years or
older or underweight (BMI <18.5), the dexamethasone dose may be administered at a dose of
20 mg weekly. During weeks when the subject receives an administration of daratumumab, half
the dexamethasone dose will be given on the day of administration via IV or PO administration
before the administration and half the dose will be given via PO administration the day after the
administration. This is applicable only for subjects taking the full 40-mg dose. Subjects 75 years
or older or underweight who may be taking the 20-mg dose should receive the entire 20 mg prior
to daratumumab administration. During weeks when no daratumumab administration is
administered, dexamethasone will be administered at a dose of 40 mg/week PO (or 20 mg/week
PO for subjects ≥75 years or BMI <18.5).
6.1.4. 
D-Kd Cohort
The Treatment Phase will consist of cycles of approximately 28 days and subjects will continue
to receive study drugs (Table 13) until disease progression, unacceptable toxicity, or other


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reasons as listed in Section 10.2 (Discontinuation of Study Treatment/Withdrawal from the
Study). Subjects will receive pre- and post-administration medications for prevention of IRRs
(Section 6.4.1.1 Pre-administration Medication).
Table 13: 
Treatment Schedule and Dosing (D-Kd Cohort)
Drug, Route of 
administration  
Cycle 1 
(28 day cycles) 
Cycle 2 
(28 day cycles) 
Cycles 36 
(28 day cycles) 
Cycles 7+
(28 day cycles)
Daratumumab, SC  
1800 mg on Days 1, 8, 
15, 22 
1800 mg on Days 1, 8, 
15, 22 
1800 mg on Days 1 
and 15
1800 mg on Day 1
Carfilzomib, IV  
20 mg/m2 C1D1, only; 
70 mg/m2 D8, 15
70 mg/m2 D1, 8, 15 
70 mg/m2 D1, 8, 15 
70 mg/m2 D1, 8, 15
Dexamethasone, IV or 
PO 
40 mg on weeklya 
40 mg on weeklya 
40 mg on Days 1a, 8, 
15a, 22 
40 mg on Days 1a, 8,
15, 22
(Day 22 Cycles 7 9,
only)
D Kd=Dara SC, carfilzomib, and dexamethasone; PO=orally, IV=intravenous, SC=subcutaneous
a 
During weeks when the subject receives an administration of daratumumab, half the dexamethasone dose should
be given on the day of administration (20 mg) and half the dose should be given via PO administration the day
after the administration (20 mg). Subjects 75 years or older or underweight (BMI <18.5) who may be taking the
20-mg dose should receive the entire 20 mg prior to daratumumab administration only.
Carfilzomib will be administered to subjects in the D-Kd cohort at a dose of 20 mg/m2 as a
30-minute IV infusion on Cycle 1 Day 1. If a dose of 20 mg/m2 is tolerated, carfilzomib will be
administered on Cycle 1 Day 8, at a dose of 70 mg/m2 as a 30-minute IV infusion. Please refer to
the United States Package Insert (USPI 201217) or Summary of Medicinal Product
Characteristics (SmPC 201818) for administration, precautions and reconstitution/preparation
guidelines. Subjects should receive carfilzomib followed by daratumumab SC when both are
given on the same day. When carfilzomib is given first, the dexamethasone dose, on carfilzomib
and daratumumab SC dosing days will be given prior to administration of carfilzomib.
Subjects will receive pre-hydration prior to each carfilzomib infusion during Cycle 1.
Pre-hydration will consist of oral fluids (30 mL per kg at least 48 hours before Cycle 1 Day 1)
and IV fluids 250-500 mL normal saline or other appropriate IV fluid prior to each dose of
carfilzomib in Cycle 1. Thereafter, carfilzomib pre-hydration should only be administered if the
subject’s condition and/or risk factors require it. Monitor subjects for evidence of volume
overload and adjust hydration as needed based on subjects’ risk including for cardiac failure.
The total volume of pre-hydration and the reason for pre-hydration after Cycle 1 will be
recorded.
Dexamethasone (or equivalent in accordance with local standards; see Attachment 5 for
conversion table) will be administered at a total dose of 40 mg weekly. During weeks when the
subject receives an administration of daratumumab, half the dexamethasone dose should be
given on the day of administration via IV or PO before the administration and half the dose
should be given via PO the day after the administration. For subjects 75 years or older or
underweight (BMI <18.5), the dexamethasone dose may be administered at a dose of 20 mg
weekly. Subjects 75 years or older or underweight who may be taking the 20-mg dose should
receive the entire 20-mg dose prior to daratumumab administration. During weeks when the
subject receives an administration of carfilzomib alone, 40 mg dexamethasone will be given on
the day of administration via IV or PO before the carfilzomib administration. This is applicable
only for subjects taking the full 40-mg dose. Subjects aged 75 years or older or underweight who


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may be taking the 20-mg dose should receive the entire 20-mg dose prior to carfilzomib
administration. During weeks when no daratumumab or carfilzomib is administration,
dexamethasone will be administered at a dose of 40 mg/week PO (or 20 mg/week PO for
subjects ≥75 years of age or BMI <18.5).
6.2. 
Study Drug Preparation
6.2.1. 
Dara SC Preparation
Dara SC is a fixed combination drug product containing rHuPH20 drug substance (2000 U/mL)
and daratumumab drug substance (120 mg/mL) in a single vial. Detailed instructions for
preparation of SC daratumumab will be supplied in the SIPPM and IPPI.
6.3. 
Study Drug Delivery
6.3.1. 
Dara SC Delivery
Dara SC will be delivered by SC injection given through a syringe and needle by a manual push
over approximately 3 to 5 minutes. Each dose should be administered at alternating locations on
the abdomen. The volume of the SC solution will be 15 mL for the 1800 mg dose. Refer to the
IPPI for additional guidance on SC administration of Dara SC. All subjects 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 consecutive injections. Reasons for continued observation on subsequent
daratumumab injections may include but are not limited to the following:
 
subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or
subjects with COPD who have an FEV1 <80% at screening or developed FEV1 <80%
during the study without any medical history),
 
subjects with an IRR occurring with the first injection of study drug,
 
subject with a decreased condition on day of dosing compared to prior dosing day.
The dose of daratumumab will remain constant throughout the study.
Subjects will receive pre-administration and post-administration medications as detailed in
Section 6.4.1 (Prevention of Infusion-related Reactions). All subjects should have vital signs
monitored as specified in the Time and Events Schedule (Table 1- Table 9). If a subject
experiences a significant medical event, then the investigator should assess whether the subject
should stay overnight for observation. If the subject has not experienced a significant medical
event but is hospitalized overnight only for observation, then the hospitalization should not be
reported as a serious adverse event.
6.4. 
Guidelines for Prevention and Management of Infusion-related Reactions
6.4.1. 
Prevention of Infusion-related Reactions due to Daratumumab
Injections
6.4.1.1. 
Pre-administration Medication


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In an effort to prevent IRRs, all subjects will receive the following medications within  1 to 3
hours prior to each study drug administration:
 
An antipyretic: paracetamol (acetaminophen) 650 to 1000 mg orally (PO)
 
An antihistamine: diphenhydramine 25 to 50 mg PO, or equivalent. Avoid IV use of
promethazine (see Attachment 8 for a list of antihistamines that may be used).
 
After Cycle 6, if a participant has not developed an infusion-related reaction and is
intolerant to antihistamines, modifications are acceptable as per investigator discretion.
 
Administer 20 mg dexamethasone or equivalent prior to every administration.
 
When dexamethasone is the background regimen specific corticosteroid, the
dexamethasone treatment dose (or its part) will instead serve as pre-medication on
daratumumab administration days.
 
Dexamethasone is given orally or intravenously prior to the first daratumumab
administration and oral administration may be considered prior to subsequent
administration.
If necessary, all PO pre-administration medications may be administered outside of the clinic on
the day of the injection, provided they are taken within 3 hours before the injection.
Pre-dose administration of a leukotriene inhibitor (montelukast 10 mg PO or equivalent) is
optional on Cycle 1 Day 1 and can be administered up to 24 hours before the injection according
to investigator discretion.
D-Kd cohort: When carfilzomib is given first, pre-administration medications as noted above
will be given prior to the carfilzomib on the daratumumab dosing days. If any delay in
administration of daratumumab following the carfilzomib, the pre-administration medications
may be repeated prior to daratumumab administration. On carfilzomib only dosing days, the
dexamethasone should be given prior to the carfilzomib infusion.
6.4.1.2. 
Post-administration Medication
For subjects at higher risk of respiratory complications (eg, subjects with mild asthma or subjects
with COPD who have an FEV1 <80% at screening or developing FEV1 <80% during the study
without any medical history), the following post-administration medications should be
considered:
 
Antihistamine (diphenhydramine or equivalent)
 
Leukotriene inhibitor (montelukast or equivalent)
 
A short-acting β2 adrenergic receptor agonist such as salbutamol aerosol
 
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or
salbutamol ± inhaled corticosteroids for subjects with COPD)


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In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after
daratumumab administration. If subjects are hospitalized, then an improvement in FEV1 should
be documented prior to discharge. If these subjects are not hospitalized, then a follow-up
telephone call should be made to monitor their condition within 48 hours after all daratumumab
administrations. If the subject has not experienced a significant medical event but is hospitalized
overnight only for observation, then the hospitalization should not be reported as a serious
adverse event. Investigators may prescribe bronchodilators, H1-antihistamines, and
corticosteroids that are deemed necessary to provide adequate supportive care in the event a
bronchospasm occurs after subjects are released from the hospital/clinic. If an at-risk subject
experiences no major IRRs, then these post-administration medications may be waived after
4 doses at the investigator’s discretion. Any post-administration medication will be administered
after the administration has completed.
6.4.2. 
Management of Infusion-related Reactions
Local Injection-site Reactions
In Study MMY1004, SC administration of daratumumab in abdominal SC tissue was associated
with local injection-site reactions such as induration and erythema in some subjects. The
reactions usually resolved within 60 minutes. Local injection-site reactions should be managed
according to institutional standards.
Infusion-related Reactions
Subjects should be observed carefully during daratumumab administration. Attention to staffing
should be considered when multiple participants will be dosed at the same time. Trained study
staff at the clinic should be prepared to intervene in case of any IRRs, and resources necessary
for resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available.
If an IRR develops, then daratumumab administration should be temporarily interrupted. Please
see the IPPI for further details. Subjects who experience adverse events during daratumumab
administration must be treated for their symptoms. Subjects should be treated with
acetaminophen, antihistamine, or corticosteroids, as needed. Intravenous saline may be indicated.
For bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen,
corticosteroids, or bronchodilators. For hypotension, subjects may require vasopressors. In the
event of a life-threatening IRR (which may include pulmonary or cardiac events) or anaphylactic
reaction, daratumumab should be discontinued and no additional daratumumab should be
administered to the subject.
Infusion-related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1 or 2 IRR adverse event to be related to administration of
the study drug, then the daratumumab administration should be paused. When the subject's
condition is stable, daratumumab administration may be re-started at the investigator's discretion.
For instructions for re-starting administration refer to the IPPI.


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If the subject 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 subject must be withdrawn from daratumumab treatment.
Infusion-related Reactions of Grade 3 or Higher
For IRR adverse events (other than laryngeal edema or bronchospasm) that are Grade 3, the
daratumumab administration must be stopped and the subject must be observed carefully until
resolution of the adverse event or until the intensity of the event decreases to Grade 1, at which
point the daratumumab administration may be re-started at the investigator’s discretion. If the
intensity of the adverse event returns to Grade 3 after re-start of the daratumumab administration,
then the subject must be withdrawn from daratumumab treatment. For IRR adverse events that
are Grade 4, the daratumumab administration must be stopped and the subject withdrawn from
daratumumab 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 daratumumab administration,
the daratumumab treatment must be discontinued.
6.5. 
Dose Delays and Dose Modification of Daratumumab
Dose modification of daratumumab is not permitted. Day 1 of a cycle should never be skipped,
however, if a Day 1 dose of any cycle is missed it should be considered a cycle delay. Dose
delay is the primary method for managing daratumumab-related toxicities.
6.5.1. 
Daratumumab Toxicity Management
On the first day of each new treatment cycle and before each daratumumab dose, the subject 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. Dose
modifications or delays will be made based on the toxicity experienced during the previous cycle
of therapy or newly encountered on Day 1 of a cycle.
The study treatment must be held if any of the following criteria below are met, to allow for
recovery from toxicity, regardless of relationship to daratumumab, bortezomib, lenalidomide,
melphalan, or carfilzomib.
 
Grade 4 hematologic toxicity, except for Grade 4 lymphopenia
 
Grade 3 thrombocytopenia with bleeding
 
Febrile neutropenia
 
Neutropenia with infection, of any grade
 
Grade 3 or higher non-hematologic toxicities, with the following exceptions:
 
Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment within 7 days


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Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
 
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
 
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
Administration of daratumumab may be re-started upon recovery from toxicity to Grade 2 or
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be
fully recovered.
For all daratumumab doses in a treatment cycle except the first dose, if daratumumab
administration does not commence within the pre-specified window for each cohort (Table 14 to
Table 16) of the scheduled administration date, 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.
The minimal time interval between daratumumab doses should be no less than 4 days.
Table 14: 
Daratumumab-Related Toxicity Management (D-VRd Cohort)
Cycles 
Frequency  
Dose Held  
Dosing Re start
1 to 3 
Weekly (q1wk) 
>3 days 
next planned weekly dosing date
D VRd=Dara SC, bortezomib, lenalidomide, and dexamethasone
Table 15: 
Daratumumab-Related Toxicity Management (D-VMP Cohort)
Cycles 
Frequency  
Dose Held  
Dosing Re start
1 
Weekly (q1wk) 
>3 days 
next planned weekly dosing date
2 to 9 
Every 3 weeks (q3wks) 
>7 days 
next planned every third week dosing date
Post VMP  
Every 4 weeks (q4wks) 
>14 days 
next planned every fourth week dosing date
D VMP=Dara SC, bortezomib, melphalan, and prednisone
Table 16: 
Daratumumab-Related Toxicity Management (D-Rd Cohort or D-Kd Cohort)
Cycles 
Frequency  
Dose Held  
Dosing Re start
1 and 2 
Weekly (q1wk) 
>3 days 
next planned weekly dosing date
3 to 6 
Biweekly (q2wks) 
>7 days 
next planned biweekly dosing date
7+ 
Every 4 weeks (q4wks) 
>14 days 
next planned every 4 weeks dosing date
D Rd=Dara SC, lenalidomide, and dexamethasone
D Kd=Dara SC, carfilzomib, and dexamethasone
For the D-VRd cohort: cycles may be delayed up to 4 weeks (Cycle 1 to Cycle 4). If Day 1 of a
cycle is delayed, Day 1 of subsequent cycles should be adjusted accordingly to maintain the
21-day cycle duration.
For the D-VMP cohort: if the daratumumab administration cannot be given on Day 1 of a cycle,
the start of the cycle should be delayed. Day 1 of a cycle should not be skipped. A maximum
delay of 4 weeks is allowed in Cycle 1 to Cycle 9. Any adverse event deemed to be related to
daratumumab that requires a dose hold of more than 4 weeks will result in permanent
discontinuation of daratumumab. After Cycle 9, any adverse event deemed to be related to
daratumumab that requires a dose hold of 2 consecutive planned doses will result in permanent
discontinuation of daratumumab.


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For the D-Rd or D-Kd cohorts: cycles may be delayed up to 4 weeks (Cycle 1 to Cycle 6) or up
to 6 weeks (Cycle 7 and beyond). If Day 1 of a cycle is delayed, Day 1 of subsequent cycles
should be adjusted accordingly to maintain the 28-day cycle duration.
However, for all cohorts, if a within-cycle dose is delayed, then the dates of the subsequent
within-cycle doses should not be adjusted. If a dose delay occurs, then PK and pharmacodynamic
assessments should be performed on the actual administration day of daratumumab, not on the
original scheduled administration day.
6.5.2. 
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 14 to Table 16) 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. If
one of the components of the standard myeloma therapy is discontinued due to toxicity, the
remaining components should continue as long as no dose interruption rules have been met.
Infusion-related reactions may occur upon re-initiation of daratumumab after a prolonged delay
in treatment. Investigators should consider the applicable infusion reaction guidance provided in
Section 6.4.2.
For the D-VRd, D-Kd, and D-Rd cohorts:
 
Subjects whose dose was delayed for more than 4 weeks (D-VRd cohort: Cycle 1 to
Cycle 4; D-Rd and D-Kd cohorts: Cycle 1 to Cycle 6) or more than 6 weeks (Cycle 7 and
beyond, D-Rd and D-Kd cohorts only) should have study treatment discontinued, unless,
upon consultation with the sponsor and the review of safety and efficacy, continuation is
agreed upon.
 
If a dose is interrupted for more than 28 days for any subject in the D-VRd, D-Kd, and D-Rd
cohorts due to unresolved direct daratumumab toxicity, then daratumumab must be
discontinued.
 
If a dose is interrupted for more than 14 days and less than 21 days for any subject in the
D-VRd cohort and more than 21 days and less than 28 days for any subject in the D-Rd and
D-Kd cohorts due to unresolved direct daratumumab toxicity, daratumumab may be
discontinued. Continued daratumumab treatment requires review by the sponsor.
 
Dose interruptions of more than 21 days (D-VRd cohort) or 28 days (D-Rd and D-Kd
cohorts) for other reasons, such as non-compliance, 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 drug administration, not on the original scheduled administration
day.
For the D-VMP cohort:
 
Subjects whose dose was delayed for more than 4 weeks (Cycle 1 to Cycle 9) or
2 consecutive planned doses (after Cycle 9) should have study drug discontinued, unless,
upon consultation with the sponsor and the review of safety and efficacy, continuation is
agreed upon.


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6.6. 
Bortezomib, Melphalan, Lenalidomide, Carfilzomib, and Prednisone
The sponsor will provide bortezomib and may provide lenalidomide and carfilzomib to the sites,
if the site, for example, cannot source the drug. Sites will use commercially available melphalan,
and prednisone for administration in this study unless otherwise communicated by the study
team to the site. Before administering any drug, refer to the currently approved package inserts
for complete prescribing information. See Section 6.1 (Treatment Schedule and Administration
for each Cohort) for the dosing and schedule of administration for each cohort.
6.6.1. 
Dose Calculation of Bortezomib, Melphalan, Carfilzomib, and
Prednisone
The amount (in mg) of bortezomib, carfilzomib, melphalan, and prednisone to be administered,
will be determined by body surface area, calculated according to a standard nomogram
(Attachment 9). If weight changes by more than 10% from baseline, the dose for bortezomib,
carfilzomib, melphalan, and prednisone will be recalculated and adjusted accordingly. The total
calculated dose of bortezomib may be rounded to the nearest decimal point (eg, a calculated dose
of 2.47 mg can be rounded to 2.5 mg).
6.7. 
Dose Reductions of Bortezomib, Lenalidomide, Melphalan, Carfilzomib,
Dexamethasone, and Prednisone
Bortezomib will be reduced or discontinued according to the guidelines presented in Table 17. If
several bortezomib doses in a cycle are withheld due to bortezomib-related toxicity (3 doses
during twice weekly administration or 2 doses during weekly administration), bortezomib dose
should be reduced by 1 dose level. For dose modification guidelines regarding allergic reactions
and constitutional toxicities related to VMP refer to Section 6.7.1 (Dose Modification Guidelines
for Bortezomib, Melphalan, and Prednisone-related Toxicities [D-VMP cohort only]). See
Section 6.7.3 (Bortezomib Toxicity) for bortezomib-related hematologic, non-hematologic and
neurologic toxicities.
Table 17: 
Dose Reduction for Bortezomib
Starting Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction
bortezomib 1.3 mg/m2 
bortezomib 1.0 mg/m2 
bortezomib 0.7 mg/m2 
discontinue bortezomib
Dose adjustments of lenalidomide will follow the approved labeling as follows (Table 18) and
should be based on the highest grade of toxicity that is ascribed to lenalidomide.
See Section 6.7.4 (Lenalidomide Toxicity) for lenalidomide toxicities.
Table 18: 
Dose Reduction for Lenalidomide
Starting Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction
25 mg 
15 mg 
10 mg 
5 mg
Melphalan will be reduced or discontinued according to the guidelines presented in Table 19.


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Table 19: 
Dose Reduction for Melphalan
Starting Dose 
First Dose Reduction  
Second Dose Reduction 
Third Dose Reduction
9 mg/m2 QD on Days 1 4 
6.75 mg/m2 QD on Days 1 4 
4.5 mg/m2 QD on Days 1 4 
discontinue melphalan
QD=every day
Carfilzomib will be reduced or discontinued according to the guidelines presented in Table 20. If
a carfilzomib dose is reduced, the reduced dose level will be continued for at least 1 cycle. If the
reduced dose level is well-tolerated, then the dose may be re-escalated to the prior dose at the
investigator’s discretion.
Table 20: 
Dose Reduction for Carfilzomib
Starting Dose 
First Dose Reduction 
Second Dose Reduction Third Dose Reduction Fourth Dose Reduction
70 mg/m2 QD 
56 mg/m2 QD 
45 mg/m2 QD 
36mg/m2 
discontinue carfilzomib
QD=every day
Prednisone will be reduced or discontinued according to the guidelines presented in Table 21.
Table 21: 
Dose Reduction for Prednisone
Starting Dose 
First Dose Reduction  
Second Dose Reduction 
Third Dose Reduction
60 mg/m2 QD on Days 2 4 
45 mg/m2 QD on Days 2 4 
30 mg/m2 QD on Days 2 4 
discontinue prednisone
QD=every day




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PO dose of dexamethasone will be continued as a prior medication before daratumumab
administration. However, subjects may receive low-dose methylprednisolone (20 mg) PO (or
equivalent in accordance with local standards) for the prevention of delayed IRRs as clinically
indicated.
Table 24: 
Dexamethasone Dose Modification
CTCAE Category  
Toxicity  
Dose Change
Gastrointestinal 
Grade 1 2 dyspepsia, gastric, or
duodenal ulcer, gastritis requiring
medical management 
Treat with H2 blockers, sucralfate, or omeprazole. If
symptoms persist despite above measure, decrease
dexamethasone dose by 50%.
≥Grade 3 requiring hospitalization 
or surgery  
Hold dexamethasone until symptoms adequately controlled.
Re start at 50% of current dose along with concurrent therapy
with H2 blockers, sucralfate, or omeprazole. If symptoms
persist despite above measure, discontinue dexamethasone and
do not resume.
Acute pancreatitis 
Discontinue dexamethasone and do not resume
Cardiovascular 
≥Grade 3 edema limiting function 
and unresponsive to therapy or 
anasarca 
Diuretics as needed and decrease dexamethasone dose by 25%.
If edema persists despite above measures, decrease dose to
50% of initial dose. Discontinue dexamethasone and do not
resume if symptoms persist despite 50% reduction
Neurology/ 
Psychiatric 
≥Grade 2 interfering with function 
but not interfering with activities of 
daily living 
Hold dexamethasone until symptoms adequately controlled.
Re start at 50% of current dose. If symptoms persist despite
above measure, discontinue dexamethasone and do not resume.
Musculoskeletal 
≥Grade 2 muscle weakness 
symptomatic and interfering with 
function but not interfering with 
activities of daily living 
Decrease dexamethasone dose by 25%. If weakness persists
despite above measures, decrease dose to 50% of initial dose.
Discontinue dexamethasone and do not resume if symptoms
persist despite 50%.
Metabolic 
≥Grade 3 hyperglycemia 
Treatment with insulin or oral hypoglycemic agents as needed.
If uncontrolled despite above measure, decrease dose by 25%
decrements until levels are satisfactory.
6.7.3. 
Bortezomib Toxicity
6.7.3.1. 
Hematologic Toxicity of Bortezomib
If the subject experiences neutropenia, then the investigator should consider the use of growth
factors in the subject’s management. If the subject’s neutrophil count decreases further, or if the
subject’s platelet count decreases, then dose adjustments should be made according to the
hematologic toxicity recommendations in Table 25. No dose adjustments are required for
anemia, lymphopenia, or leukopenia.
Table 25: 
Dose Modifications for Hematologic Toxicity
Hematologic Toxicity  
Dose Modification
Neutropenia
Grade 3 (without complications) 
No dose reduction, consider treatment with G CSF
Neutropenia associated with fever (38.5ºC): 
Grade 3 or neutropenia Grade 4 
Hold bortezomib until recovery to baseline or Grade 2. Upon recovery, re start
bortezomib at current dose and consider G CSF support. If recurrence is seen,
reduce bortezomib by 1 dose level.
Thrombocytopenia 
Grade 3 (without complications) 
Hold bortezomib until recovery to baseline or ≤Grade 2. Upon recovery, re start
bortezomib at current dose and consider G CSF support. If recurrence is seen,
reduce bortezomib by 1 dose level.
Platelet count <25,000/µL (ie, Grade 4) or 
Grade 3 thrombocytopenia with bleeding 
Hold bortezomib until recovery to baseline or Grade 2. Upon recovery, re start
at 1 dose reduced level.
G-CSF=granulocyte-colony stimulating factor


