Clinical trial NCT02951819
Conditions: Multiple Myeloma
Sponsor: Janssen Scientific Affairs, LLC
Start date: 2016-11-09; Completion date: 2020-08-17
Enrollment: 101 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate complete response plus (+) very good partial response (CR+VGPR) rate following 4 cycles of induction therapy of daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD), in previously untreated subjects, and in relapsed subjects with multiple myeloma, as defined by the International Myeloma Working Group (IMWG) criteria.

Detailed description:

Arms: arm 1: Subjects will receive Daratumumab along with Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) as induction on a 28-day cycle length and Daratumab and Dexamethasone on Day 1 of each cycle for 12 cycles as maintenance therapy.
Interventions: intervention 1: Daratumumab intervention 2: Cyclophosphamide intervention 3: Bortezomib intervention 4: Dexamethasone
Intervention descriptions: intervention 1: For induction therapy cycle 1 day 1 and day 2 doses of daratumumab will be 8 milligram/kilogram (mg/kg). Starting cycle 1 week 2 until the completion of week 8 of daratumumab patients will receive 16 mg/kg Intravenously (IV) weekly.

Starting week 9 until the completion of week 24 therapy daratumumab will be administered every other week at 16 mg/kg IV.

Starting week 25 and beyond for induction therapy daratumumab will be given once every 4 weeks. intervention 2: Subjects will receive 4 to 8 cycles of oral cyclophosphamide 300 milligram per meter square (mg/m\^2 ) on Days 1, 8, 15, and 22 for every 28 days. intervention 3: Subjects will receive 4 to 8 cycles of Bortezomib 1.5 mg/m2 subcutaneous (SC) on Days 1, 8, and 15 for every 28 days. intervention 4: Subjects will be given corticosteroids (Dexamethasone) as pre-infusion therapy prior to daratumumab and for the first 8 cycles will also receive post-infusion corticosteroids (Dexamethasone).

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 2 May 2017
Janssen Scientific Affairs, LLC*
Clinical Protocol
Daratumumab plus Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) 
in Previously Untreated and Relapsed Subjects with Multiple Myeloma 
Dara-CyBorD
Protocol 54767414MMY2012; Phase 2
Amendment 2
JNJ-54767414  (daratumumab)
* Janssen Scientific Affairs, LLC is an organization that operates through different legal entities in 
various countries, including Janssen Research & Development, LLC. The legal entity acting as the 
sponsor for studies of Janssen Scientific Affairs, LLC may vary. The term "sponsor" is used throughout 
the protocol to represent these various legal entities.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved
Date:
2 May 2017
Prepared by:
Janssen Scientific Affairs, LLC  
EDMS number:
EDMS-ERI-125925080, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 14
TIME AND EVENTS SCHEDULE .............................................................................................................. 19
ABBREVIATIONS ...................................................................................................................................... 22
1.
INTRODUCTION................................................................................................................................ 24
1.1.
Background .................................................................................................................................... 24
1.1.1.
Nonclinical Studies ..................................................................................................................... 25
1.1.2.
Clinical Studies ........................................................................................................................... 26
1.1.2.1.
Single-agent Studies of Daratumumab in Relapsed/Refractory Multiple Myeloma ................ 26
1.1.2.2.
Studies of Daratumumab in Combination with Other Backbone Chemotherapy 
Regimens in Relapsed/Refractory Multiple Myeloma ............................................................. 27
1.1.2.3.
Combination Therapy: Bortezomib, Cyclophosphamide, and Dexamethasone...................... 27
1.2.
Overall Rationale for the Study...................................................................................................... 30
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 31
2.1.
Objectives and Endpoints .............................................................................................................. 31
2.1.1.
Objectives ................................................................................................................................... 31
2.1.2.
Endpoints.................................................................................................................................... 31
2.2.
Hypothesis ..................................................................................................................................... 33
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 33
3.1.
Overview of Study Design.............................................................................................................. 33
3.2.
Study Design Rationale.................................................................................................................. 35
4.
SUBJECT POPULATION.................................................................................................................. 35
4.1.
Inclusion Criteria ............................................................................................................................ 36
4.2.
Exclusion Criteria ........................................................................................................................... 38
4.3.
Prohibitions and Restrictions ......................................................................................................... 40
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 40
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 40
6.1.
Daratumumab ................................................................................................................................ 41
6.1.1.
Preparation ................................................................................................................................. 41
6.1.2.
Treatment Schedule and Administration .................................................................................... 41
6.1.3.
Instructions for Preparing and Administering Daratumumab Infusions...................................... 41
6.1.4.
Guidelines for Prevention and Management of Infusion-related Reactions............................... 42
6.1.4.1.
Preinfusion Medication ............................................................................................................ 43
6.1.4.2.
Postinfusion Medication........................................................................................................... 43
6.1.5.
Management of Infusion-related Reactions................................................................................ 44
6.2.
Dose Delay and Modification ......................................................................................................... 44
6.2.1.
Toxicity Management.................................................................................................................. 44
6.3.
Bortezomib ..................................................................................................................................... 46
6.3.1.
Dose Adjustments of Bortezomib ............................................................................................... 47
6.4.
Cyclophosphamide......................................................................................................................... 48
6.5.
Corticosteroids ............................................................................................................................... 48
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7.
TREATMENT COMPLIANCE............................................................................................................ 49
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 50
9