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6.7.3.2. 
Neurologic Toxicity Bortezomib
If the subject experiences peripheral neuropathy, then dose adjustments should be made
according to the recommendations in Table 26.
Table 26: 
Recommended Dose Modification for Bortezomib-related Neuropathic Pain or Peripheral
Sensory or Motor Neuropathy
Severity of Peripheral Neuropathy Signs and Symptoms* 
Modification of Dose and Regimen
Grade 1 (asymptomatic; loss of deep tendon reflexes or
paresthesia) without pain or loss of function  
No action
Grade 1 with pain or Grade 2 (moderate symptoms; limiting 
instrumental Activities of Daily Living [ADL]**) 
Reduce bortezomib to 1 mg/m2 or
Change bortezomib treatment schedule to 1.3 mg/m2 once a
week
Grade 2 with pain or Grade 3 (severe symptoms; limiting self  
care ADL ***) 
Withhold bortezomib treatment until symptoms of toxicity
have resolved. When toxicity resolves, reinitiate with a
reduced dose of bortezomib at 0.7 mg/m2 once a week
Grade 4 (life threatening consequences; urgent intervention
indicated) 
Discontinue bortezomib
*Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) most recent
version **Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc;
***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not
bedridden.
6.7.3.3. 
Other Grade 3 or 4 Non-Hematologic Toxicities Bortezomib
For other Grade 3 or 4 toxicities judged by the investigator to be related to bortezomib alone,
treatment with bortezomib should be interrupted and re-started at the next lower dose level, or
the administration schedule should be changed to once a week once the toxicity has resolved to
Grade 2 or less.
6.7.4. 
Lenalidomide Toxicity
6.7.4.1. 
Deep Vein Thrombosis and Pulmonary Embolism
Lenalidomide has been associated with an increased incidence of deep vein thrombosis and
pulmonary embolism. Therefore, prophylaxis with aspirin or low molecular weight heparin
(LMWH) is strongly recommended for all subjects. The injection should be handled according to
local practice.
6.7.4.2. 
Thrombocytopenia
If the subject’s platelet count decreases, then dose adjustments should be made according to the
recommendations in Table 27.
Table 27: 
Lenalidomide Dose Adjustment for Thrombocytopenia
Platelet Count 
Recommended Course of Action
 
When count first falls to < 30 109/L
 
When count returns to 30 109/L
 
Interrupt lenalidomide treatment, follow complete blood
count weekly
 
Resume lenalidomide at 15 mg
 
For each subsequent drop in count to < 30 109/L
 
When count returns to 30 109/L
 
Interrupt lenalidomide treatment
 
Resume lenalidomide at the next lower dose level (10 mg
or 5 mg) once daily. Do not decrease dose below 5 mg
once daily


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6.7.4.3. 
Neutropenia
If the subject experiences neutropenia, then the investigator should consider the use of growth
factors in the subject’s management. If the subject’s neutrophil count decreases further, then
dose adjustments should be made according to the recommendations in Table 28.
Table 28: 
Lenalidomide Dose Adjustment for Neutropenia
Neutrophil Count 
Recommended Course of Action
 
When count first falls to < 1.0 109/L 
 
When count returns to 1.0 109/L and neutropenia is 
the only observed toxicity
 
Interrupt lenalidomide treatment, start G CSF treatment,
follow complete blood count weekly
 
Resume lenalidomide at 25 mg once daily
 
When count returns to 1.0 109/L and other toxicity is
observed
 
Resume lenalidomide at 15 mg once daily
 
For each subsequent drop in count to < 1.0 109/L
 
When count returns to 1.0 109/L
 
Interrupt lenalidomide treatment
 
Resume lenalidomide at the next lower dose level (15,
10 mg, or 5 mg) once daily. Do not decrease dose below
5 mg once daily
G CSF= granulocyte colony stimulating factor
6.7.4.4. 
Renal Impairment
Lenalidomide is primarily excreted unchanged by the kidney. Therefore, adjustments to the dose
of lenalidomide are recommended to provide appropriate drug exposure in subjects with
moderate or severe renal impairment. Lenalidomide dose adjustment should be instituted for
subjects with a creatinine clearance of 60 mL/minute or less. The recommended doses for
subjects with MM and renal impairment are shown in Table 29.
Table 29: 
Lenalidomide Dose Adjustment for Renal Impairment
Category  
Renal Functiona 
Dose
Moderate renal impairment 
CrCl 30 60 mL/min  
10 mg every 24 hours
Severe renal impairment 
CrCl <30 mL/min (not requiring 
dialysis)
15 mg every 48 hours
End stage renal disease 
CrCl <30 mL/min (requiring dialysis) 
5 mg once daily. On dialysis days, administer
the dose after dialysis
CrCl=creatinine clearance.
a 
Estimated by creatinine clearance as calculated by the Cockcroft Gault, modification of diet in renal disease (MDRD)
6.7.4.5. 
Other Grade 3 or 4 Non-Hematologic Adverse Events
For other Grade 3 or 4 toxicities judged by the investigator to be related to lenalidomide alone,
treatment with lenalidomide should be interrupted and re-started at the next lower dose level
once the toxicity has resolved to Grade 2 or less. Treatment with daratumumab and
dexamethasone may continue, unless the toxicity meets the criteria for daratumumab dose delay
as specified in Section 6.5.1 (Daratumumab Toxicity Management).






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Table 31: Carfilzomib Dose Modification Guidelines for Non-hematologic Toxicities
Toxicity  
Recommended Action
Dyspnea (Grade ≥2) 
Hold carfilzomib until resolution to Grade 1 or baseline
- Resume at one-dose level reduction unless related to other
pulmonary or cardiac toxicity, then follow that
recommended action.
Pulmonary toxicity: 
Non-infectious interstitial lung disease, 
acute respiratory failure, ARDS (≥Grade 3)
Hold carfilzomib until resolution to Grade 1 or baseline
- Restart at one-dose level reduction.
Pulmonary hypertension (Grade ≥3) 
Hold carfilzomib until resolution to Grade 1 or baseline and restart at
one-dose level reduction
Posterior reversible encephalopathy 
syndrome: 
Headaches, altered mental status, seizures, 
visual loss, and hypertension  
If PRES is suspected, hold carfilzomib.
- Consider evaluation with neuroradiological imaging,
specifically MRI, for onset of visual or neurological
symptoms suggestive of PRES.
- If PRES is confirmed, permanently discontinue carfilzomib.
- If PRES is excluded, carfilzomib administration may resume
at same dose, if clinically appropriate.
Thrombotic microangiopathy: 
Fever, microangiopathic hemolytic anemia, 
renal failure, thrombocytopenia, 
neurological manifestations 
If the diagnosis is suspected, hold carfilzomib and manage per
standard of care including plasma exchange as clinically appropriate.
If TMA is confirmed, permanently discontinue carfilzomib. If the
diagnosis is excluded, carfilzomib can be restarted
Venous thrombosis (≥Grade 3) 
Hold carfilzomib and adjust anticoagulation regimen; resume
carfilzomib at full dose once anticoagulation has been optimized per
treating investigator’s discretion.
Toxicity  
Recommended Action
drug-related non-hematologic toxicity 
≥Grade 3b 
   Exceptions: 
     -Grade3 nausea, vomiting, or diarrhea
(unless persisting > 3 days with adequate
treatment of antiemetics or antidiarrheal
agents)
    -Grade 3 dexamethasone-related
hyperglycemia
    -Grade 3 fatigue (unless persisting for
>14 days)
    -Alopecia
Hold carfilzomib dose.
Restart at one-dose level reduction when toxicity has resolved to
Grade 1 or less or to baseline grade.
ALT = alanine aminotransferase; ANC = absolute neutrophil count; ARDS = acute respiratory distress syndrome;
AST = aspartate aminotransferase; CrCl = creatinine clearance; DBP = diastolic blood pressure; G-
CSF=granulocyte-colony stimulating factor; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging;
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PRES = Posterior
Reversible Encephalopathy Syndrome; SBP = systolic blood pressure; TMA = thrombotic microangiopathy;
ULN = upper limit of normal.
a For a rapid fall from baseline in CrCl or an absolute fall of ≥60 mL/min, contact the medical monitor.


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6.7.5.2. 
Management of Peripheral Edema, Pulmonary Edema, Congestive
Heart Failure
Subjects may develop volume overload during the study. Management of volume overload is at
the discretion of the treating physician but will likely include loop diuretics (furosemide,
torsemide or equivalent), nitrate preparations, and/or ionotropic agents. Use of these medications
is permissible during the protocol and should be recorded in the electronic case report form
(eCRF) as concomitant medications. Dose reductions of carfilzomib and/or dexamethasone
(Table 20 and Table 22, respectively) would be required in this setting.
7. 
TREATMENT COMPLIANCE
The study drug (Dara SC) and the components of the backbone regimens will be administered by
qualified site staff, and the details of each administration will be recorded in the eCRF. Subjects
will be provided with a diary to record access compliance for melphalan, lenalidomide,
prednisone, and dexamethasone. Additional details are provided in the SIPPM.
8. 
PRESTUDY AND CONCOMITANT THERAPY
For those subjects in the D-Rd and D-Kd cohorts, all prior anti-myeloma therapies, including
those since diagnosis, must be recorded at screening. Throughout the study, investigators may
prescribe any concomitant medications or treatments deemed necessary to provide adequate
supportive care except for those listed in Section 8.3 (Prohibited Therapies). The sponsor must
be notified in advance (or as soon as possible thereafter) of any instances in which prohibited
therapies are administered. Concomitant medications related adverse events, pre- and
post-administration medications, and significant medical history will be collected in the eCRF
and recorded in the source documents beginning with signing of the ICF up to 30 days after the
last dose of the last study treatment or until the start of subsequent anticancer treatment, if
earlier.
8.1. 
Recommended Therapies
8.1.1. 
Bisphosphonate Therapy
Bisphosphonate therapy is strongly recommended for all subjects with evidence of lytic
destruction of bone or with osteopenia. Bisphosphonate therapy is recommended to be continued
according to treatment guidelines (Moreau 201324; NCCN 201325). 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 subjects with osteolytic or osteopenic myelomatous bone disease. Oral
bisphosphonates may be used as 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
subjects at their sites.
Subjects who are using bisphosphonate therapy when they enter the study should continue the
same treatment. Subjects with evidence of lytic destruction of bone or with osteopenia who are
not using a bisphosphonate at the time of administration of study treatment should start a
bisphosphonate as soon as possible during Cycle 1 or 2 of treatment. Investigators should not


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start bisphosphonate therapy during the study, unless it has been agreed with  the sponsor that
there is no sign of disease progression.
8.1.2. 
Therapy for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of tumor
lysis syndrome, including dehydration and abnormal laboratory test results such as
hyperkalemia, hyperuricemia, and hypocalcemia, are highly recommended. It is also
recommended that high-risk subjects (ie, those with a high tumor burden) should be treated
prophylactically in accordance with local standards (eg; rehydration, diuretics, allopurinol
300 mg daily, and medication to increase urate excretion). Subjects will receive prophylactic
therapy to prevent IRRs during the Treatment Phase, as described in Section 6.4.1 (Prevention of
Infusion-related Reactions).
8.1.3. 
Therapy for Pneumocystis carinii/jirovecii
Pneumocystis carinii/jirovecii pneumonia prophylaxis should be considered, according to
institutional guidelines.
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase,
according to institutional guidelines. Initiate antiviral prophylaxis to prevent herpes zoster
reactivation within 1 week after starting study treatment and continue for 3 months following
study treatment. Acceptable antiviral therapy includes acyclovir (eg, 400 mg given orally 3 times
a day, or 800 mg given orally 2 times a day, or per institutional standards), famcyclovir (eg, 125
mg given orally, twice a day or per institutional standards), or valacyclovir (eg, 500 mg given
orally, twice a day or per institutional standards), initiated within 1 week after the start of study
drug.
8.1.5. 
Prevention of Steroid Induced Gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are
permitted according to institutional guidelines, for example proton pump inhibitors (omeprazole
or equivalent), sucralfate, or H2 blockers (ranitidine or equivalent).
8.1.6. 
Prevention of Deep Vein Thrombosis and Pulmonary Embolism
Lenalidomide has been associated with increased incidence of deep vein thrombosis and
pulmonary embolism. Thromboprophylaxis is recommended in the D-Kd cohort due to the
combination of carfilzomib and dexamethasone. Both individual and myeloma-related risks of
venous thromboembolism should be taken into account in determining the type of
thromboprophylaxis. In summary:
 
If no risk factor, or any one risk factor is present, aspirin 81-325 mg once daily is
recommended or dose according to institutional standards
 
If 2 or more risk factors are present, LMWH (equivalent of enoxaparin 40 mg once daily) or
full-dose warfarin, international normalized ratio (INR) 2-3, is recommended


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 
If any myeloma therapy-related risk factor is present, then LMWH (equivalent of 40 mg
enoxaparin once daily) or full-dose warfarin (target INR 2-3) is recommended
8.1.7. 
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 subjects at risk for HBV reactivation (see Section 9.6).
For subjects 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.
8.1.8. 
Infection Prophylaxis
Prophylactic use of antibiotics is highly recommended due to the susceptibility of subjects with
multiple myeloma to infections. Prophylactic administration of antibiotics should be considered
and dependent on institutional guidelines.
8.2. 
Permitted Therapies
Subjects 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
 
Prevention of constipation (eg, adequate hydration, high-fiber diet, and stool softeners if
needed)
 
Prophylactic antiemetics, with the exception of corticosteroids
 
Colony stimulating factors, erythropoietin, and transfusion of platelets and RBCs except
those described in Section 4.1 (Inclusion Criteria)
 
Loperamide is recommended for the treatment of diarrhea, starting at the time of the first
watery stool. The loperamide dose and regimen is according to institutional guidelines.
Prophylactic loperamide is not recommended
 
Adequate hydration is recommended for prevention of myeloma-related kidney disease
Other symptoms may be managed according to institutional guidelines provided prohibited
therapies are not administered (see Section 8.3 [Prohibited Therapies]).


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8.3. 
Prohibited Therapies
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered. Concomitant administration of any other
antineoplastic therapy for the intention of treating MM 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 treatment (during or after emergency
orthopedic surgery or radiotherapy because of subject benefit) may only occur in the absence of
disease progression and after consultation with and approval by the sponsor.
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 subject for whom delay of systemic therapy is not appropriate.
Radiotherapy must occur within the first 2 cycles of treatment and only if disease progression
has not occurred. Before radiotherapy, the sponsor will review the evidence and confirm that
disease progression has not occurred.
Concomitant administration of investigational agents and of commercially available agents with
activity against or under investigation for MM are prohibited. Systemic corticosteroids (>10 mg
prednisone each day or equivalent) (other than those given as backbone therapy and IRRs as
described in Section 6.4.1 [Pre- and Post-administration Medications]) should be avoided.
Nonsteroidal anti-inflammatory agents should be avoided to prevent myeloma-related kidney
disease. Vaccination with live attenuated vaccines is prohibited.
Typically, IV contrast is not used in CT scanning of subjects with secretory MM because of the
risk to the kidney. If administration of IV contrast is necessary, then adequate precautions
including hydration are indicated.
Concomitant administration of strong CYP3A4 inducers is prohibited with the use of
bortezomib. Administration of strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir) should be
avoided and is not recommended in subjects receiving bortezomib. If a strong CYP3A4 inhibitor
must be given in combination with bortezomib, monitor subjects for signs of bortezomib toxicity
and consider a bortezomib dose reduction. For an ongoing list of CYP3A inhibitors and inducers,
see Attachment 12 12.
9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
9.1.1. 
Overview
The Time and Events Schedule (Table 1 to Table 9) summarizes the frequency and timing of
efficacy, PK, immunogenicity, biomarker, and safety measurements applicable to this study.
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. Additional serum or urine
pregnancy tests may be performed, as determined necessary by the investigator or required by


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local regulation, to establish the absence of pregnancy at any time during the subject's
participation in the study.
The total blood volume for the D-VRd treatment group is approximately 260 mL (117 mL for
safety, 60 mL for efficacy, 30 mL for daratumumab PK and immunogenicity, 20 mL for
rHuPH20 immunogenicity, 9 mL for biomarkers, and 24 mL for pregnancy testing [women
only]). The total blood volume for the D-VMP treatment group for the first year of treatment is
approximately 453 mL (167 mL for safety, 190 mL for efficacy, 40 mL for daratumumab PK and
immunogenicity, 30 mL for rHuPH20 immunogenicity, 24 mL for biomarkers, and 2 mL for
pregnancy testing [women only]). The total blood volume for the D-Rd treatment group for the
first year of treatment is approximately 490 mL (200 mL for safety, 140 mL for efficacy, 40 mL
daratumumab PK and immunogenicity, 30 mL for rHuPH20 immunogenicity, 24 mL for
biomarkers, and 56 mL for pregnancy testing [women only]). The total blood volume for the
D-Kd treatment group for the first year of treatment is approximately 510 mL (270 mL for
safety, 140 mL for efficacy, 40 mL daratumumab PK and immunogenicity, 30 mL for rHuPH20
immunogenicity, 24 mL for biomarkers, and 2 mL for pregnancy testing [women only]). Repeat
or unscheduled samples may be taken for safety reasons or for technical issues with the samples.
Subjects benefiting from study treatment can continue receiving the study drugs after the end of
data collection until the study drugs are commercially available, available from another source
(eg, via a dedicated long-term extension study), or until study completion (see Attachment 15).
9.1.2. 
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. The
Screening Phase begins when the first screening assessment is conducted. During the Screening
Phase, eligibility criteria will be reviewed and a complete clinical evaluation will be performed
as specified in the Time and Events Schedule (Table 1 to Table 9). Screening procedures will be
performed within 28 days before Cycle 1 Day 1; however, results of tests such as skeletal survey
and other radiologic tests (eg, X-ray, CT, PET-CT, or magnetic resonance imaging [MRI]) to
document baseline size of known or suspected extramedullary plasmacytomas, or bone marrow
aspirate/biopsy) performed up to 6 weeks (42 days) before Cycle 1 Day 1 as routine follow-up
for the subject’s disease can be used.
At screening, creatinine clearance may be measured or calculated according to local practice. If
calculated, use the formula according to the modification of diet in renal disease
(MDRD, Levey 200620). A negative pregnancy test for women of childbearing potential must be
documented within 10 to 14 days prior to the first dose of any component of the treatment
regimen and within 24 hours of the second dosing for subjects in the D-VRd and D-Rd cohorts.
All attempts should be made to determine eligibility of the subject 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.


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9.1.3. 
Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in Table 1 to
Table 9. The Treatment Phase begins on Cycle 1 Day 1 and continues until disease progression
in the D-VMP, D-Kd, and D-Rd cohorts, or for the other reasons outlined in
Section 10.2 (Discontinuation of Study Treatment/Withdrawal from the Study). Subjects in the
D-VRd cohort will be treated for 4 cycles and then will undergo ASCT as part of their standard
myeloma treatment. Subjects will be monitored closely for adverse events, laboratory
abnormalities, and clinical response. Clinical evaluations and laboratory studies may be repeated
more frequently, if clinically indicated. If disease progression is diagnosed in the D-VMP, D-Kd,
and D-Rd cohorts, then the subject will discontinue the study drug and complete the
post-treatment visits.
9.1.4. 
Post-treatment Phase (Follow-Up)
Unless a subject withdraws consent for study participation or is lost to follow-up, post-treatment
visits will be scheduled at 30 Days and 8 weeks after the final dose of study drug. If a subject is
not able to return to the site for the post-treatment visits, then the subject should be contacted
(ie, via telephone call) to collect adverse events that occur within 30 days after the final dose of
any component of the treatment regimen. Additional information on reporting of adverse events
can be found in Section 12 (Adverse Event Reporting). Information on all new SPMs will also be
collected until the end of study. If the subject has died, then the date and cause of death will be
collected and documented on the eCRF.
9.1.5. 
Final Analysis to End of Study
The data cutoff for the final analysis and the end of data collection will occur approximately
10 months after the last subject is enrolled in the D-Kd cohort. Subsequently, the clinical
database will be locked for the final analysis. Subjects benefiting from study treatment can
continue receiving the study drugs after the end of data collection. Attachment 15 describes
study procedures to be followed for subjects who continue receiving study drugs after the data
collection ends.
The end of study will occur when all subjects who are still receiving study treatment after the
clinical cutoff date of the final analysis have discontinued daratumumab treatment, or when all
subjects have access through another source such as commercial availability, continued access
through a dedicated long-term extension study, or a patient access program, or by June 2024, if
the prior 2 criteria are not met first.
9.2. 
Efficacy Evaluations
9.2.1. 
Evaluations
9.2.1.1. 
Response Categories
Assessment of tumor response and disease progression will be conducted in accordance with the
IMWG response criteria. Disease evaluations will include measurements of myeloma proteins,


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bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and
measurements of serum calcium corrected for albumin.
Disease evaluations must be performed at the end of each treatment cycle as specified in the
Time and Events Schedule (Table 1 to Table 9). Disease evaluations scheduled for treatment
days should be collected before the study drug is administered. Disease evaluations will be
performed by a central laboratory (unless otherwise specified) until disease progression or the
end of treatment. This study will use the IMWG consensus recommendations for MM treatment
response criteria (Durie 200610; Kumar 201616, Rajkumar 201127) presented in Table 32. For
quantitative immunoglobulin at baseline, M-protein, immunofixation electrophoresis (IFE), and
FLC measurements in serum and 24-hour urine, the investigator will use results provided by the
central laboratory. For subjects with suspected daratumumab interference on serum M-protein
quantitation by electrophoresis (SPEP) and IFE, a reflex assay will be performed
(Attachment 10). Subjects with confirmed daratumumab interference who meet all other clinical
criteria for CR or stringent complete response (sCR) will be considered CR/sCR.
Disease progression must be documented consistently across clinical study sites using the criteria
in Table 32. For continuation of treatment, the investigator will evaluate response and assess
progression according to the IMWG criteria on an ongoing basis.


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Table 32: 
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 hour urine M protein by 50% to
89%
 
In addition to the above criteria, if present at baseline, 25% to 49% reduction in the size of soft tissue
plasmacytomas is also required
 
No increase in size or number of lytic bone lesions (development of compression fracture does not
exclude response)
Stable disease 
 
Not meeting criteria for CR, VGPR, PR, MR, or progressive disease
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 subjects 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 subjects without measurable serum and urine M protein levels and without measurable
disease by FLC levels, bone marrow PC percentage (absolute percentage must be 10%)
 
Bone marrow plasma cell percentage: 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 ofhypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely
to the PC proliferative disorder
FLC=free light chain; PC=plasma cell
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 stable disease categories also require no known evidence of progressive or new
bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of
whether disease at baseline was measurable on serum, urine, both, or neither.
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed.
For 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 subjects in whom the only measurable disease is by serum FLC
levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such
subjects 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 subjects 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.


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9.2.1.2. 
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a
central laboratory. Only 1 serum and one 24-hour urine sample at each timepoint are required by
the central laboratory to perform the following tests:
 
Serum quantitative immunoglobulins
 
All subjects will be evaluated for IgG, IgA, IgM, IgE, and IgD as indicated in  the
Time and Events Schedule (Table 1 to Table 9)
 
SPEP
 
Serum IFE at screening and thereafter when M-protein is non-quantifiable
 
Serum FLC assay
 
24-hour urine M-protein quantitation by electrophoresis (UPEP)
 
Urine IFE at screening and thereafter when a M-protein is non-quantifiable
Blood and 24-hour urine samples will be collected as specified in the Time and Events Schedule
(Table 1 to Table 9) until the development of confirmed disease progression. If the 24-hr 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 was sent to the central laboratory for analysis
after the informed consent was obtained. Disease progression based on one of the laboratory tests
alone must be confirmed by at least 1 repeat investigation performed 1 to 3 weeks later. Disease
evaluations will continue beyond relapse from CR until disease progression is confirmed. Serum
and urine IFE and serum FLC assay will be performed at screening and thereafter when a CR is
suspected or maintained (when serum or 24-hour urine M-protein electrophoresis [by SPEP or
UPEP] are 0 or non-quantifiable). For subjects with light chain MM, both serum and urine IFE
test will be performed routinely.
Serum IFE assay samples will be split into 2 aliquots, with 1 reserved for potential follow-on
testing if daratumumab interference with IFE is suspected. As daratumumab is a monoclonal IgG
antibody, additional serum samples may be utilized to monitor for potential daratumumab
interference with the IFE.
Previous studies have demonstrated potential interference of therapeutic monoclonal antibodies
with detection of endogenous myeloma M-protein on serum IFE (McCudden 201523). For
subjects with suspected daratumumab interference on SPEP, serum IFE, or both, a follow-up test
will be run utilizing antiidiotype antibodies against daratumumab to remove antibody
interference. Subjects who meet all other IMWG criteria for CR or sCR, and whose positive IFE
is confirmed to be daratumumab, will be considered as having a CR or sCR.


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9.2.1.3. 
Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected and
analyzed centrally (as specified in the Time and Events Schedules [Table 1 to Table 9]). During
the Treatment Phase, 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, Table 32). 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”). Measurement of free ionized calcium is
an acceptable alternative to corrected serum calcium for determining hypercalcemia. Free
ionized calcium levels greater than the ULN (local laboratory reference ranges) are considered as
having achieve a CR or sCR.
9.2.1.4. 
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. The central laboratory values will be used to calculate ISS
stage.
9.2.1.5. 
Bone Marrow Examination
Bone marrow assessments to be performed locally and centrally are summarized in Table 33.
Table 33: 
Bone Marrow Testing
Local Testing 
Central Testing
Screening 
Disease characterization (morphology and
either immunohistochemistry or
immunofluorescence or flow cytometry).
Cytogenetics by conventional karyotype or
FISH.
MRD: For D VMP, D Kd, and D Rd cohorts, a portion of
the bone marrow aspirate collected at screening, will be
sent to the central laboratory.
A fresh bone marrow aspirate is preferred, but if a fresh
bone marrow aspirate is not performed at screening
because a sample is available within 42 days prior to
administration of study treatment, obtain non decalcified
slides (bone marrow aspirate, touch preparation or clot
selection) or FFPE block (clot section only, no bone
marrow biopsy).
CR, sCR  
For response confirmation, additional bone
marrow aspirates or biopsies (or both) will
be performed locally to confirm sCR or CR.
Response characterization (morphology by 
immunohistochemistry or 
immunofluorescence or flow cytometry). 
For sCR: Detection of kappa/lambda ratio 
by 2 4 color flow cytometry is strongly
preferred. If flow cytometry is not available
at site, either immunohistochemistry or 
immunofluorescence can be done, however, 
kappa/lambda ratio from analysis of 
100 plasma cells is required to confirm 
sCR. 
If sCR is not met, repeat local testing for
sCR with subsequent bone marrow
examinations will be done.
MRD Assessment: 
For D-VMP, D-Kd, and D-Rd cohorts, a portion of
the bone marrow aspirate collected for confirmation
of CR/sCR will be sent to the central laboratory for
MRD assessment. For subjects who achieve CR and
remain on study, an additional bone marrow aspirate
will be obtained at 12, 18, and 24 months (±1
month) post C1D1 and every 12 months thereafter
(±1 month) until disease progression. If one of these
timepoints occur within 1 month of suspected CR, a
repeat bone marrow will not be requested.
CR=complete response; FFPE=formalin fixed, paraffin embedded; FISH=fluorescence in situ hybridization; MRD=minimal
residual disease; sCR=stringent complete response


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9.2.1.6. 
Minimal Residual Disease Assessment
Minimal residual disease (MRD) evaluation of the number of cells remaining after treatment by
next-generation sequencing (NGS) is a relatively new and effective tool in the assessment of
subjects with MM (Ladetto 201419). Daratumumab containing regimens demonstrated
significantly greater MRD negative rates as compared to the control group was demonstrated in
the MMY3003 and MMY3004 clinical trials (Avet-Loiseau, 20161). Several studies have
demonstrated that MRD status is correlated with PFS and OS (Martinez-Lopez 201422). In the
present study, bone marrow aspirate will be collected for MRD analysis, in the D-VMP, D-Kd,
and D-Rd cohorts only, when bone marrow samples are obtained at screening, confirmation of
CR/sCR, and subsequent timepoints after the first dose (see Table 33).
9.2.1.7. 
Assessment of Lytic Disease
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri,
femora, and any other bones for which the investigator suspects involvement by disease) is to be
performed and evaluated by the local laboratory by roentgenography (or the local standard of
care imaging, eg, low-dose whole body CT) during the Screening Phase. Please note that the
same methodology used at screening should be used throughout the study for comparison
purposes. During the Treatment Phase and before disease progression is confirmed, imaging
should be performed whenever clinically indicated based on symptoms, to document response or
progression. Magnetic resonance imaging is an acceptable method for evaluation of bone disease
and may be included as an additional assessment at the discretion of the investigator (see the
disease response criteria in Table 32).
Subjects may present with disease progression manifested by symptoms of pain due to bone
changes. Therefore, disease progression may be documented, in these cases, by skeletal survey
or other radiographs, depending on the symptoms that the subject experiences. If the diagnosis of
disease progression is obvious by radiographic investigations, then no repeat confirmatory
imaging is necessary. In instances where changes may be subtler, repeat imaging may be
performed in 1 to 3 weeks according to investigator discretion.
9.2.1.8. 
Documentation of Extramedullary Plasmacytomas
Sites of known extramedullary plasmacytomas must be documented during the Screening Phase.
Clinical examination or MRI may be used to document extramedullary sites of disease.
Computed tomography scan evaluations are an acceptable alternative if there is no
contraindication to the use of IV contrast. Positron emission tomography scan alone (ie, without
a CT) or ultrasound tests are not acceptable to document the size of extramedullary
plasmacytomas.
Extramedullary plasmacytomas should be assessed for all subjects with a history of
plasmacytomas or if clinically indicated at screening, by clinical examination or radiologic
imaging. For subjects with a history of plasmacytomas assessed by physical examination,
physical examination should be repeated on Cycle 1 Day 1 if not done within 14 days prior to
administration of study treatment. Assessment of measurable sites of extramedullary disease will
be performed and evaluated locally approximately every 4 weeks (every 3 weeks in the D-VRd


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cohort) by physical examination or approximately every 12 weeks by imaging (ifrequired) for
subjects with a history of plasmacytomas or as clinically indicated during treatment for other
subjects, until development of confirmed CR or confirmed disease progression. For every
subject, the methodology used for evaluation of each disease site should be consistent across all
visits. Irradiated or excised lesions will be considered not measurable and will be monitored only
for disease progression.
To qualify for PR, the sum of products of the perpendicular diameters of the existing
extramedullary plasmacytomas must have decreased by at least 50%, and new plasmacytomas
must not have developed (see the disease response criteria in Table 32). To qualify for disease
progression, either the sum of products of the perpendicular diameters of the existing
extramedullary plasmacytomas must have increased by at least 50% or a new plasmacytoma
must have developed. In the cases where not all existing extramedullary plasmacytomas are
reported, but the sum of products of the perpendicular diameters of the reported plasmacytomas
have increased by at least 50%, this will also qualify as disease progression.
9.3. 
Pharmacokinetics and Immunogenicity
9.3.1. 
Evaluations
Samples to assess both the serum concentration (PK) of daratumumab and the generation of
anti-daratumumab antibodies (immunogenicity) will be obtained from all subjects according to
the Time and Events Schedules (Table 2, Table 5, Table 7, and Table 9). Samples will also be
collected from all subjects to evaluate the immunogenicity of rHuPH20 according to the Time
and Events Schedules (Table 2, Table 5, Table 7, and Table 9). The exact dates and times of
blood sampling must be documented. Refer to the Laboratory Manual or equivalent document
for sample collection requirements. Collected samples must be stored under the specified and
controlled conditions for the temperatures indicated in the Laboratory Manual. Samples collected
for determining serum concentrations/ immunogenicity of daratumumab or immunogenicity of
rHuPH20 in this study may be retained to address questions about drug characteristics that may
arise at a later timepoint.
9.3.2. 
Analytical Procedures
Samples will be analyzed to determine concentrations of daratumumab or generation of
antibodies to daratumumab or rHuPH20 using validated immunoassay methods by or under the
supervision of the sponsor. 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.


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9.3.3. 
Pharmacokinetic Parameters
The PK parameters are defined as:
Cmax  
Maximum observed concentration
Cmin  
Minimum observed concentration
For daratumumab, the PK evaluations include Cmin  and Cmax. and will be determined based on
the assigned collection timepoints. If sufficient data are available, then other PK parameters may
be calculated. If sufficient data are available, population PK analysis of serum
concentration-time data of daratumumab may be performed and may include data from other
clinical studies; details will be provided in a population PK analysis plan and results will be
presented in a separate report.
9.3.4. 
Immunogenicity Assessments
Serum from venous blood samples collected from all subjects will be assessed for the generation
of anti-daratumumab antibodies (immunogenicity) according to the Time and Events
PK/Immunogenicity Sample Collection Tables (Table 2, Table 5, Table 7, and Table 9).
Daratumumab concentration will be evaluated at all immunogenicity timepoints 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 subjects and assessed for anti-rHuPH20 antibodies.
When an IRR occurs associated with the second daratumumab administration or beyond, 2 blood
samples should be obtained, if possible, for determination of both anti-daratumumab antibodies
and anti-rHuPH20 antibodies. No unscheduled samples need to be collected for IRRs associated
with the first administration of daratumumab. Daratumumab serum concentration will also be
determined from the daratumumab IRR sample for the purpose of interpreting immunogenicity
data. These samples will be stored and evaluated if deemed necessary. If an IRR results in
treatment discontinuation, then a subject 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
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or
after the study period or for the evaluation of relevant biomarkers by the sponsor or sponsor’s
designee. Subjects who discontinue treatment or withdraw from the study before confirmation of
PD should have samples collected at the time of early discontinuation. Subjects who discontinue
treatment will also be asked to return for immunogenicity evaluation during the Follow-up
Phase.


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9.4. 
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. If these analyses are performed, then the details and results will be
presented in a separate report.
9.5. 
Biomarkers
As permitted by local rules and regulations, bone marrow aspirates in the D-VMP, D-Kd, and
D-Rd cohorts will be collected at screening and following treatment as outlined in the Time and
Events Schedule for MRD monitoring (Table 3, Table 6, and Table 8). Baseline bone marrow
aspirate samples will be subjected to DNA sequencing to establish a MM clone for MRD
monitoring. A fresh bone marrow aspirate at screening is required, if possible. By exception,
non-decalcified diagnostic tissue slides (bone marrow aspirate, touch preparation or clot
selection) or formalin-fixed, paraffin-embedded (FFPE) block (clot selection only, no bone
marrow biopsy) may be supplied for MRD assessment. For subjects who achieve a CR, bone
marrow aspirates will be utilized for assessment of MRD by NGS of Ig heavy and light chains. If
this 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 subjects as specified in the Time and Events
Schedule for processing to plasma and peripheral blood mononuclear cells. These samples may
be used to evaluate the mechanism of action of subcutaneously delivered daratumumab in
combination with standard of care regimens. As daratumumab has been demonstrated to have an
immunomodulatory mechanism, specific subsets of immune cells such as cytotoxic T cells,
regulatory T cells, and activated NK cells may be evaluated by fluorescence-activated cell
sorting (FACS) or cytometry/time-of-flight mass spectrometry and T-cell receptor sequencing.
Proteomic analysis may also be used to evaluate changes in proteins in circulation to evaluate
potential biomarkers of response and resistance.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or responders to allow for adequate
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy,
completion of biomarker assessments is based on justification and intended utility of the data.
Samples for biomarker evaluations will be collected as specified in the Time and Events
Schedule (Table 1 to Table 9).


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Additional Collections
If it is determined at any time before study completion that additional material is needed from a
FFPE tumor sample for the successful completion of the protocol-specified analyses, the sponsor
may request that additional material be retrieved from existing samples. Also, based on emerging
scientific evidence, the sponsor may request additional material from previously collected tumor
samples during or after study completion for a retrospective analysis. In this case, such analyses
would be specific to research related to the study drug(s) or diseases being investigated.
9.6. 
Safety Evaluations
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign
measurements, physical examination findings, SC injection-site assessments, and assessment of
ECOG performance status score. In addition, TTE monitoring will be performed in subjects in
the D-Kd cohort only. All toxicities will be graded according to the NCI-CTCAE Version 4.03.
Any clinically relevant changes occurring during the study must be recorded on the Adverse
Event 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 endpoint is reached.
Based on the previous clinical experience with daratumumab, in vitro studies, and animal
toxicological findings, IRRs/allergic reactions, hemolysis, infection, neutropenia, and
thrombocytopenia will be closely monitored. As a biologic agent, immunogenicity also will be
monitored. Any of the safety monitoring assessments may be performed more frequently, and
adverse events should be evaluated by the investigator according to the standard practice, if
clinically indicated. Details regarding the SET are provided in Section 11.9 (Study Evaluation
Team).
The study will include the following evaluations of safety and tolerability according to the
timepoints provided in the Time and Events Schedule (Table 1 to Table 9):
Adverse Events
Adverse events (with the exception of progression of MM) will be reported by the subject (or,
when appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative)
from the time a signed and date informed consent is obtained until 30 days following the final
dose of daratumumab. Adverse events will be followed by the investigator as specified in
Section 12 (Adverse Event Reporting). After the data collection has ended, only serious adverse
events will be collected, as described in Attachment 15.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must
review the laboratory results, document this review, and record any clinically relevant changes
occurring during the study in the adverse event section of the eCRF. The laboratory reports must
be filed with the source documents.


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The following tests will be performed by the local laboratory, unless otherwise specified:
 
Hematology panel
-hemoglobin
-white blood cell (WBC) count
-absolute neutrophil count (ANC)
-absolute lymphocyte count (ALC)
-platelet count
 
Serum chemistry panel
-AST 
-alkaline phosphatase
-ALT  
-uric acid
-total bilirubina 
-blood urea nitrogen or urea
-glucose 
-calcium and albumin-adjusted calciumb
-creatinine 
-lactic acid dehydrogenase
-sodium  
-potassium
a 
If Gilbert's disease, assessment of direct bilirubin.
b 
These parameters will be part of the efficacy evaluations as specified in Section 9.2.1.3, Serum Calcium
Corrected for Albumin, and will be analyzed at a central laboratory.
Pregnancy Testing
Serum beta-human chorionic gonadotropin (-hCG) or urine pregnancy testing for women of
childbearing potential will be collected as specified in the Time and Events Schedule (Table 1 to
Table 9).
For women of childbearing potential only: lenalidomide is a thalidomide analogue and is
contraindicated for use during pregnancy. Birth defects have been observed in preclinical studies
of lenalidomide similar to thalidomide in humans. Therefore, strict monitoring for pregnancy
must be conducted during Screening and throughout the Treatment Phase, as specified in the
Time and Events Schedule. Where lenalidomide is supplied locally, subjects must adhere to the
local lenalidomide REMS program. Where lenalidomide is supplied centrally and no local
lenalidomide REMS program exists, then subjects must adhere to the Lenalidomide Global
Pregnancy Prevention Plan in Attachment 14.
If pregnancy or positive pregnancy test does occur, then study treatment should be discontinued
immediately, and the subject should be referred to an obstetrician experienced in reproductive
toxicity for further evaluation and counseling.


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Daratumumab Interference with Indirect Antiglobulin Test Results
Daratumumab interferes with the indirect antiglobulin test (IAT), which is a routine
pre-transfusion test performed to identify a subject’s antibodies to minor antigens so that suitable
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/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. Subjects will receive a subject identification wallet card for the
study that includes the blood profile (ABO, Rh, and IAT) determined before the first
administration of daratumumab along with information on the IAT interference for healthcare
providers/blood banks. Subjects are to carry this card throughout the treatment period and for at
least 6 months after treatment ends. Blood banks can eliminate the daratumumab IAT
interference by treating reagent RBCs with dithiothreitol (DTT) (Chapuy 20154, Chapuy 20165).
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving
daratumumab include:
a) Providing ABO/RhD compatible, phenotypically or genotypically matched units
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is
needed urgently according to 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
Investigator’s Brochure for daratumumab13.
FEV1 Test
Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
Refer to Section 6.4.1.2 (Post-administration Medication) for details on subjects with higher risk
of respiratory complications.
HBV Serology
Subjects in the D-Kd cohort 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.
Additionally, subjects ongoing in the Treatment Phase who are within 6 months of starting study
treatment when Protocol Amendment 3 is implemented will be required to have HBV serology
performed locally upon signing the updated ICF. If the hepatitis B serologic status of a subject in
the DVMP, DRd, or DVRd cohort is unknown, HBsAg, Anti-HBs, and Anti-HBc testing is
recommended if the subject is still receiving daratumumab (or is within 6 months after the last
dose). For subjects ongoing in the Treatment Phase who are within 6 months of starting study


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treatment, HBV serology is not required if this was performed as part of standard of care within
3 months prior to first dose.
HBV DNA Tests
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by
PCR. Subjects 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 study treatment and within 6 months of the last dose of
daratumumab, subjects who have history of HBV infection will be closely monitored by the
investigator for clinical and laboratory signs ofreactivation of HBV as specified in the Time and
Events Schedule (Table 1, Table 3, Table 6, and Table 8). Where required by local law, the
results of HBV testing may be reported to the local health authorities.
Electrocardiogram (ECG)
Electrocardiograms will be performed as specified in the Time and Events Schedule (Table 1 to
Table 9). Whenever possible, ECGs should be performed immediately before chemistry and PK
assessments. During the collection of ECGs, subjects should be in a quiet setting without
distractions (eg, television, cell phones). Subjects 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 timepoint as ECG recording,
the procedures should be performed in the following order: ECG(s), vital signs, blood draw.
Transthoracic Echocardiogram
Participants in the D-Kd cohort must have a TTE according to the Time and Events Schedule
(Table 8). Two-dimensional TTE to assess left ventricular ejection fraction for eligibility
purposes will be assessed during screening and will serve as the baseline echocardiogram.
Vital Signs
Vital signs (temperature, pulse/heart rate, respiratory rate, and blood pressure) will be performed
as specified in the Time and Events Schedule (Table 1 to Table 9). 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).
Physical Examination
A complete physical examination should be performed during the Screening Phase. Thereafter,
only a symptom-directed physical examination is required. Abnormalities will be recorded in the
appropriate section of the eCRF.
Eastern Cooperative Oncology Group (ECOG) Performance Status
Eastern Cooperative Oncology Group 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.


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9.7. 
Sample Collection and Handling
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. Samples for
PK and immunogenicity testing must not be taken from the same arm as drug administration.
Refer to the Time and Events Schedule (Table 1 to Table 9) for the timing and frequency of all
sample collections. Instructions for the collection, handling, storage, and shipment of samples are
found in the Laboratory Manual that will be provided. Collection, handling, storage, and
shipment of samples must be under the specified, and where applicable, controlled temperature
conditions as indicated in the Laboratory Manual.
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/
WITHDRAWAL FROM THE STUDY
10.1. Completion
A subject will be considered to have completed the study if he or she has completed all
protocol-specified procedures before the end of the study, has not been lost to follow-up, or has
not withdrawn consent for study participation before the end of the study, or has transitioned to
study drugs which are commercially available or available from another source.
10.2. Discontinuation of Study Treatment/Withdrawal from the Study
The sponsor's medical monitor will review the provided documentation and confirm PD has
occurred according to IMWG criteria (see Section 9.2.1.1, Response Categories) and that study
treatment should be discontinued. After confirmation of PD by the sponsor, the subject will
discontinue study treatment and enter the Follow-up Phase.


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Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if he or she must discontinue
treatment before the end of the treatment regimen. The End-of-Treatment Visits and Follow-up
visit assessments should continue as specified in the Time and Events Schedule (Table 1 to
Table 9).
Subjects who discontinue treatment with any one component of study treatment (daratumumab
or bortezomib, melphalan, prednisone [D-VMP]; lenalidomide, dexamethasone [D-Rd];
carfilzomib, dexamethasone [D-Kd]) may continue to receive treatment with the other
components of study treatment, as assigned.
A subject's study treatment (daratumumab and combination therapy) must be discontinued if:
 
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it
is in the best interest of the subject to discontinue study treatment
 
If the subject becomes pregnant or a positive pregnancy test does occur and she is enrolled
in a lenalidomide containing cohort, lenalidomide must be discontinued immediately.
Continuation of other drugs may be considered if the subject (or the subject's legally
acceptable representative), investigator, and sponsor agree the benefits to the subject
outweigh the risks to the fetus and continuation of treatment is in the best interests of the
subject. If the male participant’s partner becomes pregnant and is enrolled in a lenalidomide
containing cohort, they must immediately inform the investigator.
 
The subject (or the subject’s legally acceptable representative) withdraws consent for
administration of the study drug
 
The subject initiates treatment with a prohibited medication
 
The subject received concurrent (non-protocol) treatment for MM
 
The subject experiences unacceptable toxicity, including IRRs described in Section 6.4,
Management of Injection-site and Infusion-related Reactions
 
The subject’s dose of daratumumab is held for a prolonged period (unless sponsor approves
continuation). See Section 6.5 for a description of the management of dose delays for each
cohort
 
The subject experiences disease progression (see below).
 
A subject who experiences a second primary malignancy that cannot be treated by surgery
or radiotherapy alone must be withdrawn from the study. However, a subject who develops
a malignancy that can be cured surgically or with definitive radiotherapy may continue to
receive the assigned study treatment and should continue to be followed for subsequent
progression of MM.
Study treatment will continue for 4 cycles in the D-VRd cohort, or until confirmation of PD in
the D-VMP, D-Kd, and D-Rd cohorts. Before subjects are discontinued from study treatment
because of suspected PD, the investigator (or designee) will provide documentation of disease
progression (for example, by completing a disease progression form or by contacting the
interactive web response system [IWRS]) as soon as possible and within 48 hours of


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confirmation of disease progression. Documentation of PD status into IWRS is not required after
end of data collection (see Attachment 15).
If a subject's study treatment must be discontinued, then this will not result in automatic
withdrawal of the subject from the study; instead, the subject will enter the Post-treatment
Follow-up Phase. For subjects who discontinue treatment prior to PD, disease evaluations should
continue every 28 days until the Follow-up Visit is completed. For subjects in the D-VRd cohort,
subsequent therapy will be collected potentially after the End-of-Treatment Visits and best
response after transplant will be collected in the eCRF. The End-of-Treatment Visit and
Follow-up Visit assessments should continue as specified in the Time and Events Schedule
(Table 1 to Table 9). For additional clarification regarding continued assessments for subjects
who continue receiving study drugs after data collection ends, see Attachment 15.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent for study participation
 
Death
 
Sponsor terminates the study
Before a subject is considered lost to follow-up, every reasonable effort must be made by the
study-site 
personnel 
to 
contact 
the 
subject 
and 
determine 
the 
reason 
for
discontinuation/withdrawal. The measures taken to follow-up must be documented.
When a subject withdraws consent before completing the study, the reason for study end should
be recorded as ‘withdrawal of consent’ and all data collection should stop immediately. Study
drug assigned to the withdrawn subject may not be assigned to another subject. If subjects
withdraw from the study after Cycle 1, additional subjects will not be enrolled. Subjects who
withdraw from the study during Cycle 1 for reasons other than toxicity may be replaced at the
discretion of the sponsor. If a subject discontinues study drug and withdraws from the study
before the end of treatment, assessments outlined in the End-of-Treatment Visit should be
obtained (Table 1). If the reason for withdrawal from the study is withdrawal of consent, then no
additional assessments are allowed.


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10.3. Withdrawal From the Use of Research Samples
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5,
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will
be destroyed after they are no longer needed for the clinical study. Details of the sample
retention for research are presented in the main ICF.
11. 
STATISTICAL METHODS
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.
11.1. Subject Information
The analysis sets for this study include:
 
All treated analysis set: defined as all subjects who receive at least 1 dose of study treatment.
This analysis set will be used for analyses of disposition, demographic and baseline disease
characteristics, treatment exposure, safety and efficacy. All subjects in the all treated
analysis set will be analyzed according to the treatment that they actually received.
 
PK analysis set: defined as subjects who received at least 1 administration of study drug and
have at least 1 PK sample concentration value after the first dose. All PK parameters will be
analyzed based on the PK analysis set.
 
Immunogenicity-evaluable analysis set is defined as all subjects who receive at least 1 dose
administration of daratumumab SC and have at least 1 immunogenicity sample for detection
of anti-daratumumab antibodies after the first dose.
 
Immunogenicity-evaluable analysis set for rHuPH20 is defined as all subjects who receive at
least 1 dose of daratumumab SC and have appropriate plasma samples for detection of
antibodies to rHuPH20 (at least 1 sample after the start of the first dose of daratumumab
SC).
Descriptive statistics will be used to summarize data. For continuous parameters, number of
observations, mean, standard deviation, median, and range will be used. For discrete parameters,
frequency will be summarized. For time-to-event parameters, Kaplan-Meier estimates will be
produced. When sample sizes are small, sample listings may be provided instead.
11.2. Sample Size Determination
For the D-VMP cohort, 60 subjects will be required to test the null hypothesis that the ORR is at
most 70%, against the alternative hypothesis that the ORR is at least 90% with a 1-sided alpha of
0.05 and at least 98% power (Table 34). For the D-Rd cohort, 60 subjects will be required to test
the null hypothesis that the ORR is at most 75% against the alternative hypothesis that the ORR
is at least 90% with a 1-sided alpha of 0.05 and at least 90% power. Similarly, for the D-Kd
cohort, the corresponding power is >80% to test the null hypothesis that the ORR is at most 65%,
against the alternative hypothesis that the ORR is at least 80%. For the D-VRd cohort, 60
subjects will achieve a power of at least 93% to test the null hypothesis that the response rate of


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VGPR or better is at most 50%, against the alternative hypothesis that the ORR is at least 70%
with a 1-sided alpha of 0.05.
Table 34: 
Hypothesis and Power Table
Cohort 
N 
H0 
H1 
Power
D VRd 
60
VGPR or better rate 
≤50%
VGPR or better rate
≥70%
>93%
D VMP  
60 
ORR ≤70%  
ORR ≥90%  
>98%
D Rd 
60 
ORR ≤75%  
ORR ≥90%  
>90%
D Kd 
60 
ORR ≤65%  
ORR ≥80%  
>80%
D VRd=Dara SC, bortezomib, lenalidomide, and dexamethasone; D VMP=Dara SC, bortezomib, melphalan, and prednisone;
D Rd=Dara SC, lenalidomide, and dexamethasone; ORR=overall response rate; D Kd=Dara SC, carfilzomib, and dexamethasone
11.3. Efficacy Analyses
A computerized algorithm will be used to derive the response and disease progression based on
the central laboratory results (unless otherwise specified) for the analysis and reporting. The
primary analysis for the study will occur at least 6 months after approximately the 60th  subject is
enrolled in the last treatment cohort (D-VRd, D-VMP, or D-Rd). The cutoff for the primary
analysis for the D-Kd cohort will occur at least 6 months after approximately the 60th  subject is
enrolled in the D-Kd cohort. No formal comparisons between the treatment cohorts will be
performed.
Primary Endpoint
The primary efficacy endpoint for the D-Kd, D-VMP, and D-Rd cohorts is ORR, which is
defined as the proportion of subjects who achieve a response of PR or better according to IMWG
response criteria. The ORR, along with its 2-sided 90% exact CI, will be calculated.
At the time of the primary analysis for the study, the D-Kd cohort will not be included in the
analysis and will be analyzed in subsequent analyses at least 6 months after approximately the
60th  subject is enrolled in the D-Kd cohort.
The primary efficacy endpoint for the D-VRd cohort is VGPR or better rate, which is defined as
the proportion of subjects who achieve a response of VGPR or better according to IMWG
response criteria. The VGPR or better rate, along with its 2-sided 90% exact CI, will be
calculated.
Secondary Endpoints
VGPR or Better Rate (D-Kd, D-VMP, and D-Rd cohorts)
The proportion of subjects who achieve a response of VGPR or better according to the IMWG
response criteria and its two-sided exact 90% CI will be calculated for D-Kd, D-VMP, and D-Rd
cohorts.


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ORR (D-VRd cohort)
The proportion of subjects who achieve a response of PR or better according to the IMWG
response criteria and its two-sided exact 90% CI will be calculated for D-VRd cohort.
CR or Better Rate
The proportion of subjects who achieve a response of CR or better according to the IMWG
response criteria and its two-sided 90% exact CI will be calculated for each treatment cohort.
Duration of Response
Duration of response is calculated from the date of initial documented response (PR or better for
D-Kd, D-VMP, and D-Rd cohorts) to the date of first documented evidence of progressive
disease as defined according to IMWG criteria or death due to PD, whichever occurs first, for the
subjects who had achieved a response (PR or better for D-Kd, D-VMP, and D-Rd cohorts).
Median DOR with 90% CI will be estimated based on the Kaplan-Meier method for each
treatment cohort.
MRD Negativity Rate
Minimal residual disease (MRD) negativity rate is defined as the proportion of subjects who are
considered MRD negative after MRD testing at any timepoint after first dose by bone marrow
aspirate. The MRD negative rate will be calculated for cohorts D-VMP, D-Kd, and D-Rd. The
corresponding two-sided 90% exact CI will be provided.
Exploratory Analysis
Best overall response based on the IMWG criteria will be collected after autologous stem cell
transplantation for the D-VRd cohort after 4 cycles of treatment. These data may be used in an
exploratory analysis.
11.4. Pharmacokinetic Analyses
Daratumumab Pharmacokinetic Analysis
Pharmacokinetic analyses will be performed on the PK-evaluable analysis set, defined as
subjects who have received at least 1 dose of daratumumab and have at least 1 post-dose sample.
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. Descriptive statistics will be used to summarize
daratumumab serum concentrations at each sampling timepoint. Cmin  is defined as the minimum
concentration observed immediately before daratumumab administration and Cmax  is defined as
the maximum concentration observed following daratumumab administration, as presented in the
summary of serum concentration by sampling timepoint. Other PK parameters, if available, may
also be summarized.
If sufficient data are available, population-PK analysis of serum concentration-time data of
daratumumab may be performed and may be combined with data from other studies. If the


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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. Exposure-response analyses may
also be performed and may use data from other studies; if performed, details will be provided in
a separate analysis plan and report.
11.5. Immunogenicity Analyses
The incidence of anti-daratumumab antibodies will be summarized for all subjects who receive
at least 1 dose of daratumumab and have at least 1 sample for detection of anti-daratumumab
antibodies after the first dose. The prevalence and incidence of anti-rHuPH20 antibodies will be
summarized for all subjects who receive a dose of daratumumab and have at least 1 sample for
detection of anti-rHuPH20 antibodies after the first dose. A listing of subjects who are positive
for antibodies to daratumumab or rHuPH20 will be provided.
11.6. Pharmacodynamic Analyses, and Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to
daratumumab. Analyses will be stratified by clinical covariates using the appropriate statistical
methods (eg, parametric or non-parametric, univariate or multivariate, analysis of variance
[ANOVA], or survival analysis, depending on the endpoint). Baseline level and changes in
expression patterns of specific cell types (NK, T, and B cells), CD38 expression in MM cells,
and complement inhibitory proteins expression in MM cells will be evaluated for association
with PK, clinical response, and disease parameters. Other biomarker parameters may be
evaluated in a similar fashion.
Any pharmacodynamic measures will be listed, tabulated, and where appropriate, plotted.
Subjects may be grouped by cohort, dose, or clinical response. Results of biomarker and
pharmacodynamic analyses may be presented in a separate report. 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.
11.7. Pharmacokinetic/Pharmacodynamic Analyses
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 performed, details and results of the analysis will be
presented in a separate report.
11.8. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse
events are adverse events with onset during the Treatment Phase or that are a consequence of a
pre-existing condition that has worsened since baseline. All reported adverse events with onset
during the treatment phase (ie, TEAEs, and adverse events that have worsened since baseline)
will be included in the analysis. For each adverse event, the percentage of subjects who


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experience at least 1 occurrence of the given event will be summarized for each treatment cohort.
The proportion of subjects who have an IRR and its two-sided 90% exact CI will be calculated
for each treatment cohort.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe
or a serious adverse event.
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 each laboratory analyte at baseline
and for observed values and changes from baseline at each scheduled timepoint. A listing of
subjects with any laboratory results outside the reference ranges will be provided.
Parameters with predefined NCI-CTCAE (Version 4.03) toxicity grades will be summarized.
Worst toxicity grade during treatment will be presented. Change from baseline to the worst
adverse event grade experienced by the subject during the study will be provided as shift tables.
Electrocardiogram (ECG)
Electrocardiogram data will be summarized based on categories of normal, abnormal either
clinically significant or not clinically significant and listed.
Vital Signs
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
timepoint.
Stem Cell Collection (D-VRd cohort only)
Descriptive statistics of number of stem cells collected, number of days of autologous stem cell
collection, drugs used for autologous stem cell mobilization, and requirement special stem cell
mobilizing agent (eg, mozobil) will be summarized.
11.9. Study Evaluation Team
A SET consisting of the participating investigators, the sponsor’s medical monitor, the sponsor’s
clinical pharmacologist (if PK data are being evaluated), the sponsor’s statistician the sponsor’s
safety officer, and the sponsor’s study manager will evaluate safety data after at least
6 toxicity-evaluable subjects complete Cycle 1 in each cohort. Additional data reviews by the
SET can be scheduled as needed to support decisions on dose selection or schedule modification.
The SET reviews and dose selection decisions will be documented in writing.


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12. 
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of subjects, 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.
12.1. Definitions
12.1.1. 
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a
medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the treatment. An adverse event 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 according to
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 adverse events starting with the signing of the ICF
(refer to Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse 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 subject 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 subject


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or may require intervention to prevent one of the other outcomes listed in the definition above.
Examples of such medical events include second primary malignancy. These should usually be
considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study drug and the event (eg, death from anaphylaxis), the event must
be reported as a serious and unexpected suspected adverse reaction even if it is a component of
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the
applicable product reference safety information. For daratumumab, the expectedness of an
adverse event will be determined by whether or not it is listed in the Investigator's Brochure13.
Anticipated events will be recorded and reported as described in Attachment 11. In Japan, the
Investigator's Brochure of bortezomib will be referred for the expectedness of an adverse event.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible,
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2. 
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
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.
Possible
An adverse event that might be due to the use of the drug. 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 drug. 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).


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12.1.3. 
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using
the NCI-CTCAE Version 4.03. Any adverse event or serious adverse event not listed in the
NCI-CTCAE Version 4.03 will be graded according to investigator clinical judgment by using
the standard grading outlined in the NCI-CTCAE Version 4.03.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the subject (eg, laboratory abnormalities).
12.2. Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety
evaluation include, but are not limited to:
 
Overdose of a sponsor study drug. No MTD 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.
 
Suspected abuse/misuse of a sponsor study drug
 
Accidental or occupational exposure to a sponsor study drug
 
Medication error involving a sponsor product (with or without subject/patient exposure to
the sponsor study drug, eg, name confusion)
 
Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of a serious adverse event should be recorded on the serious adverse event page
of the CRF.
12.3. Procedures
12.3.1. 
All Adverse Events
All events that meet the definition of a serious adverse event will be reported as serious adverse
events, regardless of whether they are protocol-specific assessments. Anticipated events will be
recorded and reported as described in Attachment 11. (Note: Some countries require reporting of
all adverse events to the health authorities, eg, Japan will not identify anticipated events for the
health authorities).
All adverse events 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 final dose of
study drug. The only exception is for subjects who have withdrawn informed consent for study
participation or for subjects who have received additional treatment with therapeutic intent for
MM within 30 days after the final dose of any component of the treatment regimen. For subjects
who have received additional treatment with therapeutic intent for MM during the adverse event
reporting period, only adverse events that are considered to be possibly, probably, or definitely


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related to the study drug or any part of the backbone treatment regimen must be reported (unless
the subject has been withdrawn from the study).
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the final dose of study drug, must be reported using the Serious Adverse Event Form. The
sponsor will evaluate safety information that is spontaneously reported by an investigator beyond
the timeframe specified in the protocol.
Death should not be recorded as an adverse event or serious adverse event, but as the outcome of
an adverse event. The event that resulted in the death should be reported as a serious adverse
event.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug,
must be recorded using medical terminology in the source document and the CRF. Whenever
possible, diagnoses should be given when signs and symptoms are due to a common etiology
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper
respiratory infection"). Investigators must record in the CRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events 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 serious adverse events 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 investigational 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.
For all studies with an outpatient Phase, including open-label studies, the subject 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 subject 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
 
Subject number


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 
Any other information that is required to do an emergency breaking of the blind
12.3.2. 
Serious Adverse Events
All serious adverse events 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 serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the CRF, which must be completed and
reviewed 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).
All serious adverse events that have not resolved by the end of the study, or that have not
resolved upon discontinuation of the subject'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 drug or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (subject 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 a
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization)
that occurs during the course of a subject's participation in a study must be reported as a serious
adverse event, except hospitalizations for the following:
 
If the subject has not experienced a significant medical event but is hospitalized overnight
only for observation following administration of study drug, then the hospitalization should
not be reported as a serious adverse event.
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons
such as pending placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not
be considered serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
 
For convenience, the investigator may choose to hospitalize the subject for the duration of
the treatment period. Note: This should not be considered a serious adverse event.


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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 (see Section 12, Adverse Event Reporting).
Refer to Attachment 15 for details on serious adverse event reporting after the end of the data
collection.
12.3.3. 
Pregnancy
All initial reports of pregnancy 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, stillbirth, and congenital
anomaly) are considered serious adverse events and must be reported using the Serious Adverse
Event Form. Any subject who becomes pregnant or experiences a positive pregnancy test during
the study must discontinue further study treatment. The subject should be referred to a physician
experienced in teratology for evaluation and advice. Investigators should follow the local label
for guidance on subject education and ensure that all subjects adhere to the local lenalidomide
REMS program (when lenalidomide is supplied locally), or the Lenalidomide Global Pregnancy
Prevention Plan provided in Attachment 14 (when lenalidomide is supplied centrally and no local
lenalidomide REMS program exists). Follow-up  information regarding the outcome of the
pregnancy and any postnatal sequelae in the infant will be required.
Because the effect of the study drug on sperm is unknown, pregnancies or positive pregnancy
tests in partners of male subjects included in the study will be reported by the study-site
personnel within 24 hours of their knowledge of the event using the appropriate pregnancy
notification form.
Pregnancy reporting will continue as described above after the end of the data collection until the
end of study (see Attachment 15).
12.4. 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.
13. 
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 subjects,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor
has established procedures in conformity with regulatory requirements worldwide to ensure


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appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates
will be conducted in accordance with those procedures.
13.1. 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 a serious adverse event, the
study-site personnel must report the PQC to the sponsor according to the serious adverse event
reporting timelines (refer to Section 12.3.2, Serious Adverse Events). A sample of the suspected
product should be maintained for further investigation if requested by the sponsor.
13.2. 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.
14. 
STUDY DRUG INFORMATION
14.1. Physical Description of the Study Drug
The daratumumab supplied for SC injection (Dara SC) in this study is a colorless to yellow
liquid and sterile concentrate of 120 mg/mL daratumumab + 2000 U/mL rHuPH20 as a liquid in
vial. The study agent should be essentially free of visible particulate matter at the time of syringe
preparation and drug product administration. It will be manufactured and provided under the
responsibility of the sponsor. Refer to the Investigator's Brochure for a list of excipients (Note:
In some countries, both daratumumab and rHuPH20 are treated as an investigative product. In
this study, the study drug refers to the co-formulation of daratumumab and rHuPH20)13. In
Japan, bortezomib is treated as an investigative product and will be provided by the sponsor.
14.2. Packaging
Dara SC is supplied in glass vials containing daratumumab at a concentration of 120 mg/mL and
rHuPH20 at a concentration of 2000 U/mL (~20 g/mL). It will be supplied to the site/pharmacy
as open-label supply.
14.3. Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each
vial will contain a study-specific label with a unique identification number.
14.4. Preparation, Handling, and Storage
14.4.1. 
Dara SC Formulation
Dara SC must be stored in the original carton in a refrigerator at controlled temperatures ranging
from 2°C to 8°C until it is removed for dose preparation. The study drug must not be utilized
after the expiry date printed on the label. Dara SC must be protected from light and must not be
frozen. The product does not contain preservatives; therefore, any unused portion remaining in


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the vial must be discarded. Refer to the IPPI for additional guidance on study drug preparation,
handling, and storage.
14.5. Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried
and accounted for throughout the study. The study drug administered to the subject must be
documented on the drug accountability form. All study drug will be stored and disposed of
according to the sponsor's instructions. Study-site personnel must not combine contents of the
study drug containers.
Study drug 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 drug 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
drug will be documented on the drug return form. When the study site is an authorized
destruction unit and study drug supplies are destroyed onsite, this must also be documented on
the drug 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 drug accountability purposes.
Study drug 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 drug will be supplied only
to subjects participating in the study. Returned study drug must not be dispensed again, even to
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the
study sites agreed upon with the sponsor.


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15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
 
Investigator's Brochure for daratumumab
 
Investigator’s Brochure for rHuPH20
 
Investigator's Brochure for bortezomib (in Japan only)
 
Investigational Product Preparation Instructions
 
Investigational Product and Procedures Manual
 
Laboratory Manual
 
IWRS Manual
 
eCRF completion guidelines
 
Sample ICF
 
Subject identification wallet card, including space for blood type and IAT result
 
Subject diaries for recording pre-dose and post-dose medications that are administered at
home
 
Other manuals and guidance documents as needed
16. 
ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
As discussed in Section 1.1.2.2, Preliminary Data from Study MMY1004 Part 2, preliminary
efficacy data suggest that SC administration of Dara SC may provide comparable or better
response rates compared with IV administration of Dara-IV. Additional benefits of Dara SC
compared with Dara-IV include:
 
Potential reduction in the incidence rate and severity of IRRs (compared with IV infusion),
due to slower absorption of daratumumab into systemic circulation
 
Shorter administration time (approximately 3 to 5 minutes compared with 4 to 7 hours for
IV infusion)
 
Reduced administration volume (SC administration of approximately 15 mL instead of
500 mL to 1000 mL IV infusion), which may be clinically meaningful for elderly subjects
with comorbid cardiac or renal insufficiency
Based on the mechanism of action of daratumumab, a potential risk could be infection; therefore,
the protocol requires the review of hematological laboratory results prior to daratumumab
administration. CD38 is distributed in erythrocytes and platelets. Safety data from a phase 3
clinical study (Study MMY3004) in subjects with relapsed or refractory MM comparing
daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd),
showed daratumumab may increase thrombocytopenia associated with bortezomib-based
regimens. Additionally, safety data from the phase 3 clinical study (Study MMY3003) in


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subjects with relapsed or refractory MM comparing daratumumab, lenalidomide and
dexamethasone (DRd) vs bortezomib and dexamethasone (Rd), showed daratumumab may
increase neutropenia associated with lenalidomide-based regimens. However, bleeding events
were low and the majority of events were minor (less than 1% of subjects experienced Grade 3
or 4 bleeding events). Anemia, all grades and Grade 3 or 4 in the MMY3004 study, were similar
among the 2 treatment groups. Routine safety laboratory measurement of hemoglobin and
platelets will be closely monitored in this study. Safety data from the phase 2 Study MMY1001,
evaluating the combination of daratumumab in combination with carfilzomib and
dexamethasone, showed a safety profile consistent with the individual agents. Carfilzomib has
been associated with cardiac toxicity, thus additional monitoring of cardiac function with
echocardiograms will be performed to monitor for cardiac safety in the D-Kd cohort of the study.
In a previous study with SC administration of daratumumab (MMY1004), a lower incidence of
IRRs was observed compared to the IRR rate reported from studies with IV infusion of
daratumumab. However, IRRs may still occur and may develop at a later timepoint than
previously observed with IV infusion due to the more gradual absorption (see Section 6.4 for
guidelines for prevention and management of IRRs). Subjects will therefore be observed for at
least 6 hours on their first day of SC daratumumab administration. Apart from IRRs, a similar
toxicity profile has been shown for SC versus IV infusion for anemia, thrombocytopenia, and
other toxicities. During this study, local tolerability at the SC injection site will be closely
monitored as well.
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects 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 subjects who are fully able to understand the risks, benefits, and
potential adverse events of the study, and provide their consent voluntarily will be enrolled. Note
that as specified in Section 16.2.3, Informed Consent, a legally acceptable representative may
provide consent on behalf of the subject.
16.2. Regulatory Ethics Compliance
16.2.1. 
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 subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study subjects are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.


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16.2.2. 
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 subjects)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved subject recruiting materials
 
Information on compensation for study-related injuries or payment to subjects 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 subjects
 
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 subjects, data or study conduct, unless required locally), the ICF, applicable
recruiting materials, and subject 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 subjects, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to subjects
 
If applicable, new or revised subject recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to subjects for participation
in the study, if applicable
 
New edition(s) of the Investigator's Brochure and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the
study drug
 
New information that may adversely affect the safety of the subjects or the conduct of the
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 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects
 
Report of deaths of subjects 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 subjects, 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).
16.2.3. 
Informed Consent Form
Each subject (or a legally acceptable representative) 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 subject 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 subjects or their legally acceptable representatives the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Subjects 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 subject will receive for the treatment
of his or her disease. Subjects 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 subject 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 subject, to the extent permitted by
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable
representative is authorizing such access. It also denotes that the subject agrees to allow his or
her study physician to recontact the subject for the purpose of obtaining consent for additional
safety evaluations, and subsequent disease-related treatments, if needed.


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The subject or legally acceptable representative 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 either the subject's or his or her legally acceptable
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject. Where local regulations require, a separate ICF may be used for the
required DNA component of the study.
If the subject or legally acceptable representative 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
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject's legally acceptable
representative is not available, 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 subject and to ensure compliance with applicable regulatory requirements. The
subject or legally acceptable representative must be informed about the study as soon as possible
and give consent to continue.
16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from subjects 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 subjects
confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative)
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 subject 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 biomarker, PK, and immunogenicity research is not conducted under standards
appropriate for the return of data to subjects. 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 subjects or investigators, unless required by law or local


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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.
16.2.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local
regulations) for additional research. Samples will only be used to understand daratumumab, to
understand MM to understand differential drug responders, and to develop tests/assays related to
daratumumab and MM. The research may begin at any time during the study or the post-study
storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be
stored for research (refer to Section 10.3, Withdrawal From the Use of Research Samples).
16.2.6. 
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 16.1, Study-Specific Design
Considerations.
17. 
ADMINISTRATIVE REQUIREMENTS
17.1. 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 subjects, 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) involves only logistic or administrative aspects of the study, the
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any
departure from the protocol. In all cases, contact with the sponsor must be made as soon as
possible to discuss the situation and agree on an appropriate course of action. The data recorded
in the CRF and source documents will reflect any departure from the protocol, and the source
documents will describe this departure and the circumstances requiring it.


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17.2. Regulatory Documentation
17.2.1. 
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.
17.2.2. 
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug 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 according to local regulations),
written IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, subject compensation programs. This approval must clearly identify the specific
protocol by title and number and must be signed (or sealed, where appropriate according to
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 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 subject:
 
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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17.3. Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy
identification of each subject during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and date of birth (as allowed by local regulations). In cases where the subject is not enrolled into
the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who
were seen to determine eligibility for inclusion in the study.
17.4. Source Documentation
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:
subject 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 adverse events and follow-up of adverse events; concomitant medication;
drug receipt/dispensing/return records; study drug administration information; and date of study
completion and reason for early discontinuation of study drug 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 minimum source documentation requirements for
Section 4.1, Inclusion Criteria and Section 4.2, Exclusion Criteria that specify a need for
documented medical history are as follows:
 
Referral letter from treating physician
 
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 subject interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An electronic source 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 the electronic source system is utilized, references made to
the CRF in the protocol include the electronic source system but information collected through


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the electronic source system may not be limited to that found in the CRF. Data in this system
may be considered source documentation.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
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
electronic CRF, 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 subject's source documents. Data must be entered into
CRF in English. The eCRF must be completed as soon as possible after a subject visit and the
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever
possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
a CRF are needed after the initial entry into the CRF, this can be done in either of the following
ways:
 
Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and
study-site personnel.
 
There will be no data collection in the eCRF after the database is closed for the final
analysis. Attachment 15 describes study procedures for subjects who continue receiving
study drugs after the end of the data collection.
17.6. Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central 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 CRF for accuracy and completeness during on-site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with


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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.
17.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF
and all source documents that support the data collected from each subject, 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.
17.8. Monitoring
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 the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
CRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of
verifying that the recorded data are consistent with the original source data. Findings from this
review will be discussed with the study-site personnel. The sponsor expects that, during
monitoring visits, the relevant study-site personnel will be available, the source documents will


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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 may take place for data identified by the sponsor as
requiring central review.
17.9. Study Completion/Termination
17.9.1. 
End of Data Collection and End of Study
The end of data collection occurred 10 months after the last subject was enrolled in the D-Kd
cohort.
The end of study will occur when any of the following occurs:
 when all subjects have discontinued daratumumab treatment,
 or when all subjects who are still receiving study treatment after the clinical cutoff date of
the final analysis have access through another source such as commercial availability,
continued access through a dedicated long-term extension study, or a patient access
program,
 or by June 2024, if the prior 2 criteria are not met first.
The final data from the study site will be sent to the sponsor (or designee) after completion of the
final subject assessment at that study site, in the time frame specified in the Clinical Trial
Agreement.
After the end of the data collection, the clinical database will be closed, and no additional data
will be collected in the eCRF. Attachment 15 describes study procedures for subjects who
continue receiving study drugs after the end of the data collection.


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17.9.2. 
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 subjects by the investigator
 
Discontinuation of further study drug development
17.10. 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. Subject 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.
17.11. Use of Information and Publication
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


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information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain eCRF data from all study sites that participated in the study according to the
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. Results
of biomarker analyses performed after the Clinical Study Report has been issued may be reported
in a separate report and will not require a revision of the Clinical Study Report. Study subject
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 study end
date, or the sponsor confirms there will be no multicenter study publication. Authorship of
publications resulting from this study will be based on the guidelines on authorship, such as
those described in the 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 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.


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REFERENCES
1. 
Avet-Loiseau H, et al. Oral presentation presented at: ASH; December 3-6, 2016; San Diego, CA.
2. 
Bittner B, Richter WF, Hourcade-Potelleret F, et al. Development of a subcutaneous formulation for
trastuzumab - nonclinical and clinical bridging approach to the approved intravenous dosing regimen.
Arzneimittelforschung. 2012;62:401-409.
3. 
Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry. 3rd ed. Philadelphia: WB Saunders; 1998.
4. 
Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with blood
compatibility testing. Transfusion. 2015;55:1545-1554.
5. 
Chapuy CI, Aguad MD, Nicholson RT, et al. International validation of dithiothreitol (DTT)-based method to
resolve the daratumumab interference with blood compatibility testing. Transfusion. 2016;56:2964-2972.
6. 
Chiu C, Casneuf T, Axel A, et al. Daratumumab in combination with lenalidomide plus dexamethasone
induces clonality increase and t-cell expansion: results from a phase 3 randomized study (POLLUX). Presented
at 58th  Annual Meeting and Exposition of the American Society of Hematology (ASH); December 3-6, 2016;
San Diego, CA. Abstract 4531.
7. 
Davies A, Merli F, Mihaljevic B, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular
lymphoma (SABRINA): stage 1 analysis of a randomised Phase 3 study. Lancet Oncol. 2014;15:343-352.
8. 
DARZALEX (daratumumab) for infusion. Summary of Product Characteristics. (2020). Available at
https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information en.pdf.
9. 
DARZALEX (daratumumab) for injection. United States Package Insert (2020). Available at
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761145.
10. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma.
Leukemia 2006;20:1467-1473.
11. Engelhardt M, Terpos E, Kleber M, et al. European Myeloma Network Recommendations on the Evaluation
and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014;99(2): 232-42.
12. Indiana University Department of Medicine, Clinical Pharmacology: Flockhart Table. 2016. Available at:
http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed on 30 April 2018.
13. Investigator's Brochure: JNJ-54767414 (daratumumab). Edition 14 Addendum 1; Janssen Research &
Development, LLC (30 Nov 2017).
14. Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of (neo)adjuvant
trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a Phase 3,
open-label, multicentre, randomised trial. Lancet Oncol. 2012;13:869-878.
15. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell
expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016; 128:384-394.
16. 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.
17. KYPROLIS (carfilzomib) for injection. Initial US Approval 2012. [Prescribing Information]. Onyx
Pharmaceuticals, Inc.
18. KYPROLIS for Injection Summary of Product Characteristics. (May 2018).
19. Ladetto M, Bruggemann M, Monitillo L, et al. Next-generation sequencing and real-time PCR for minimal
residual disease detection in B-cell disorders. Leukemia. 2014;28:1299-1307.
20. 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.
21. Lonial S, San-Miguel J, Martinez-Lopez J, et al. Daratumumab in combination with carfilzomib and
dexamethasone in patients (pts) with relapsed multiple myeloma (MMY1001): an open-label, Phase 1b study.
Poster presented at the 59th ASH annual meeting and exposition, Atlanta, GA. Dec 9-12, 2017.


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22. Martinez-Lopez J, Lahuerta J, Pepin, F, et al. Prognostic value of deep sequencing method for minimal residual
disease detection in multiple myeloma. Blood. 2014;123:3073-3079.
23. McCudden C, Axel A, Slaets D, et al. Assessing clinical response in multiple myeloma (MM) patients treated
with monoclonal antibodies (mAbs): Validation of a daratumumab IFE reflex assay (DIRA) to distinguish
malignant M protein from therapeutic antibody. J Clin Oncol. 2015 (suppl; abstr 8590).
24. Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up. Annals Oncol. 2013; 24 Suppl 6:vi133-7.
25. 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.
26. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology
Group. Am J Clinc Oncol. 1982;5:649-655.
27. 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.
28. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for
the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548.
29. Salar A, Bittner B, Bouabdallah R, et al. Comparison of subcutaneous versus intravenous administration of
rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase Ib study. J. Clin
Oncol. 2014;32:1782-1791
30. Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin)
using hyaluronidase. Br J Cancer. 2013;109:1556-1561.
31. Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner B. Comparison of subcutaneous and
intravenous administration of trastuzumab: a Phase I/Ib trial in healthy male volunteers and patients with
HER2-positive breast cancer. J Clin Pharmacol. 2013;53:192-201.


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ATTACHMENTS
Attachment 1: International Myeloma Working Group Diagnostic Criteria
Multiple myeloma is defined as clonal bone marrow plasma cells 10% or biopsy-proven bony or
extramedullary plasmacytomaa and any one or more of the following myeloma defining events:
 
Myeloma defining events:
 
Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative
disorder, specifically:
o 
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of
normal or >2.75 mmol/L (>11 mg/dL)
o 
Renal insufficiency: creatinine clearance <40 mL per minb or serum creatinine
>177 μmol/L (>2 mg/dL)
o 
Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin
value <100 g/L
o 
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc,d
 
Any one or more of the following biomarkers of malignancy:
 
Clonal bone marrow plasma cell percentagea 60%
 
Involved:uninvolved serum FLC ratioe 100
 
>1 focal lesions on MRI studiesf
a. 
Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry,
immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be
estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the
highest value should be used.
b. 
Measured or estimated by validated equations.
c. 
If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish
from solitary plasmacytoma with minimal marrow involvement.
d. 
PET-CT=18F-fluorodeoxyglucose positron emission tomography with computed tomography.
e. 
These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The
involved free light chain must be 100 mg/L.
f. 
Each focal lesion must be 5 mm or more in size.
(Rajkumar 201428)


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Attachment 2: Eastern Cooperative Oncology Group Performance Status Grade
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 MD, Group Chair (Oken 198226)


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Attachment 3: Modified Diet in Renal Disease Formula
For creatinine in mg/dL, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal
disease (MDRD) formulas 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 estimated glomerular filtration rate (e-GFR) for the modified diet in renal
disease (MDRD) formulas is:
e-GFR (MDRD) mL/min per 1.73m2= 175 × [serum creatinine µmol/L/88.4]-1.154 × [age]-0.203 ×
[1.212 if black] × [0.742 if female]
(Levey 200620)


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Attachment 4: 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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Attachment 5: 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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Attachment 6: Asthma Guidelines
Components of
Severity  
Classification ofAsthma Severity
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%
60-80 yr 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
Daily  
Several times 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
Risk
Exacerbations
requiring oral
systemic
corticosteroids
0-1/year
≥2 exacerbations in 6
months 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 6
months 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
6 months 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 subjects in any severity category.
Recommended
Step for
Initiating Treatment
Step 1 
Step 2 
Step 3 and consider 
short course of oral 
steroids 
Step 3: 
medium  
dose ICS  
and 
consider 
short 
course of
Step 3 and 
consider 
short course 
of oral 
steroids 
Step 3 and 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 2-6 weeks, evaluate level of asthma control that is achieved.
0-4years: If no clear benefit is observed in 4-6 weeks, 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
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 up
1 step
• Reevaluate
in 2 6
week
s
• For side
effects,
consider
alternativ
e
treatment
options
• Consider short course
of oral steroids
• Step up 1 2 steps
•
Consider
short course
of oral
steroids
•
Step up 1-2
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 2-6 weeksto achieve
control.
0-4 years: If no 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 2-6 weeks to achieve
control.
0-4 years: If no 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.


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Attachment 7: New York Heart Association (NYHA) 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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Attachment 8: Antihistamines That May Be Used Pre-dose
The following antihistamines may be used pre-dose, 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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Attachment 9: Body Surface Area Nomogram
Body surface area should be calculated according to the following formula:


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Attachment 10: 
Interpretation of The SEBIA Hydrashift 2/4 Daratumumab IFE 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 subject 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 subject 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 subject 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 subject 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 subject is not in a complete response (CR), because the CR response criteria requires a
negative SPEP and serum IFE.


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Attachment 11: 
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (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 in Section 12.3.1. Any anticipated event that meets serious
adverse event criteria will be reported to the sponsor as described in Section 12.3.2. 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 IRB/ECs. If an anticipated event is considered disease-related or not related to study drug
the event will be exempt from expedited reporting.
To meet US 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/ECs. 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 cohort.
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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Attachment 12: 
Inhibitors and Inducers of CYP3A
Examples of inhibitors and inducers of CYP3A are as shown below12:
Inhibitors of CYP3A
Strong inhibitors: 
Moderate inhibitors:
INDINAVIR  
amiodarone
TIPRANAVIR  
chloramphenicol
COBICISTAT  
boceprevir
INDINAVIR  
ciprofloxacin
TROLEANDOMYCIN  
delavirdine
TELAPRAVIR  
diethyl-dithiocarbamate
DANOPREVIR  
fluoxetine
ELVITEGRAVIR  
fluvoxamine
SAQUINAVIR  
atazanavir/RIT
LOPINAVIR  
gestodene
NELFINAVIR  
imatinib
RITONAVIR  
mifepristone
CLARITHROMYCIN  
norfloxacin
MIBEFRADIL 
norfluoxetine
LCL161 
star fruit
ITRACONAZOLE 
voriconazole
KETOCONAZOLE  
Darunavir
POSACONAZOLE 
dronedarone
NEFAZODONE  
crizotinib
TELITHROMYCIN  
casopitant
CONIVAPTAN 
amprenavir
BOCEPREVIR  
imatinib
VORICONAZOLE  
tofisopam
SUBOXONE  
cyclosporine
GRAPEFRUIT JUICE DSb
Moderate inhibitors:
aprepitant
erythromycin
diltiazem
fluconazole
grapefruit juice
Seville oranges
verapamil
cimetidine
a. Azithromycin is unique in that it does not inhibit CYP3A
b. 240 mL GFJ double-strength administered TID for 3 days


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Inducers of CYP3A
Potent inducers 
Moderate inducers
rifampin  
ritonavir and St. Johns wort
mitotane 
[semagacestat]
avasimibe 
efavirenz
phenytoin  
tipranavir and ritonavir
carbamazepine 
bosentan
enzalutamide 
genistein
St John's Wort 
thioridazine
rifabutin
phenobarbital 
nafcillin
[talviraline]
lopinavir
modafinil
etravirine
lersivirine


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Attachment 13: 
Contraceptive (and Barrier) Guidance and Collection of Pregnancy
Information
Subjects must follow contraceptive measures as outlined in Section 4.1, Inclusion Criteria. Pregnancy
information will be collected and reported as noted in Section 9.6 Safety Evaluations (Pregnancy
Testing).
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy (HRT), however in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient. (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.)
Contraceptive (birth control) use by men or women should be consistent with local regulations regarding
the acceptable methods of contraception for those participating in clinical studies. Typical use failure
rates may differ from those when used consistently and correctly. Use should be consistent with local
regulations regarding,
DARATUMUMAB specific
Participants must be willing and able to adhere to the following prohibitions and restrictions during the
course of the study to be eligible for participation. For restrictions related to concomitant medications,
please refer to Section 8.3 Prohibited Therapies
1. 
Female subjects of reproductive childbearing potential (defined as post-menarche until
post-menopause unless permanently sterilized) must commit to either abstain continuously from
heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during
the Treatment Period, during any dose interruptions, and for 3 months after the last dose of any study
drug. Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study drug and is


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consistent with the usual lifestyle of the subject. This birth control method must include one highly
effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control
pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy with
confirmation of procedure) and one additional effective contraceptive method (male latex or
synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing.
Reliable contraception is indicated even where there has been a history of infertility, unless due to
hysterectomy or bilateral oophorectomy.
 
A woman of childbearing potential must have 1 negative serum or urine pregnancy tests at
Screening. For requirements during the Treatment Phase, refer to Section 4.1.
 
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 study drug.
 
Male subjects of reproductive potential who are sexually active with females of reproductive
potential must always use a latex or synthetic condom during the study and for 3 months after
discontinuing daratumumab (even after a successful vasectomy).
 
Male subjects of reproductive potential must not donate semen or sperm during the study,
during dose interruptions, or for 3 months after the last dose of any study drug.
2. 
Typically, IV contrast is not used in CT scanning of subjects with secretory multiple myeloma
because of the risk to the kidney. If administration of IV contrast is necessary, then adequate
precautions including hydration are indicated.
For Lenalidomide studies
For women of childbearing potential, adequate contraception, without interruption, must begin 28 days
before starting lenalidomide and continue during the Treatment Phase, during any dose interruptions, and
for at least 4 weeks after the last dose of lenalidomide. All women must not donate ova during the study
and for at least 4 weeks after the last dose of lenalidomide. All women must not breastfeed while taking
lenalidomide and for at least 28 days after the last dose of lenalidomide.
Prior to starting lenalidomide, 2 negative pregnancy tests are required. The first pregnancy test must be
performed within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be
performed within 24 hours prior to the start of lenalidomide.
During the Treatment Phase, pregnancy tests are required weekly during Cycle 1 and then monthly in
subsequent cycles in women with regular menstrual cycles or every 2 weeks in women with irregular
menstrual cycles. A pregnancy test is also required at the End-of-Treatment Visit and 28 days following
the last dose of lenalidomide for women with regular menstrual cycles or 14 and 28 days following the
last dose of lenalidomide for women with irregular menstrual cycles.  Additional pregnancy tests may be
required, as specified in the local lenalidomide REMS (where lenalidomide is supplied locally) or the
Lenalidomide Global Pregnancy Prevention Plan in Attachment 14 (where lenalidomide is supplied
centrally and no local lenalidomide REMS program exists).
A man who is sexually active with a pregnant woman or a woman of childbearing potential must always
use a latex or synthetic condom during the study and for at least 4 weeks after discontinuing lenalidomide
(even if he has undergone a successful vasectomy). All men must not donate semen or sperm during the
study, during dose interruptions, or for 3 months after the last dose of any study drug.
Because of the embryo-fetal risk of lenalidomide, all subjects must adhere to the local lenalidomide
REMS program (when lenalidomide is supplied locally), or the Lenalidomide Global Pregnancy


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Prevention Plan provided in Attachment 14 (when lenalidomide is supplied centrally and no local
lenalidomide REMS program exists).
Subjects must not donate blood during therapy, during dose interruptions, and for at least 4 weeks
following discontinuation of lenalidomide.
For Carfilzomib studies
1. 
Women of childbearing potential should be advised to avoid becoming pregnant while being treated
with carfilzomib. Given that carfilzomib was clastogenic in the in vitro chromosomal aberration test
in peripheral blood lymphocytes, as a precaution, women of childbearing potential and/or their male
partners should use highly effective contraception methods or abstain from sexual activity during
treatment and for 30 days after treatment with carfilzomib and for 3 months after cessation of
daratumumab treatment.
2. 
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 1
additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical
cap).  It cannot be excluded that the efficacy of oral contraceptives may be reduced during
carfilzomib treatment.  In addition, due to an increased risk of venous thromboembolic events
associated with carfilzomib, females should avoid the use of hormonal contraceptives that are
associated with a risk of thrombosis during treatment with carfilzomib. Female subjects 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 non-hormonal method of
highly effective contraception. Contraception must begin 4 weeks prior to dosing. Reliable
contraception is indicated even where there has been a history of infertility, unless due to
hysterectomy.
3. 
Women of childbearing potential must have a negative urine or serum pregnancy test at screening
within 14 days prior to randomization.
4. 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 month after receiving the last dose of carfilzomib.
5. 
Male subjects of reproductive potential who are sexually active with females of reproductive
potential or pregnant must always use a latex or synthetic condom during the study and for 3 months
after discontinuing study treatment (even after a successful vasectomy).
6. 
Male subjects of reproductive potential must not donate semen or sperm during the study, during
dose interruptions, or for 3 months after the last dose of any study drug.


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Attachment 14: 
Lenalidomide Global Pregnancy Prevention Plan
Where lenalidomide is supplied locally, subjects must adhere to the local lenalidomide REMS program.
Where lenalidomide is supplied centrally and no local lenalidomide REMS program exists, then subjects
must adhere to the lenalidomide Global Pregnancy Prevention Plan provided in this attachment.
Within this attachment only, use of the phrase “study drug” refers to lenalidomide.
1.1 Pregnancy Prevention Risk Management Plans
1.1.1 Lenalidomide Pregnancy Prevention Risk Management Plan
1.1.1.1 Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials
This attachment applies to all subjects receiving lenalidomide therapy. The following Pregnancy Risk
Minimisation Plan documents are included:
1) Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control
Methods (Section 1.1.1.2);
2) Lenalidomide Education and Counseling Guidance Document (Section 1.1.1.3);
3) Lenalidomide Information Sheet (Section 1.1.1.4).
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth
Control Methods document (Section 1.1.1.2) provides the following information:
 
Potential risks to the fetus associated with lenalidomide exposure
 
Definition of Female of Childbearing Potential
 
Pregnancy testing requirements for subjects receiving Lenalidomide who are females of
childbearing potential
 
Acceptable birth control methods for both female subjects of childbearing potential and male
subjects receiving Lenalidomide in the study
 
Requirements for counseling of all study subjects receiving Lenalidomide about pregnancy
precautions and the potential risks of fetal exposure to lenalidomide
2. The Lenalidomide Education and Counseling Guidance Document (Section 1.1.1.3) must be
completed and signed by either a trained counselor or the Investigator at the participating clinical
center prior to each dispensing of lenalidomide study treatment. A copy of this document must be
maintained in the subject records.
3. The Lenalidomide Information Sheet (Section 1.1.1.4) will be given to each subject receiving
lenalidomide study therapy. The subject must read this document prior to starting lenalidomide
study treatment and each time they receive a new supply of study drug.


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1.1.1.2 Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth
Control Methods)
Risks Associated with Pregnancy
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. An embryofetal development study in animals
indicates that lenalidomide produced malformations in the offspring of female monkeys who received the
drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore,
a risk minimization plan to prevent pregnancy must be observed.
Criteria for females of childbearing potential (FCBP)
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has not
undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive
months (ie, has had menses at any time in the preceding 24 consecutive months).
Counseling
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following are met
(ie, all females of childbearing potential must be counseled concerning the following risks and
requirements prior to the start of lenalidomide study therapy):
 
She understands the potential teratogenic risk to the unborn child
 
She understands the need for effective contraception, without interruption, 4 weeks before
starting study treatment, throughout the entire duration of study treatment, dose interruption
and 28 days after the end of study treatment
 
She should be capable of complying with effective contraceptive measures
 
She is informed and understands the potential consequences of pregnancy and the need to
notify her study doctor immediately if there is a risk of pregnancy
 
She understands the need to commence the study treatment as soon as study drug is dispensed
following a negative pregnancy test
 
She understands the need and accepts to undergo pregnancy testing based on the frequency
outlined in this protocol (Section 1.1.1.2)
 
She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide
The investigator must ensure that for females of childbearing potential:
 
Complies with the conditions for pregnancy risk minimization, including confirmation that
she has an adequate level of understanding
 
Acknowledge the aforementioned requirements
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the following
are met (ie, all females NOT of childbearing potential must be counseled concerning the following risks
and requirements prior to the start of lenalidomide study therapy):
 
She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide


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Traces of lenalidomide have been found in semen.  Male subjects taking lenalidomide must meet the
following conditions (ie, all males must be counseled concerning the following risks and requirements
prior to the start of lenalidomide study therapy):
 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female
or a female of childbearing potential
 
Understand the need for the use of a condom even if he has had a vasectomy, if engaged in
sexual activity with a pregnant female or a female of childbearing potential.
Contraception
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of
contraception simultaneously or to practice complete abstinence from heterosexual contact during the
following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while
participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment
discontinuation.
The two methods of reliable contraception must include one highly effective method and one additional
effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if
needed. The following are examples of highly effective and additional effective methods of contraception:
 
Highly effective methods:
 Intrauterine device (IUD)
 Hormonal (birth control pills, injections, implants)
 Tubal ligation
 Partner’s vasectomy
 
Additional effective methods:
 Male condom
 Diaphragm
 Cervical Cap
Because of the increased risk of venous thromboembolism in subjects with multiple myeloma taking
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a subject is
currently using combined oral contraception the subject should switch to one of the effective method
listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing
combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment
with dexamethasone.
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be
considered particularly in subjects with neutropenia.
Pregnancy testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for
females of childbearing potential, including females of childbearing potential who commit to complete
abstinence, as outlined below.


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Before starting study drug
Female Subjects:
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting study
drug. The first pregnancy test must be performed within 10 to 14 days prior to the start of study drug and
the second pregnancy test must be performed within 24 hours prior to the start of study drug. The subject
may not receive study drug until the study doctor has verified that the results of these pregnancy tests are
negative.
Male Subjects:
Must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female
or a female of childbearing potential while participating in the study, during dose interruptions and for at
least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy.
During study participation and for 28 days following study drug discontinuation
Female Subjects:
 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the
first 28 days of study participation and then every 28 days while on study, at study
discontinuation, and at day 28 following study drug discontinuation. If menstrual cycles are
irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14
days while on study, at study discontinuation, and at days 14 and 28 following study drug
discontinuation.
 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two
reliable methods of birth control.
 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be
conducted at a minimum of every 28 days.
 
If pregnancy or a positive pregnancy test does occur in a study subject, study drug must be
immediately discontinued.
 
Pregnancy testing and counseling must be performed if a subject misses her period or if her
pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be
discontinued during this evaluation.
 
Females must agree to abstain from breastfeeding during study participation and for at least
28 days after study drug discontinuation.
Male Subjects:
 
Counseling about the requirement for complete abstinence or condom use during sexual
contact with a pregnant female or a female of childbearing potential and the potential risks of
fetal exposure to lenalidomide must be conducted at a minimum of every 28 days.
 
If pregnancy or a positive pregnancy test does occur in the partner of a male study subject
during study participation, the investigator must be notified immediately.
Additional precautions
 
Subjects should be instructed never to give this medicinal product to another person and to
return any unused capsules to the study doctor at the end of treatment.


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 
Female subjects should not donate blood during therapy, during dose interruptions, and for at
least 28 days following discontinuation of study drug.
 
Male subjects should not donate blood, semen or sperm during therapy, during
dose-interruptions, or for at least 28 days following discontinuation of study drug.
 
Only enough study drug for one cycle of therapy may be dispensed with each cycle of
therapy.
1.1.1.3 Lenalidomide Education and Counseling Guidance Document
To be completed prior to each dispensing of study drug.
Protocol Number: 
Subject Name (Print): 
 DOB: 
/
/
 (mm/dd/yyyy)
(Check the appropriate box to indicate risk category)
Female: □
If female, check one:
□ FCBP (Female of childbearing potential): sexually mature female who: 1) has not
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least
24 consecutive months (ie, has had menses at any time during the preceding 24
consecutive months)
□ NOT FCBP
Male: 
□
Do Not Dispense study drug if:
 
The subject is pregnant.
 
No pregnancy tests were conducted for a FCBP.
 
The subject states she did not use TWO reliable methods of birth control (unless
practicing complete abstinence of heterosexual contact) [at least 28 days prior to
therapy, during therapy and during dose interruption].
FCBP:
1. I verified that the required pregnancy tests performed are negative.
2. I counseled FCBP regarding the following:
 
Potential risk of fetal exposure to lenalidomide: If lenalidomide is taken during pregnancy, it
may cause birth defects or death to any unborn baby. Females are advised to avoid pregnancy
while taking lenalidomide. The teratogenic potential of lenalidomide in humans cannot be
ruled out. FCBP must agree not to become pregnant while taking lenalidomide.


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 
Using TWO reliable methods of birth control at the same time or complete abstinence from
heterosexual contact [at least 28 days prior to therapy, during therapy, during dose
interruption and 28 days after discontinuation of study drug].
 
That even if she has amenorrhea, she must comply with advice on contraception
 
Use of one highly effective method and one additional method of birth control AT THE
SAME TIME. The following are examples of highly effective and additional effective
methods of contraception:
 Highly effective methods:
o Intrauterine device (IUD)
o Hormonal (birth control pills, injections, implants)
o Tubal ligation
o Partner’s vasectomy
 Additional effective methods:
o Male condom
o Diaphragm
o Cervical Cap
 
Pregnancy tests before and during treatment, even if the subject agrees not to have
reproductive heterosexual contact. Two pregnancy tests will be performed prior to receiving
study drug, one within 10 to 14 days and the second within 24 hours of the start of study
drug.
 
Frequency of pregnancy tests to be done:
 Every week during the first 28 days of this study and a pregnancy test every 28 days
during the subject’s participation in this study if menstrual cycles are regular or every 14
days if cycles are irregular.
 If the subject missed a period or has unusual menstrual bleeding.
 When the subject is discontinued from the study and at day 28 after study drug
discontinuation if menstrual cycles are regular. If menstrual cycles are irregular,
pregnancy tests will be done at discontinuation from the study and at days 14 and 28 after
study drug discontinuation.
 
Stop taking study drug immediately in the event of becoming pregnant and to call their study
doctor as soon as possible.
 
NEVER share study drug with anyone else.
 
Do not donate blood while taking study drug, during dose interruptions, and for 28 days after
stopping study drug.
 
Do not breastfeed a baby while participating in this study and for at least 28 days after study
drug discontinuation.
 
Do not break, chew, or open study drug capsules.
 
Return unused study drug to the study doctor.


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3. Provide Lenalidomide Information Sheet to the subject.
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST
24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY):
1. I counseled the female NOT of child bearing potential regarding the following:
 
Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP)
 
NEVER share study drug with anyone else.
 
Do not donate blood while taking study drug, during dose interruptions, and for 28 days after
stopping study drug.
 
Do not break, chew, or open study drug capsules
 
Return unused study drug capsules to the study doctor.
2. Provide Lenalidomide Information Sheet to the subject.
MALE:
1. I counseled the Male subject regarding the following:
 
Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP).
 
To engage in complete abstinence or use a condom when engaging in sexual contact
(including those who have had a vasectomy) with a pregnant female or a female of
childbearing potential, while taking study drug, during dose interruptions and for 28 days
after stopping study drug.
 
Males should notify their study doctor when their female partner becomes pregnant and
female partners of males taking study drug should be advised to call their healthcare provider
immediately if they get pregnant.
 
NEVER share study drug with anyone else.
 
Do not donate blood, semen or sperm while taking study drug, during dose interruptions, and
for 28 days after stopping study drug.
 
Do not break, chew, or open study drug capsules.
 
Return unused study drug capsules to the study doctor.
2. Provide Lenalidomide Information Sheet to the subject.
Investigator/Counselor Name (Print): 
(circle applicable)
Investigator/Counselor Signature: 
 Date: 
/
/
(circle applicable)
**Maintain a copy of the Education and Counseling Guidance Document in the subject records.**


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1.1.1.4 Lenalidomide Information Sheet
FOR SUBJECTS ENROLLED IN CLINICAL RESEARCH STUDIES
Please read this Lenalidomide Information Sheet before you start taking study drug and each time you get
a new supply. This Lenalidomide Information Sheet does not take the place of an informed consent to
participate in clinical research or talking to your study doctor or healthcare provider about your medical
condition or your treatment.
What is the most important information I should know aboutlenalidomide?
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby.
Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide causes life-
threatening birth defects. Lenalidomide has not been tested in pregnant women but may also
cause birth defects. Findings from a monkey study indicate that lenalidomide caused birth defects
in the offspring of female monkeys who received the drug during pregnancy.
If you are a female who is able to become pregnant:
 
Do not take study drug if you are pregnant or plan to become pregnant
 
You must practice complete abstinence or use two reliable, separate forms of effective
birth control at the same time:
 for 28 days before starting study drug
 while taking study drug
 during dose interruptions of study drug
 for 28 days after stopping study drug
 
You must have pregnancy testing done at the following times:
 within 10 to 14 days and again 24 hours prior to the first dose of study drug
 weekly for the first 28 days
 every 28 days after the first month or every 14 days if you have irregular menstrual
periods
 if you miss your period or have unusual menstrual bleeding
 28 days after the last dose of study drug (14 and 28 days after the last dose if menstrual
periods are irregular)
 
Stop taking study drug if you become pregnant during treatment
 If you suspect you are pregnant at any time during the study, you must stop study drug
immediately and immediately inform your study doctor. Your study doctor will report all
cases of pregnancy to Celgene Corporation
 
Do not breastfeed while taking study drug
 
The study doctor will be able to advise you where to get additional advice on contraception.
If you are a female not of childbearing potential:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor will
confirm that you are not able to become pregnant.


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If you are a male:
Lenalidomide is detected in trace quantities in human semen. The risk to the foetus in females of
child bearing potential whose male partner is receiving lenalidomide is unknown at this time.
 
Male subjects (including those who have had a vasectomy) must practice complete abstinence
or must use a condom during sexual contact with a pregnant female or a female that can
become pregnant:
 While you are taking study drug
 During dose interruptions of study drug
 For 28 days after you stop taking study drug
 
Male subjects should not donate sperm or semen while taking study drug and for 28 days
after stopping study drug.
 
If you suspect that your partner is pregnant any time during the study, you must
immediately inform your study doctor. The study doctor will report all cases of
pregnancy to Celgene Corporation. Your partner should call their healthcare provider
immediately if they get pregnant.
2. Restrictions in sharing study drug and donating blood:
 
Do not share study drug with other people. It must be kept out of the reach of children
and should never be given to any other person.
 
Do not donate blood while you take study drug, during dose interruptions, and for 28 days
after stopping study drug.
 
Do not break, chew, or open study drug capsules.
 
You will get no more than a 28-day supply of study drug at one time.
 
Return unused study drug capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your study
doctor for more information.


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Attachment 15: 
Continuation of Treatment After Clinical Cutoff for the Final Analysis (End
of the Data Collection)
Protocol Amendment 5 will allow those subjects who are benefiting from study treatment to continue
receiving study drugs after the end of data collection until the study drugs are commercially available,
available from another source (eg. via a dedicated long-term extension study), or until study completion.
The following limited schedule is applicable.
Documentation of assessments performed is required only in the subject file/source notes.
Dosage and Administration
Daratumumab will be administered according to the regimen established prior to Amendment 5 (see
Section 6 [Dosage and Administration]).
Treatment Period
Once the sponsor has notified investigators that the clinical cutoff for the final analysis has been achieved
(end of the data collection), subjects may continue treatment with daratumumab until PD per investigator
evaluation, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the
start of subsequent anticancer therapy. Post-treatment follow-up is not applicable for subjects who
discontinue study treatment in this period, except for HBV DNA testing as described below.
Efficacy Evaluations
Investigators should monitor and assess subjects for response to treatment or disease progression
according to local institutional practice and make decisions if treatment should be continued based on
benefit /risk evaluation. The assessments and outcome should be entered in the subject file/source notes.
Safety Evaluations
Once the data collection has ended, local hematology laboratory assessments, chemistry laboratory
assessments, and assessment of vital signs should still be performed on Day 1 of each dosing cycle for
consistency with previous cycles and to guide safe use of study treatment. For patients in D-Kd cohort
transthoracic echocardiogram should still be performed every 6 cycles. These local results do not need to
be reported to the sponsor.
Safety Reporting
Once the data collection has ended, serious adverse events that occur while the subject is receiving study
drug and within 30 days after the last dose of study drug will be collected and reported to the sponsor’s
global medical safety database only via the same serious adverse event reporting process used over the
course of the study (see Section 12.3.2 [Serious Adverse Events]). Serious adverse events should also be
documented in the subject file/source notes.
Pregnancy reporting should continue as described in Section 12.3.3 [Pregnancy]. The pregnancy should
be documented in the subject file/source notes.
HBV DNA Tests
Subjects who are positive for anti-HBc or anti-HBs will undergo testing for HBV DNA by PCR every
12 weeks (±1 month) after entering this treatment period. Testing will continue for 6 months after the last
dose of study treatment. Subjects 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


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tested for HBV by PCR. Results of the HBC-DNA tests should be documented in the subject’s file. If the
hepatitis B serologic status of a subject in the DVMP, DRd, or DVRd cohort is unknown, HBsAg,
Anti-HBs, and Anti-HBc testing is recommended if the subject is still receiving daratumumab (or is
within 6 months after the last dose).
Sample Collection and Handling
There are no PK, immunogenicity, or biomarker assessments during this treatment period, and any sample
collection or test for safety or disease evaluation should comply with standard local institution practice.
Case Report Form Completion
No data will be collected in the eCRF during this treatment period.
Source Documentation
At a minimum, the type and level of detail of source data collected should be consistent with that
commonly recorded at the site as a basis for standard medical care. This should include subject
identification and study identification, study discussion, documentation of the informed consent process
including the date, dates of visits, drug dispensing/return records, and study drug administration
information.


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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 drug, 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): 
Ming Qi, MD, PhD.
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 course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.


Signature
User 
Date 
Reason
QI MING 
 
10-Mar-2022
12:34:28
(GMT)
Document Approval
PPD

SAP_003.pdf: 
           CONFIDENTIAL - FOIA Exemptions Apply in U.S.
          1
Approved, Date: 8 September 2020
Janssen Research & Development
Statistical Analysis Plan
A Multicenter Phase 2 Study to Evaluate Subcutaneous Daratumumab in Combination 
with Standard Multiple Myeloma Treatment Regimens
Protocol 54767414MMY2040; Phase 2
JNJ-54767414  (daratumumab)
Status:
Approved
Date:
8 September 2020
Prepared by:
Janssen Research & Development, LLC 
Document No.: EDMS-RIM-153664: 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under the Trade Secrets Act, Procurement Integrity Act, other applicable
statutes, regulations, rules, protective orders or otherwise and as such, the information provided herein is exempt from 
disclosure under Exemption 4 of the Freedom of Information Act (“FOIA”).
.
NCT03412565


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Approved, Date: 8 September 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 5
AMENDMENT HISTORY.............................................................................................................................. 6
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 9
1.4.
Sample Size Justification ................................................................................................................. 9
1.5.
Randomization and Blinding ............................................................................................................ 9
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 10
2.1.
Visit Windows................................................................................................................................. 10
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 10
2.3.
Study Treatment and Study Drug................................................................................................... 10
2.4.
Study Treatment Dosing Date........................................................................................................ 10
2.5.
Analysis Sets.................................................................................................................................. 11
2.6.
Definition of Subgroups.................................................................................................................. 11
2.7.
Baseline Definition ......................................................................................................................... 12
2.8.
Imputation Rules for Missing Dates ............................................................................................... 12
2.8.1.
Adverse Event Start and End Date............................................................................................. 12
2.8.2.
Prior and Concomitant Medication/Therapy Start and End Date ............................................... 13
2.8.3.
Multiple Myeloma Diagnosis Date .............................................................................................. 13
2.8.4.
Subsequent Anti-cancer Therapy Start Date.............................................................................. 14
2.9.
Unique Lab Value........................................................................................................................... 14
2.10.
Other General Definitions............................................................................................................... 14
2.10.1.
Measurable Disease of Multiple Myeloma at Baseline and Measurable Type........................... 14
2.10.2.
Type of Multiple Myeloma........................................................................................................... 15
2.10.3.
International Staging System (ISS)............................................................................................ 15
2.10.4.
Hepatic Function......................................................................................................................... 15
2.10.5.
Relapsed Disease....................................................................................................................... 15
2.10.6.
Refractory Disease ..................................................................................................................... 15
2.10.7.
High Risk/Standard Risk Cytogenetics....................................................................................... 16
2.10.8.
Years since Initial Multiple Myeloma Diagnosis ......................................................................... 16
2.10.9.
End of Follow-up and Duration of Follow-up .............................................................................. 16
2.11.
General Analysis Method............................................................................................................... 16
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 16
4.
SUBJECT AND TREATMENT INFORMATION................................................................................ 16
4.1.
Demographics and Baseline Characteristics ................................................................................. 17
4.2.
Disposition Information................................................................................................................... 17
4.3.
Extent of Exposure......................................................................................................................... 18
4.4.
Medical History............................................................................................................................... 19
4.5.
Prior Therapies............................................................................................................................... 19
4.5.1.
Prior Multiple Myeloma Therapies .............................................................................................. 19
4.5.2.
Refractory Status to Prior Systemic Therapy ............................................................................. 20
4.6.
Prior and Concomitant Medications ............................................................................................... 20
4.7.
Subsequent Anti-cancer Therapies................................................................................................ 21
4.8.
Protocol Deviations ........................................................................................................................ 21
5.
EFFICACY ......................................................................................................................................... 21


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5.1.
Analysis Specifications................................................................................................................... 22
5.1.1.
Level of Significance................................................................................................................... 22
5.1.2.
Data Handling Rules................................................................................................................... 22
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 22
5.2.1.
Definition..................................................................................................................................... 22
5.2.2.
Estimand..................................................................................................................................... 22
5.2.3.
Analysis Methods........................................................................................................................ 23
5.3.
Major Secondary Endpoints........................................................................................................... 23
5.3.1.
VGPR or Better Rate (D-VMP, D-Rd and D-Kd cohorts) ........................................................... 23
5.3.1.1.
Definition.................................................................................................................................. 23
5.3.1.2.
Analysis Methods .................................................................................................................... 23
5.3.2.
ORR (D-VRd cohort)................................................................................................................... 23
5.3.2.1.
Definition.................................................................................................................................. 23
5.3.2.2.
Analysis Methods .................................................................................................................... 23
5.3.3.
CR or Better Rate ....................................................................................................................... 24
5.3.3.1.
Definition.................................................................................................................................. 24
5.3.3.2.
Analysis Methods .................................................................................................................... 24
5.3.4.
Duration of Response................................................................................................................. 24
5.3.4.1.
Definition.................................................................................................................................. 24
5.3.4.2.
Analysis Methods .................................................................................................................... 24
5.3.5.
MRD Negativity Rate .................................................................................................................. 24
5.3.5.1.
Definition.................................................................................................................................. 24
5.3.5.2.
Analysis Methods .................................................................................................................... 25
5.4.
Other Efficacy Variable(s) .............................................................................................................. 25
5.4.1.
Progression-free Survival (D-VMP, D-Rd and D-Kd cohorts)..................................................... 25
5.4.1.1.
Definition.................................................................................................................................. 25
5.4.1.2.
Analysis Methods .................................................................................................................... 26
5.4.2.
Overall Survival (D-VMP, D-Rd and D-Kd cohorts).................................................................... 26
5.4.2.1.
Definition.................................................................................................................................. 26
5.4.2.2.
Analysis Methods .................................................................................................................... 26
5.5.
Subgroup Analysis for Efficacy Endpoints.................................................................................. 27
6.
SAFETY............................................................................................................................................. 27
6.1.
Adverse Events .............................................................................................................................. 27
6.1.1.
Overview of TEAEs..................................................................................................................... 28
6.1.2.
All TEAEs.................................................................................................................................... 28
6.1.3.
Toxicity Grade 3 or 4 TEAEs ...................................................................................................... 28
6.1.4.
Treatment-related TEAEs........................................................................................................... 28
6.1.5.
Serious TEAEs ........................................................................................................................... 28
6.1.6.
TEAEs Leading to Treatment Discontinuation............................................................................ 29
6.1.7.
TEAEs Leading to Dose Modifications ....................................................................................... 29
6.1.8.
TEAEs with Fatal Outcome......................................................................................................... 29
6.2.
Deaths......................................................................................................................................... 29
6.3.
Adverse Events of Clinical Interest............................................................................................. 29
6.3.1.
Infusion-related Reactions.......................................................................................................... 29
6.3.1.1.
Rate of Infusion-related Reactions .......................................................................................... 29
6.3.1.2.
Summary of Infusion-related Reactions .................................................................................. 29
6.3.2.
Injection-site Reactions............................................................................................................... 30
6.3.3.
Infections and Infestations.......................................................................................................... 30
6.3.4.
Hemorrhage Events.................................................................................................................... 30
6.3.5.
Tumor Lysis Syndrome............................................................................................................... 30
6.3.6.
Second Primary Malignancies .................................................................................................... 30
6.3.7.
Cardiac-related Treatment-emergent Adverse Events of Interest (D-Kd cohort only) ............... 30
6.3.8.
Adverse Events by Subgroups ................................................................................................... 31
6.4.
Clinical Laboratory Tests................................................................................................................ 31
6.5.
Vital Signs and Physical Examination Findings ............................................................................. 32
6.6.
Electrocardiogram.......................................................................................................................... 32
6.7.
ECOG Performance Status............................................................................................................ 32


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6.8.
Stem Cell Collection (D-VRd cohort only)...................................................................................... 32
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS .......................................... 32
7.1.
Pharmacokinetics........................................................................................................................... 33
7.2.
Immunogenicity........................................................................................................................... 33
7.3.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 33
8.
BIOMARKER..................................................................................................................................... 34
8.1.
Minimal Residual Disease (MRD) .................................................................................................. 34
9.
MEDICAL RESOURCE UTILIZATION.............................................................................................. 34
REFERENCES............................................................................................................................................ 35


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LIST OF IN-TEXT TABLES
Table 1:
Hypothesis and Power Table...................................................................................................... 9
Table 2:
Subgroup Analyses for Efficacy and Safety Endpoints ............................................................ 12
Table 3:
PFS Event and Censoring Method ........................................................................................... 26


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AMENDMENT HISTORY
SAP Version
Issue Date
Original SAP
20 March 2019
Amendment 1
08 September 2020
The following is a summary of the major changes from the original version of the SAP:
1. Primary analysis about the safety and efficacy of daratumumab SC in combination with 
carfilzomib and dexamethasone (D-Kd) was added.
2. Updated the intercurrent event in estimand (section 5.2.2)
ABBREVIATIONS
AE
adverse event
ALB
albumin
ALKY
alkylating agent
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCT
autologous stem cell transplant 
AST
aspartate aminotransferase
B2MG
beta2 microglobulin
BUN
blood urea nitrogen
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CR
complete response
CT
cancer therapy
CTSQ
Cancer Therapy Satisfaction Questionnaire
Dara-IV
daratumumab for intravenous infusion
Dara-SC
daratumumab administered subcutaneously
DMC
Data Monitoring Committee
DOR
duration of response
DPS
Data Presentation Specifications
ECG
electrocardiograms
ECOG
European Cooperative Oncology Group
eCRF
electronic case report form
FLC
free light chain
FM
Farrington-Manning
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
GM
geometric mean 
HLT
high level term
ICH
International Conference on Harmonization
LDH
lactic acid dehydrogenase
LLN
lower limit normal
IMiD
immunomodulatory drug
IMWG
International Multiple Myeloma Working Group


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IRR
infusion-related reaction
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
MRD
minimal residual disease
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
not evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression free survival
PI
proteasome inhibitor
PK
pharmacokinetic
PN
peripheral neuropathies
PP
per-protocol 
PR
partial response
PT
preferred term
RBC
red blood cell
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCR
stringent complete response
SD
stable disease
SET
study evaluation team
SMQ
standardized MedDRA queries 
SOC
system organ class
SWT
satisfaction with therapy
TEAE
treatment-emergent adverse event
TLFs
tables, listings and figures
TLS
tumor lysis syndrome 
TNT
time to next therapy
TTP
time to disease progression
TTR
time to response
ULN
upper limit normal
VGPR 
very good partial response
WBC
white blood cell


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of the analysis set(s), derived variables 
and statistical methods for the primary analysis of the open-label, multicenter, Phase 2 study to 
demonstrate that daratumumab administered by subcutaneous (SC) injection in combination with 
standard treatment regimens is safe and efficacious in subjects with newly diagnosed multiple 
myeloma (MM) or in subjects with relapsed or refractory disease.
1.1.
Trial Objectives
Primary Objectives

To evaluate the clinical benefit of SC daratumumab administered in combination with 
standard MM regimens in subjects with MM as measured by overall response rate (ORR) or 
very good partial response (VGPR) or better rate
Secondary Objectives

To evaluate safety and pharmacokinetics (PK) of SC administration of daratumumab in 
combination with standard MM regimens

To evaluate additional clinical benefit of SC daratumumab administered in combination with 
standard MM regimens in subjects with MM 

To characterize the immunogenicity of daratumumab and rHuPH20 following SC 
administration

To evaluate minimal residual disease (MRD) negativity rate in the D-VMP (daratumumab in 
combination with bortezomib, melphalan and prednisone), D-Rd (daratumumab in  
combination with lenalidomide and dexamethasone) cohorts, and D-Kd (daratumumab in 
combination with carfilzomib and dexamethasone)
1.2.
Trial Design
This is a multicenter, open-label, phase 2 study to investigate the efficacy and safety of Dara SC 
in combination with bortezomib, lenalidomide, and dexamethasone (VRd) in subjects with newly 
diagnosed MM who are transplant eligible; or in combination with bortezomib, melphalan, and 
prednisone (VMP) in subjects with newly diagnosed MM who are ineligible for transplant; or in 
combination with lenalidomide and dexamethasone (Rd) in subjects with relapsed or refractory 
MM; or in combination with carfilzomib and dexamethasone (Kd) in subjects in first relapse or 
refractory MM after initial treatment with a lenalidomide-containing regimen.  Approximately 
60 subjects will be treated in each cohort. Subjects enrolled in the daratumumab, bortezomib, 
lenalidomide, and dexamethasone cohort (D-VRd) will be treated for 4 cycles and will be 
evaluated for a VGPR or better rate thereafter. Hematopoietic stem cell collection and autologous 
transplant will be performed off protocol. Subjects enrolled in the D-VMP, D-Rd and D-Kd 
cohorts will be treated until disease progression. 
The data cutoff for the primary analysis will occur at least 6 months after approximately the 
sixtieth subject is enrolled in the last treatment cohort (D-VRd, D-VMP, or D-Rd). All available 


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data at the time of this data cutoff will be included in the Clinical Study Report. The cutoff for 
the primary analysis for the D-Kd cohort will occur at least 6 months after approximately the 
60th subject is enrolled in the D-Kd cohort. The study will end 18 months after the last subject is 
enrolled in the D-Kd cohort. Data collected through the end of the study will be reported as an 
addendum to the Clinical Study Report.
A study evaluation team (SET) consisting of the participating investigators the sponsor’s medical 
monitor, the sponsor’s clinical pharmacologist (if PK data are being evaluated), the sponsor’s 
statistician the sponsor’s safety officer, and the sponsor’s study manager will evaluate safety data 
after at least 6 toxicity-evaluable subjects complete Cycle 1 in each cohort. 
1.3.
Statistical Hypotheses for Trial Objectives
The hypothesis is that the addition of daratumumab administered SC to standard MM regimens 
will improve responses compared to response data observed in completed phase 3 studies 
without daratumumab.
1.4.
Sample Size Justification
For the D-VMP cohort, 60 subjects will be required to test the null hypothesis that the ORR is at 
most 70%, against the alternative hypothesis that the ORR is at least 90% with a 1-sided alpha of 
0.05 and at least 98% power (Table 1). Similarly, for the D-Rd cohort, the corresponding power 
is >90% to test the null hypothesis that the ORR is at most 75%, against the alternative 
hypothesis that the ORR is at least 90% (Table 1). For the D-VRd cohort, 60 subjects will 
achieve a power of at least 93% to test the null hypothesis that the response rate of VGPR or 
better is at most 50%, against the alternative hypothesis that the ORR is at least 70% with a 
1-sided alpha of 0.05 (Table 1).  For the D-Kd cohort, the corresponding power is >80% to test 
the null hypothesis that the ORR is at most 65%, against the alternative hypothesis that the ORR 
is at least 80%. (Table 1).
Table 1:
Hypothesis and Power Table
Cohort
N
H0
H1
Power
D-VRd
60
VGPR or better rate ≤50%
VGPR or better rate ≥70%
>93%
D-VMP
60
ORR ≤70%
ORR ≥90%
>98%
D-Rd
60
ORR ≤75%
ORR ≥90%
>90%
D-Kd
60
ORR ≤65%
ORR ≥80%
>80%
1.5.
Randomization and Blinding
This is a non-randomized open-label study, no randomization and blinding procedures will be
performed for this study. Each subject will be assigned into the treatment cohort for which he or 
she is eligible and will receive a unique subject number.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
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 cycle is defined as the first scheduled dose date
of the study treatment for that particular cycle, 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 dose date plus 30 days or subsequent anticancer therapy minus 1 day, if the
end of treatment visit date is not available. 
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 summary by study week.
2.2.
Pooling Algorithm for Analysis Centers
Data from all study centers will be pooled for analyses.
2.3.
Study Treatment and Study Drug
For subjects who receive D-VRd treatment, study treatment refers to bortezomib, dexamethasone,
lenalidomide, and daratumumab SC.
For subjects who receive D-VMP treatment, study treatment refers to bortezomib, melphalan,
prednisone, and daratumumab SC.
For
subjects
who
receive
D-Rd treatment, study
treatment
refers
to
lenalidomide,
dexamethasone, and daratumumab SC.
For subjects who receive D-Kd treatment, study treatment refers to carfilzomib, dexamethasone, 
and daratumumab SC.
Study drug refers to daratumumab SC for all the subjects treated in 4 treatment cohorts.
2.4.
Study Treatment Dosing Date
Study treatment dosing date is the date on which a subject actually received study treatment
(partial or complete) and will be recorded in the study treatment administration dataset.
For subjects who receive D-VRd treatment, the first study treatment dosing date is defined as the 
earliest date of non-zero dose of the following administration: bortezomib, lenalidomide, 
dexamethasone or daratumumab SC.  The last study treatment dosing date is defined as the latest 
date of non-zero dose of the following administration: bortezomib, lenalidomide, dexamethasone 
or daratumumab SC.


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For subjects who receive D-VMP treatment, the first study treatment dosing date is defined as
the earliest date of non-zero dose of the following administration: bortezomib, melphalan,
prednisone or daratumumab SC. The last study treatment dosing date is defined as the latest
date of non-zero dose of the following administration: bortezomib, melphalan, prednisone or 
daratumumab SC.
For subjects who receive D-Rd treatment, the first study treatment dosing date is defined as the 
earliest date of non-zero dose of the following administration: lenalidomide, dexamethasone or 
daratumumab SC. The last study treatment dosing date is defined as the latest date of non-zero dose 
of the following administration: lenalidomide, dexamethasone or daratumumab SC.
For subjects who receive D-Kd treatment, the first study treatment dosing date is defined as the 
earliest date of non-zero dose of the following administration: carfilzomib, dexamethasone or 
daratumumab SC. The last study treatment dosing date is defined as the latest date of non-zero dose 
of the following administration: carfilzomib, dexamethasone or daratumumab SC.
2.5.
Analysis Sets
The analysis sets for the study are:

All treated analysis set: defined as all subjects who receive at least 1 dose of study treatment. 
This analysis set will be used for analyses of disposition, demographic and baseline disease 
characteristics, treatment exposure, safety and efficacy. All subjects in all treated analysis 
set will be analyzed according to the treatment that they actually received.

Pharmacokinetics (PK) analysis set: defined as subjects who received at least 1 dose
administration of daratumumab SC and have at least 1 PK sample concentration value after 
the first dose. All PK parameters will be analyzed based on the PK analysis set.

Immunogenicity-evaluable analysis set is defined as all subjects who receive at least 1 dose 
administration of daratumumab SC and have at least 1 immunogenicity sample for detection 
of anti-daratumumab antibodies after the first dose.

Immunogenicity-evaluable analysis set for rHuPH20 is defined as all subjects who receive at 
least one dose of daratumumab SC and have appropriate plasma samples for detection of 
antibodies to rHuPH20 (at least 1 sample after the start of the first dose of daratumumab
SC).
2.6.
Definition of Subgroups
In general, subgroup analyses on the pre-specified subgroups in Table 2 will be performed for the 
primary efficacy endpoints of ORR and VGPR or better rate, major secondary endpoint of rate of 
infusion-related reactions (IRRs), and safety endpoints treatment-emergent adverse event
(TEAE). Additional exploratory subgroup analyses may be performed for selected efficacy 
and/or safety endpoints. 


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Table 2:
Subgroup Analyses for Efficacy and Safety Endpoints
Subgroup
Definition
Analysis Type
Sex
Male, Female
E, S
Race
White, Other
S
Weight 
≤ 65 kg, 66 to 85 kg, and >85 kg
S
Baseline renal function 
(Glomerular filtration rate [GFR]
[mL/min/1.73m2])
S: ≤60, >60 (mL/min/1.73m2)
S
Baseline hepatic function
Normal, Impaireda
S
ISS staging 
I, II, and III
E 
Type of myeloma 
IgG, non-IgG
E
Cytogenetic risk
High risk, Standard risk
E 
ECOG performance score
0, ≥1
E
E: efficacy (ORR and VGPR or better rate); S: safety (IRR, TEAE)
a:
Includes mild, moderate and severe.
2.7.
Baseline Definition
The baseline value is defined as the last non-missing measurement taken on or prior to the first 
dose administration of study treatment (including time if time is available).
2.8.
Imputation Rules for Missing Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy
evaluations. For analysis and reporting purpose, partial dates in adverse event (AE onset date;
AE end date), concomitant therapies (start date; end date), MM diagnosis date, and start date
of subsequent anti-cancer therapy will be imputed.
2.8.1.
Adverse Event Start and End Date
Adverse Event Start Date
If the onset date of an adverse event is completely or partially missing, the following imputation 
rules will be used.

When month and year are present and the day is missing:

If the onset month and year are the same as the month and year of first dosing date, the 
day of first dosing or the day-component of the AE end date (possibly imputed) is 
imputed, whichever is earlier; 

If the onset month and year are not the same as the month and year of first study 
treatment, the first day of the month is imputed.

When only a year of the onset date is present:

If the onset year is the same as the year of first study treatment:
o
If AE end date is available and is prior to first dosing date, the day and month of 
AE end date are imputed; 
o
Otherwise, the day and month of the first dosing date are imputed. 


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
If the onset year is different from the year of first study treatment, the 1st of January is 
imputed.

If the onset date is completely missing, the first dosing date is imputed as the onset date.
No imputation will be done for partial or missing AE onset time.
Adverse Event End Date
If the end date of an adverse event is completely or partially missing, the following imputation 
rules will be used.

If month and year are present and the day of the month is missing, the last day of the month 
is imputed. 

If only a year is present, the 31st of December is used. 
After the imputation, if the imputed date is later than the date of death (if available) after 
imputation, the date of death will be used as the imputed date.
No imputation will be done for partial or missing AE end time.
2.8.2.
Prior and Concomitant Medication/Therapy Start and End Date
For prior or concomitant medications/therapy, if the start or end date is completely missing, no 
imputation will be performed. If the start or end date is partially missing, the following 
imputation rules will be used. 

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 medication/therapy was taken prior to study start, and the imputed start date is after first 
dosing date, further adjust the imputed start date as the day prior to first dosing date; if the 
medication/therapy was taken after study start, and the imputed start date is prior to first dosing 
date, further adjust the imputed start date as first dosing date. Also adjust the imputed 
medication/therapy end date so that it is on or after first dosing date.
2.8.3.
Multiple Myeloma Diagnosis Date
If the diagnosis date of multiple myeloma (MM) is completely missing, no imputation will be 
applied. If the diagnosis date is partially missing, the following imputation rules will be applied:

If only the day of the diagnosis date is missing:

If the month and year of the diagnosis date are the same as the month and year of the 
start date of the first line of prior MM therapy, and day of the start date of the first line 
of prior MM therapy is available, impute day of the diagnosis date with the day of the 
start date of the first line of prior MM therapy; 

Otherwise, impute day of diagnosis date with 15;

If both month and day of the diagnosis date are missing:


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
If the year of the diagnosis date is the same as the year of the start date of the first line 
of prior MM therapy, and the month of the start date of the first line of prior MM 
therapy is available:
o
if both month and day of the start date of the first line of prior MM therapy are 
available, impute diagnosis month and day with the month and day of the start date 
of the first line of prior MM therapy; 
o
if only the month of the start date of the first line of prior MM therapy is available, 
impute the month of diagnosis date with the month of the start date of the first line 
of prior MM therapy and the day of the diagnosis date with 15; 

Otherwise, impute the month and day of the diagnosis date with June 30.  
2.8.4.
Subsequent Anti-cancer Therapy Start Date
If the start date of subsequent anti-cancer therapy is completely missing or the month is missing, 
no imputation will be performed. If only the day of subsequent therapy start date is missing, the 
following imputation rules will be applied:

If the month and year of the start date are the same as the month and year of the last dosing 
date, the day of last dosing date or the day-component of the stop date of subsequent anti-
cancer therapy will be imputed, whichever is earlier. 

If the month and year of the start date are not the same as the month and year of last dosing 
date, the first day of the month will be imputed.
2.9.
Unique Lab Value 
In general, in instances when there are multiple records at a given visit date for lab parameters 
associated with disease assessment, the following rules will be applied to select the unique lab 
value for analysis: a.) multiple records from both central and local lab, central lab value always 
takes precedence over local lab value; b) multiple records from central lab, select the latest value 
as the unique lab value; c.) multiple records from local lab, select the latest lab value as the 
unique lab value.
2.10.
Other General Definitions
2.10.1.
Measurable Disease of Multiple Myeloma at Baseline and Measurable 
Type
Measurable disease at baseline is defined by any of the following: 

Serum M-protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or 

Light chain multiple myeloma without measurable disease in the serum or the urine: Serum 
immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin 
kappa lambda FLC ratio.
If a subject meets the criteria for serum M-protein, the measurable disease type is serum; 
otherwise, if a subject meets the criteria for urine M-protein, the measurable disease type is 
urine; otherwise if a subject meets the criteria for FLC, the measurable disease type is FLC. If a 


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subject meets both of the criteria for serum M-protein and urine M-protein, then the measurable 
disease type is “serum and urine”.
2.10.2.
Type of Multiple Myeloma
Type of myeloma for a subject is determined by serum heavy chain or serum FLC or urinary 
FLC. Serum heavy chain refers to serum immunoglobulin of IgG, IgA, IgM, IgD, or IgE. Serum 
and urine FLC refers to kappa or lambda type. 
A subject will be classified as IgG type of myeloma if any reported result contains serum heavy 
chain ‘IgG’ regardless of FLC reported, similarly for IgA, IgM, IgD and IgE type. A subject will 
be classified as the light chain type of myeloma if any reported result is either ‘Lambda light 
chains’ or ‘Kappa light chains’ but without heavy chain reported. A subject will be reported as 
‘biclonal’ if the distinct test results contain different heavy chain values or different FLC values. 
A subject will be classified as “Negative immunofixation” if the reported result is “Not 
Detected” and with no serum heavy chain, serum light chain and urine light chain reported.
2.10.3.
International Staging System (ISS)
ISS staging is based on the combination of serum β2-microglobulin (B2MG) and serum
albumin (ALB) at baseline.

Stage I:    β2-microglobulin<3.5 mg/L and serum albumin≥ 35 g/L

Stage III: β2-microglobulin ≥ 5.5 mg/L

Stage II:  Neither stage I nor stage III

   (β2-microglobulin<3.5 mg/L but serum albumin< 35 g/L, or β2-microglobulin    

    ≥3.5 mg/L to 5.5 mg/L irrespective of the serum albumin level)
2.10.4.
Hepatic Function
Hepatic impairment is classified into 4 levels per NCI organ dysfunction criteria, using baseline 
total bilirubin and Aspartate Aminotransferase (AST):

Normal: total bilirubin ≤ ULN and AST ≤ ULN 

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
2.10.5.
Relapsed Disease
For D-Rd cohort, relapsed disease is defined as an initial response to previous treatment, followed 
by progressive disease (PD) by IMWG criteria >60 days after cessation of treatment.
2.10.6.
Refractory Disease
For D-Rd cohort, 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. 


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2.10.7.
High Risk/Standard Risk Cytogenetics
The high risk and standard risk cytogenetics are defined as follows:

High risk: subjects that are positive for any of del17p, t(14;16), t(4;14) by FISH/Karyotype

Standard risk: subjects that are negative for del17p, t(14;16), t(4;14) by FISH/Karyotype 
2.10.8.
Years since Initial Multiple Myeloma Diagnosis
This is calculated as date of first dosing – date of initial MM diagnosis + 1, divided by 365.25.
2.10.9.
End of Follow-up and Duration of Follow-up
The end of follow-up is defined as the maximum date of the following study evaluations: labs 
(hematology, chemistry, immunology), adverse events, vital signs, ECOG performance status,
bone marrow cytogenetics, lytic bone lesions, extra-medullary plasmacytomas, study treatment 
administration, ECG, pre-infusion medications, post-infusion medications, concomitant 
medications, subsequent therapy, medical encounters, clinical events/disease response per 
investigator and date of last known to be alive. For subjects who died, the end of follow-up is the 
date of death.
Duration of follow-up (in months) = the date of end of follow-up - the date of first dose + 1, 
divided by 365.25/12.
2.11.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as mean,
standard deviation (SD), median and range. Categorical variables will be summarized using
frequency and percentage. For time-to-event variables, which is defined as from the date of 
first dose to the date of the event, the Kaplan-Meier method will be used for descriptive
summaries. For the calculation of time-to-event and duration-of-event variables, the difference
between the start date and the end date plus 1 day will be used.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis is planned for this study.
A SET consisting of the participating investigators, the sponsor’s medical monitor, the sponsor’s 
clinical pharmacologist (if PK data are being evaluated), the sponsor’s statistician the sponsor’s 
safety officer, and the sponsor’s study manager will evaluate safety data after at least 
6 toxicity-evaluable subjects complete Cycle 1 in each cohort. The details will be provided in a 
separate SET charter.
4.
SUBJECT AND TREATMENT INFORMATION
Analyses of subject disposition, demographic and baseline disease characteristics, and extent of 
exposure will be conducted on all treated analysis set. 


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4.1.
Demographics and Baseline Characteristics
The following subject demographics will be summarized using descriptive statistics:

Age (continuous)

Age category (< 65 years, 65 to < 75 years, and ≥75 years)

Sex (male, female)

Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, and Not reported) 

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Height (cm)

Weight (kg) 

Baseline ECOG performance status (0, 1, 2)
The following baseline disease characteristics will be summarized using descriptive statistics: 

Type of myeloma (IgA, IgD, IgE, IgG, IgM, light chain, biclonal, or negative 
immunofixation)

Type of measurable disease (serum and urine, serum, urine, FLC)

ISS staging (I, II, III)

standard-risk and high-risk cytogenetic abnormalities (del17p, t(4;14), t(14;16))

Time since initial diagnosis (years) 

Number of lytic bone lesions (None, 1-3, 4-10, more than 10) 

Presence of diffuse myeloma-related osteopenia (Yes, No) 

Presence of extramedullary plasmacytomas (Yes, No) 

Bone marrow % plasma cells (<10, 10 – 30, > 30) 
In addition, a descriptive summary of selected hematology and chemistry laboratory analytes at 
baseline will be provided for each treatment cohort and overall. The baseline toxicity grade of
selected laboratory analyte in hematology and chemistry panel will be summarized by treatment 
cohort using frequency.
4.2.
Disposition Information
The number of subjects who are treated, ongoing, and discontinued treatment with reasons of 
discontinuation reported on eCRF will be summarized. The number of subjects who discontinued 
from study with the reported reasons will also be presented. The number of subjects who 
discontinued treatment by cycle with the reported reasons will also be provided.
Subject enrollment will also be summarized by country and site for all treated analysis set. 


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A listing of subjects who discontinued study treatment including reasons for discontinuation will 
be provided. A similar listing will be provided for subjects who discontinued study.
4.3.
Extent of Exposure
Extent of exposure to study treatments will be summarized and presented based on all treated 
analysis set.
The number and percentage of subjects treated within each cycle will be summarized for each 
treatment cohort. The maximum number of treatment cycles received for each subject 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 daratumumab administrations (continuous and categorical variables) will be
summarized for each treatment cohort. 
For subjects treated with D-VRd, the total dose administered for daratumumab (mg),
lenalidomide (mg), bortezomib (mg/m2), and dexamethasone (mg) will be summarized overall,
by cycle, by high-intensity (Cycles 1-3) and low-intensity (Cycles 4) for daratumumab.
For subjects treated with D-VMP, the total dose administered for daratumumab (mg),
bortezomib (mg/m2), melphalan (mg/m2), prednisone (mg/m2), and dexamethasone (mg) will
be summarized overall, by cycle, by high-intensity (Cycle 1) a n d low-intensity (Cycles 2-
9) for bortezomib, and by Cycle 1, Cycles 2-9 and Cycles 10+ for daratumumab and 
dexamethasone.
For subjects treated with D-Rd, the total dose administered for daratumumab (mg), lenalidomide 
(mg), and dexamethasone (mg) will be summarized overall, by cycle, by high-intensity 
(Cycles 1-2) and low-intensity (Cycles 3-6 and Cycles 7+) for daratumumab.
For subjects treated with D-Kd, the total dose administered for daratumumab (mg), carfilzomib
(mg/m2), and dexamethasone (mg) will be summarized overall, by cycle, by high-intensity 
(Cycles 1-2) and low-intensity (Cycles 3-6 and Cycles 7+) for daratumumab.
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 treatment and summarized
accordingly. Additionally, the daratumumab dose intensity will be summarized by cycles with 
high-intensity and low-intensity for each treatment cohort (i.e., Cycles 1-3 and Cycles 4 for 
D-VRd; Cycle 1, Cycles 2-9 and Cycles 10+ for D-VMP; Cycles 1-2, Cycles 3-6 and Cycles 7+ 
for D-Rd and D-Kd). In addition, for the D-VMP treatment cohort, the bortezomib dose intensity 
will be summarized by cycles with high-intensity and low-intensity (i.e., Cycle 1 and Cycles 2-
9).


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The relative dose intensity (%), which is defined as the ratio of total dose actually received
and total planned dose, will be calculated for each study treatment and summarized using
descriptive statistics for each treatment cohort.
The number of subjects with cycle delays or dose modifications (dose delays, dose skipping, or 
dose reduction) including reasons (AE or other) for cycle delays or dose modifications, will be 
reported. In addition, a summary of study treatment dose modifications by cycle will be 
provided.
4.4.
Medical History 
General medical history will be summarized by body system organ class and preferred term for 
each treatment cohort. 
4.5.
Prior Therapies 
4.5.1.
Prior Multiple Myeloma Therapies
D-Rd and D-Kd Cohort:
For the subjects enrolled in D-Rd and D-Kd treatment cohort with relapsed or refractory MM, 
the number and percentage of subjects who had prior exposure to multiple myeloma therapies 
(systemic therapy, ASCT, radiotherapy, cancer-related surgery) will be summarized. 
Specifically, for prior systemic therapies, the number of prior lines of therapy will be 
summarized descriptively and summarized by the following categories: 1, 2, 3 and > 3(for D-
Rd); 1 and >1 (for D-Kd)
The summary of prior systemic therapies will be presented by therapy class and therapy. The 
therapy classes include proteasome inhibitors (PI), immunomodulatory drugs (IMiD), steroids, 
alkylating agents and anthracyclines. 

PI therapy class includes: bortezomib, carfilzomib (D-Rd only), oprozomib, ixazomib, and
marizomib;

IMiD therapy class includes:  lenalidomide, pomalidomide, and thalidomide;

Steroids therapy class includes: dexamethasone and prednisone, among others.
Further update of the above lists will be specified in the Data Presentation Specifications (DPS). 
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 class or therapies is sufficient.
Additionally, the prior systemic therapy will be summarized by therapeutic class, pharmacologic 
class and preferred term.
D-VMP Cohort:
With the study population of newly diagnosed subjects with multiple myeloma who are not
candidates for high dose chemotherapy and autologous stem cell transplant (ASCT), prior 


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systemic use of corticosteroids is limited to a short course of emergency use to treat multiple 
myeloma symptoms. If any, a listing of all prior systemic use of corticosteroids will be provided.
D-VRd Cohort:
With the study population of newly diagnosed subjects with multiple myeloma who are eligible 
for transplant, a listing of prior systemic use of corticosteroids will be provided. A listing of prior 
radiotherapies may also be provided.
4.5.2.
Refractory Status to Prior Systemic Therapy
For the subjects enrolled in D-Rd and D-Kd treatment cohorts with relapsed or refractory MM, 
the refractory status to prior systemic therapy will be summarized. Refractory status (yes, no) to 
a particular prior systemic therapy class (i.e., PI/IMiD) or prior systemic therapy (e.g., 
bortezomib or thalidomide) will be based on refractory status to each line of therapy, or each 
specific 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 the most recent PI or IMiD therapy 
class will be summarized by the following 4 categories: none (neither PI-refractory nor 
IMiD-refractory), PI only (PI-refractory but not IMiD-refractory), IMiD only (IMiD-refractory 
only but not PI-refractory), both PI and IMiD. Refractory to specific prior therapy, such as 
bortezomib, carfilzomib (D-Rd only), ixazomib, lenalidomide, pomalidomide, or thalidomide 
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.
Prior and Concomitant Medications
Medications administered prior to the first dose date of study treatment will be considered as 
prior medications. Concomitant medications are defined as those medications taken on or after
the first dose date through 30 days after the last dose date.  
Prior and concomitant medications will be summarized on all treated analysis set by therapeutic 
class, pharmacologic class, and preferred term. Similar summaries will be provided for subjects
who received growth factor support, systemic steroids, and prophylactic antiviral medication as 
concomitant medication use during the study, respectively.
Pre-infusion medications and post-infusion medications will also be summarized, respectively. 
Pre-infusion medications will be grouped by analgesics, antihistamines, corticosteroids
(intermediate acting, long acting), and other. The incidence of pre-infusion medications will be
presented by the aforementioned groups and preferred terms. The similar summary will be
provided for post-infusion medications.


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4.7.
Subsequent Anti-cancer Therapies
The total number of subjects who received subsequent anti-cancer therapy for multiple myeloma
will be reported for all treated analysis set in each treatment cohort. A summary of subsequent 
anti-cancer therapy will be presented by therapeutic class, pharmacologic class and preferred 
term.
4.8.
Protocol Deviations
Subjects with major protocol deviations will be identified prior to database lock and the subjects 
with major protocol deviations will be summarized for all treated analysis set by the following 
categories of deviation for each treatment cohort: 

Entered but did not satisfy criteria 

Developed withdrawal criteria but not withdrawn 

Received wrong treatment or incorrect dose 

Received a disallowed concomitant treatment 

Other 
A list of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided.
5.
EFFICACY
A validated computerized algorithm, which is based on the IMWG response criteria (Durie 2006, 
Rajkumar 2011)1,2 and has been used and validated by an independent review committee in 
study MMY2002, also used in MMY3003, MMY3004, MMY3006, MMY3007, 
MMY3008, and MMY3012 will be used to determine response and disease progression for 
each subject. Unless specified otherwise, relapse from CR by positive immunofixation or trace 
amount (defined as less than 0.5 g/dl) of M protein is not considered to be progressive disease in 
the IMWG response criteria. 
The primary efficacy analyses will be based on the computerized algorithm assessments. The 
primary analysis will occur at least 6 months after approximately the sixtieth subject is enrolled 
in the last treatment cohort (D-VRd, D-VMP, or D-Rd). The primary efficacy analysis for D-Kd 
cohort will occur at least 6 months after approximately the sixtieth subject is enrolled in the D-
Kd cohort.  Analyses for the primary endpoint and selected major secondary efficacy endpoints 
based on investigator assessments using the IMWG response criteria will also be performed as 
sensitivity analyses. 
No formal comparisons between treatment cohorts will be performed.


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5.1.
Analysis Specifications
5.1.1.
Level of Significance
All statistical hypothesis tests will be based on one-sided test at significance level of alpha=0.05.
All interval estimations will be reported using 2-sided 90% confidence interval (CI).
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
5.2.
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is ORR for the D-VMP, D-Rd and D-Kd cohorts and VGPR or 
better response rate for the D-VRd cohort.
5.2.1.
Definition
The ORR, which is the primary efficacy endpoint for the D-VMP, D-Rd and D-Kd cohorts, is 
defined as the proportion of subjects who achieve a response of PR or better according to IMWG 
response criteria, including the subjects with either complete response (including stringent 
complete response [sCR]) or partial response (including VGPR), during or after the study 
treatment but prior to the start of subsequent anti-cancer therapy.
The VGPR or better response rate, which is the primary efficacy endpoint for the D-VRd cohort,
is defined as the proportion of subjects who achieve a response of VGPR or better (VGPR, CR or 
sCR) according to IMWG response criteria, during or after the study treatment but prior to the 
start of subsequent anti-cancer 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: 

D-VRd cohort: subjects with newly diagnosed MM who are transplant eligible; 

D-VMP cohort: subjects with newly diagnosed MM who are ineligible for transplant; 

D-Rd cohort: subjects with relapsed or refractory MM.

D-Kd cohort: subjects in first relapse or refractory MM after initial treatment with a 
lenalidomide-containing regimen.

Variable: overall response for D-VMP, D-Rd and D-Kd cohorts and VGPR or better 
response D-VRd cohort;

Intercurrent event: Treatment discontinuation is considered as an intercurrent event for 
overall response and treatment policy strategy will be implemented, i.e., analysis of overall 
response ignores treatment discontinuation.


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
Population-level summary: overall response rate for D-VMP, D-Rd and D-Kd cohorts and 
VGPR or better response rate for D-VRd cohort.
5.2.3.
Analysis Methods
The primary analysis of ORR for D-VMP, D-Rd and D-Kd cohorts and the primary analysis of 
VGPR or better response rate for D-VRd cohort will be performed on all treated analysis set. The 
number and percentage of subjects in the following response categories will be tabulated for each 
treatment cohort: sCR, CR, VGPR, PR, stable disease (SD), progressive disease (PD), and not 
evaluable (NE). The overall response (including sCR + CR + VGPR + PR), VGPR or better 
(sCR + CR + VGPR), and CR or better (sCR + CR) will also be summarized. For each of the 
above categories, two-sided 90% Clopper-Pearson exact CI will also be presented
Sensitivity analyses of ORR for D-VMP, D-Rd and D-Kd cohorts and a sensitivity analysis of
VGPR or better response rate for D-VRd cohort, in which disease response is based on 
investigator assessment according to the IMWG response criteria, will also be performed in a 
similar manner.
No formal comparisons between treatment cohorts will be performed.
5.3.
Major Secondary Endpoints
The major secondary efficacy endpoints include VGPR or better response rate (for D-VMP, D-
Rd and D-Kd cohorts), ORR (for D-VRd cohort), CR or better response rate, duration of 
response (DOR), and MRD negativity rate (for D-VMP, D-Rd, and D-Kd cohorts).
5.3.1.
VGPR or Better Rate (D-VMP, D-Rd and D-Kd cohorts)
5.3.1.1.
Definition
The secondary endpoint of VGPR or better rate for D-VMP, D-Rd and D-Kd cohorts is defined 
as the same as specified in Section 5.2.1.
5.3.1.2.
Analysis Methods
The secondary analysis of VGPR or better response rate for D-VMP, D-Rd and D-Kd cohorts
will be performed on all treated analysis set. The VGPR or better response rate and 
corresponding two-sided 90% Clopper-Pearson exact CI will be provided.
5.3.2.
ORR (D-VRd cohort)
5.3.2.1.
Definition
The secondary endpoint of ORR for D-VRd cohort is defined as the same as specified in 
Section 5.2.1.
5.3.2.2.
Analysis Methods
The secondary analysis of ORR for D-VRd cohort will be performed on all treated analysis set.
The ORR and corresponding two-sided 90% Clopper-Pearson exact CI will be provided.


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5.3.3.
CR or Better Rate
5.3.3.1.
Definition
CR or better response rate is defined as the proportion of subjects with a response of a CR or 
better (CR or sCR) according to IMWG response criteria, during or after the study treatment but 
prior to the start of subsequent anti-cancer therapy. 
5.3.3.2.
Analysis Methods
CR or better response rate will be calculated on all treated analysis set for each treatment cohort. 
The corresponding two-sided 90% Clopper-Pearson exact CI will be provided. 
5.3.4.
Duration of Response
5.3.4.1.
Definition
Duration of response is calculated from the date of initial documentation of a response (PR or 
better for D-VMP, D-Rd and D-Kd cohorts) to the date of first documented evidence of 
progressive disease as defined according to IMWG criteria or death due to PD, whichever occurs 
first, for the subjects who had achieved a response (PR or better for D-VMP, D-Rd and D-Kd
cohorts). 
Subjects who start subsequent anti-cancer therapies without PD will be censored at the date of 
the last disease assessment prior to the start of subsequent anti-cancer therapies. Subjects who 
have not progressed or subjects who die due to causes other than disease progression will be 
censored at the last disease assessment date.
5.3.4.2.
Analysis Methods
At the time of the primary analysis, data for DOR may not be mature and may be analyzed later.
Analysis of DOR will be based on subjects who achieved a response (PR or better for D-VMP,
D-Rd and D-Kd cohorts.). Median DOR with 90% CI will be estimated based on the 
Kaplan-Meier method for each treatment cohort. The Kaplan-Meier curve for DOR will be 
plotted.
5.3.5.
MRD Negativity Rate
5.3.5.1.
Definition
MRD negativity rate is defined as the proportion of subjects who are considered MRD negative 
after MRD testing by bone marrow aspirate at any timepoint after first dose and before disease 
progression or starting subsequent 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 or not evaluated will be considered as MRD positive.


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5.3.5.2.
Analysis Methods
At the time of the primary analysis, data for MRD negative data may not be mature and may be 
analyzed later.
The MRD negativity rate will be calculated for D-VMP, D-Rd and D-Kd cohorts based on all
treated analysis set. The corresponding two-sided 90% Clopper-Pearson exact CI will be 
provided.
For this study, threshold value of 10-5 will be used for the primary MRD negativity analysis. 
Additional 
supportive 
analyses 
will 
be 
performed 
using 
different
thresholds
(i.e. <10-6 and <10-4). 
5.4.
Other Efficacy Variable(s)
Other efficacy endpoints include the proportion of subjects with best M-protein response for 
subjects with measurable disease in serum or urine, and the proportion of subjects with maximal 
reduction of ≥90% and ≥50% from baseline in the difference between involved and uninvolved 
serum FLC (dFLC) for subjects with measurable disease of FLC only.
For the treatment cohorts of D-VMP, D-Rd and D-Kd, other efficacy endpoints may also include 
progression-free survival (PFS) and overall survival (OS).
5.4.1.
Progression-free Survival (D-VMP, D-Rd and D-Kd cohorts)
5.4.1.1.
Definition
At the time of the primary analysis, data for PFS may not be mature and may be analyzed later.
PFS for D-VMP, D-Rd and D-Kd cohorts is defined as the duration from the date of the first
study treatment administration to either progressive disease, according to the IMWG response 
criteria, or death due to any cause, whichever occurs first. Subjects who start subsequent anti-
cancer therapies for multiple myeloma without disease progression will be censored at the last 
disease assessment before the start of subsequent therapies. Subjects who withdrew consent from 
the study before disease progression will be censored at the last disease assessment before 
withdrawal of consent to study. Subjects who are lost to follow-up will be censored at the last 
disease assessment before the subjects were lost to follow-up. Subjects who have not progressed 
and are still alive at the clinical cut-off 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
the first study treatment administration. 


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Determination of dates of PFS event and dates for censoring is summarized in Table 3 as follows.
Table 3:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No postbaseline disease assessment
Date of the first study treatment
administration
Censored
Disease progression prior to start of 
subsequent anti-cancer therapy
Earliest date that indicates disease
progression
PFS event
Death prior to start of subsequent anti-
cancer therapy
Date of death
PFS event
Other, such as:
o
Withdrawal of consent to study
participation,
o
Lost to follow-up
o
Start of subsequent anti-cancer therapy 
prior to disease progression or death 
Date of last disease assessment prior to 
withdrawal of consent to study
participation, lost to follow-up, or 
start of subsequent anti-cancer therapy  
Censored
5.4.1.2.
Analysis Methods
Analysis of PFS will be performed on all treated analysis set for the treatment cohorts of D-
VMP, D-Rd and D-Kd. The Kaplan-Meier method will be used to estimate the distribution of 
overall PFS. The median PFS with 90% CI will be provided. The Kaplan-Meier curve for PFS
will also be plotted.
5.4.2.
Overall Survival (D-VMP, D-Rd and D-Kd cohorts)
5.4.2.1.
Definition
At the time of the primary analysis, data for overall survival may not be mature and may be 
analyzed later. Descriptive summaries overall survival data may be provided for exploratory 
purposes. 
Overall survival for D-VMP, D-Rd and D-Kd cohorts is defined as the duration from the date of 
the first study treatment administration 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. Subject 
who is still alive at the clinical cut-off date for the analysis will be censored at the date of last 
known to be alive. The date of last known to be alive will be determined by the maximum 
collection/assessment date from among selected data domains within the clinical database.
5.4.2.2.
Analysis Methods
OS will be analyzed using similar statistical methods as described in Section 5.4.2.2 for PFS 
analysis.


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5.5.
Subgroup Analysis for Efficacy Endpoints
For assessment of internal consistency and investigation of homogeneity of the treatment effect 
across subgroups, subgroup analyses of the primary efficacy endpoints of ORR (D-VMP, D-Rd 
and D-Kd cohorts) and VGPR or better rate (D-VRd cohort) based on pre-specified subgroups 
defined in Section 2.6 will be conducted.
Additional exploratory subgroup analyses may be performed for selected efficacy and/or safety 
endpoints.
6.
SAFETY
Analysis of safety data will be provided on all treated analysis set. All subjects will be analyzed 
according to the actual treatment they received.
The safety assessments to be evaluated include AEs, deaths, clinical laboratory tests 
(hematology, chemistry), vital signs, electrocardiogram (ECG) and ECOG performance scores.
6.1.
Adverse Events
AEs will be recorded in standard medical terminology and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 
4.03. For AE reporting, the verbatim term used in the CRF by investigators to identify adverse 
events will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary.  
The relationships to study treatment will be recorded as not related, doubtful, possible, probable, 
or very likely on eCRF for all the AEs. Adverse events will be categorized and summarized 
according to their highest relationship to study treatment. An adverse event is considered as 
related to study treatment if the relationship is recorded as possible, probable or very likely.
Treatment-emergent adverse events (TEAEs) are defined as any AE with onset date and time on 
or after that of the first dose through 30 days after the last dose of study treatment, or the day 
prior to start of subsequent 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; or any AE that is considered related to (very likely, 
probably, or possibly related) study treatment regardless of the start date of the event; or any AE 
that is present at baseline but worsens in toxicity grade or is subsequently considered treatment-
related by the investigator. AEs with missing or partial onset date and time will be considered as 
treatment-emergent unless the onset date and time of an AE can be determined as earlier than 
that of the first dose, or later than 30 days after last dose of study treatment.
Unless otherwise specified, at each level (e.g., system organ class and/or preferred term) of 
subject summarization in reporting the incidence of the AE, a subject is counted once if one or 
more events were recorded. For summarizing new onset events, all event records of the same 
preferred term from the same subject are to be linked by the onset date and the end date. If an 
event is followed by another event of the same preferred term with an onset date (or date/time) 


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the same as or 1 day (or 1 minute if applicable) after the end date (or date/time) of the previous 
record and any features of the adverse event (i.e.: toxicity grades/seriousness/action taken) are 
different between these two records, these 2 records should be linked together and considered as 
1 event. A Grade 5 event will be linked to previous event of the same preferred term if the onset 
date of Grade 5 record is the same or one day after the end date of previous record.
6.1.1.
Overview of TEAEs
An overview of TEAEs reported through the study will be provided for each treatment cohort. 
Overall summary of TEAE will include the subjects with TEAEs, serious TEAEs, TEAEs related 
to study treatment, TEAEs of maximum toxicity grade of 1 to 5, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modifications, and TEAEs with fatal outcome.
A similar overview of TEAEs will be presented by treatment cycle.
6.1.2.
All TEAEs
The following summaries will be provided for all TEAEs:

TEAEs by system organ class (SOC) and preferred term (PT)

Most common (e.g., ≥10%) TEAEs by SOC and PT

TEAEs by SOC, PT, and maximum toxicity grade
6.1.3.
Toxicity Grade 3 or 4 TEAEs
The following grade 3 or 4 TEAEs will be summarized:

Grade 3 or 4 TEAEs by SOC and PT

Most commonly reported (e.g., ≥5%) grade 3 or 4 TEAE by SOC and PT 
A similar summary of grade 3 or 4 TEAEs will be presented by SOC, PT and by treatment cycle.
In addition, a listing of grade 3 or 4 TEAEs will also be provided.
6.1.4.
Treatment-related TEAEs
The following TEAEs will be summarized by relationship to study treatment:

TEAEs by SOC, PT, and relationship

Grade 3 or 4 TEAEs by SOC, PT and relationship
6.1.5.
Serious TEAEs
The incidence of serious TEAEs will be summarized as below:

Serious TEAEs by SOC and PT 

Serious TEAEs by SOC, PT and relationship to study treatment

Most commonly reported (e.g., ≥2%) serious TEAEs by SOC and PT 
A similar summary of serious TEAEs will be presented by SOC, PT and treatment cycle. 


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In addition, a listing of serious TEAEs will be provided.
6.1.6.
TEAEs Leading to Treatment Discontinuation
The TEAEs leading to permanent treatment discontinuation will be summarized by SOC, PT and 
grade 3/4 for those subjects indicated as having discontinued study treatment due to an adverse 
event on the eCRF “End of Treatment” page. 
A listing for subjects who discontinued study treatment due to AE will be provided.
6.1.7.
TEAEs Leading to Dose Modifications
Incidence of TEAEs leading to treatment cycle delays or dose modifications will be summarized 
by SOC, PT and grade 3/4 for each treatment cohort.
6.1.8.
TEAEs with Fatal Outcome 
The TEAEs with fatal outcome will be summarized by PT and relationship to study treatment for 
each treatment cohort. A listing of TEAEs with fatal outcome will also be provided.
6.2.
Deaths
The number of subjects who died during the study and the primary causes of death will be
summarized for all treated analysis set. In addition, the similar summaries will be presented for 
all deaths within 30 days of last dose of study treatment and deaths within 60 days of first dose 
of study treatment, respectively.
A listing of subjects who died during the study will be provided.
6.3.
Adverse Events of Clinical Interest 
6.3.1.
Infusion-related Reactions
6.3.1.1.
Rate of Infusion-related Reactions
For the major secondary endpoint of rate of IRRs, the proportion of subjects who have an IRR 
along with its two-sided 90% Clopper-Pearson exact CI will be calculated for each treatment 
cohort on all treated analysis set.  
6.3.1.2.
Summary of Infusion-related Reactions
The incidence of infusion-related reactions (IRRs), as recorded on eCRF, will be presented by 
SOC, PT, and toxicity grade 3/4. In addition, the total number of subjects with IRR in more than 
1 infusion will be presented. The timing of IRR will also be evaluated through a summary of IRR 
by event onset time. 
A listing of infusion-related reactions will be provided.


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6.3.2.
Injection-site Reactions 
The incidence of injection-site reactions, as recorded on eCRF, will be summarized by SOC, PT, 
and toxicity grade 3/4. A listing of injection-site reactions will be provided.
6.3.3.
Infections and Infestations
Infections and infestations refer to the adverse events with SOC of infections and infestations.
The grade 3 or 4 treatment-emergent infections and infestations will be summarized by preferred 
term and relationship to treatment. Treatment-emergent infections and infestations may also be 
summarized by preferred term and treatment cycles.
6.3.4.
Hemorrhage Events
Hemorrhage events refer to the adverse events defined by Standardized MedDRA Queries 
(SMQ) with the first subcategory SMQ of hemorrhage terms (exclude laboratory terms).
Incidences will be summarized by MedDRA system organ class and preferred term. The
summaries will be presented by all grades and maximum toxicity grade for each treatment
cohort.
6.3.5.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) events refer to the adverse events defined by narrow SMQ of 
tumor lysis syndrome (e.g., haemorrhagic tumour necrosis, tumour lysis syndrome, or tumour 
necrosis). A listing of subjects who reported any treatment-emergent TLSs during the study will
be provided.
6.3.6.
Second Primary Malignancies
The second primary malignancies during the study will be summarized by cancer type and 
preferred term. A listing of subjects who reported second primary malignancies during the study 
will also be provided. This listing will include diagnosis, study day of diagnosis, recurrence of a 
prior existing malignancy (yes, no) and pathology diagnosis (biopsy, aspirate etc.) information 
whenever a second primary malignancy is observed. In addition, cumulative study treatment 
exposure, the treatment for second primary malignancy and the outcome information will also be 
presented in the listing.
6.3.7.
Cardiac-related Treatment-emergent Adverse Events of Interest (D-Kd 
cohort only)
A summary of subjects with 1 or more treatment-emergent cardiac events of interest by
standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQ) and
preferred term will be summarized for D-Kd cohort.  A listing of D-Kd subjects with cardiac 
disorders will be provided.  


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6.3.8.
Adverse Events by Subgroups
The subgroup analysis for the following TEAEs will be performed based on the subgroups 
specified in Section 2.6:

Overview of TEAEs 

Summary of all TEAEs 

Grade 3 or 4 TEAEs

Serious TEAEs
The subgroup analysis for the rate of IRRs will be performed by weight categories specified in 
section 2.6.
6.4.
Clinical Laboratory Tests
The evaluation of clinical laboratory tests will focus on the following selected laboratory 
analytes:

Hematology Panel:
-
hemoglobin
-
white blood cell (WBC) count, absolute neutrophil count, and absolute lymphocyte 
count
-
platelet count

Serum Chemistry Panel:
-
AST
-
alkaline phosphatase
-
ALT
-
uric acid
-
total bilirubin
-
blood urea nitrogen (BUN) or urea
-
glucose
-
calcium and albumin-adjusted calcium
-
creatinine
-
lactic acid dehydrogenase (LDH)
-
sodium
-
potassium
Descriptive statistics for values and changes from baseline at each scheduled visit for 
hematology and chemistry laboratory parameters will be provided. Line plot of mean with 
standard error for each laboratory analyte over time will be displayed for hemoglobin, 
neutrophils, lymphocytes, platelets, WBC, AST, ALT, creatinine, and creatinine clearance/GFR.
In addition, the worst toxicity grade in hematology and chemistry during the treatment will be 
summarized by toxicity grade. Shifts tables from baseline to the worst toxicity grade during 
treatment will be generated.
A listing of subjects with any laboratory results outside the reference ranges will be provided. 


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6.5.
Vital Signs and Physical Examination Findings
Descriptive statistics will be provided for values and changes from baseline over time for vital 
signs (pulse, temperature, systolic and diastolic blood pressure) at each scheduled visit and 
timepoint. Similar analysis may be performed for weight at Day 1 of each treatment cycle.
Clinically significant physical examination findings occurred at post-baseline were collected as 
AEs, and therefore will not be summarized.
6.6.
Electrocardiogram
The ECG data will be collected at Screening, visits as clinically indicated during treatment, and 
End-of-Treatment visit. 
The number and percentage of subjects with normal and abnormal either clinically significant or 
not clinically significant ECG results will be summarized for each treatment cohort.
A listing of subjects who experienced clinically significant abnormal ECGs in either baseline or 
post-baseline will be produced.
Both the summary and the listing of left ventricular ejection fraction (LVEF) will be provided
(D-Kd cohort only).
6.7.
ECOG Performance Status 
ECOG performance status, which evaluates the effect of the disease status on the activities of 
daily living, will be assessed at Screening, Day 1 of each treatment cycle and end-of-treatment 
visit. The shift summaries of ECOG performance status from baseline to each scheduled visit, 
including Day 1 of each treatment cycle and end-of-treatment visit, will be provided for each 
treatment cohort. The shift summary from baseline to the worst performance score during 
treatment will also be presented.
6.8.
Stem Cell Collection (D-VRd cohort only)
Descriptive statistics of number of stem cells collected, number of days of autologous stem cell 
collection, drugs used for autologous stem cell mobilization, and requirement special stem cell 
mobilizing agent (e.g. mozobil) will be summarized for D-VRd cohort.
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS
Unless specified otherwise, descriptive statistics will be used to summarize pharmacokinetics 
and pharmacodynamics data. In addition, coefficient variation and geometric mean will be 
provided in the pharmacokinetic concentration summary.


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7.1.
Pharmacokinetics
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. 
The pharmacokinetic parameters are defined as:
-
Cmin: Minimum observed concentration, defined as the concentration observed 
immediately before the drug administration;
-
Cmax: Maximum observed concentration, defined as the concentration observed after the 
end of drug administration.
The Cmin and Cmax will be determined based on the assigned collection timepoints. Descriptive 
statistics will be used to summarize daratumumab serum concentrations at each sampling time 
point specified in protocol on the pharmacokinetics analysis set. Plot of mean (±SD) 
daratumumab serum peak and trough concentrations over time by cohort will be provided. If 
sufficient data are available, other pharmacokinetic parameters may be calculated and analyzed.
If there are sufficient data, population pharmacokinetic analysis of serum concentration-time data 
of daratumumab may be performed using nonlinear mixed effects modeling and may include
data from other clinical studies. If performed, details will be provided in a population 
pharmacokinetic analysis plan and results of the analysis will be presented in a separate report.
7.2.
Immunogenicity
The incidence of anti-daratumumab antibodies along with the titer and incidence of neutralizing 
antibodies will be summarized for all subjects who receive a dose of daratumumab and have at 
least 1 sample for detection of anti-daratumumab antibodies after the first dose (daratumumab 
immunogenicity-evaluable analysis set).
The prevalence and incidence of anti-rHuPH20 antibodies along with the titer will be 
summarized for all subjects who receive a dose of daratumumab and have at least 1 sample for 
detection of anti-rHuPH20 antibodies after the first dose (rHuPH20 immunogenicity-evaluable 
analysis set).
A listing of anti-daratumumab antibody sample and subject status with concurrent daratumumab 
concentration will be provided.  A listing of anti-rHuPH20 antibody sample and subject status 
will also be provided.    
7.3.
Pharmacokinetic/Pharmacodynamic Relationships
Pharmacokinetic/pharmacodynamic modeling may be performed, including exploring the 
relationship between serum concentrations of daratumumab and endpoints of clinical efficacy 
and safety. If performed, details and results of the analysis will be presented in a separate report.


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8.
BIOMARKER  
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Samples for biomarker evaluations will be collected as specified in the protocol 
Time and Events Schedule. Baseline bone marrow aspirate samples are required, if feasible. In 
addition to planned bone marrow aspirate assessment, whole blood samples will be collected 
from subjects as outlined in the Time and Events Schedule for processing to plasma and 
peripheral blood mononuclear cells (PBMCs). Results of biomarker analyses may be presented 
in a separate report.
8.1.
Minimal Residual Disease (MRD)
Bone marrow aspirate will be collected for MRD analysis, in the D-VMP, D-Rd and D-Kd
cohorts only, when bone marrow samples are obtained at screening, confirmation of CR/sCR, 
and subsequent timepoints after the first dose as outlined in the protocol Time and Events 
Schedule.
Minimal residual disease (MRD) negativity rate is defined as the proportion of subjects who are 
considered MRD negative after MRD testing at any timepoint after first dose and before disease 
progression or starting subsequent therapy by bone marrow aspirate. 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 or not evaluated will be considered as MRD 
positive.
The MRD negativity rate will be calculated for treatment cohorts D-VMP, D-Rd and D-Kd on 
the pharmacokinetics analysis set. The corresponding two-sided 90% exact CI will be provided. 
Reasons for missing or unevaluable MRD status will be tabulated by treatment group.
In addition, MRD negativity rate will be summarized at each post-baseline sampling timepoints. 
The percentage of subjects with MRD negative by different thresholds (i.e. <10-6, <10-5, and 
<10-4) at each sampling timepoints will also be reported, based on bone marrow aspirate.
9.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data associated with medical encounters due to IRRs, primarily 
hospitalizations, outpatient visits and emergency room visits, will be collected on eCRF by the 
investigator and study-site personnel for all subjects throughout the study.
Medical resource utilization will be descriptively summarized for each treatment cohort. 
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 will be tabulated. The treatment-
emergent adverse events leading to the hospitalization/outpatient visits and leading to on-study 
transfusions will also be summarized.


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Statistical Analysis Plan 54767414MMY2040
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Approved, Date: 8 September 2020
REFERENCES  
1.
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.
2.
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of 
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 4691-4695.


Signature
User
Date
Reason
QI MING 
08-Sep-2020
15:08:27
(GMT)
Document Approval
RAO SUDHAKAR 
08-Sep-2020
15:11:38
(GMT)
Document Approval
PPD
PPD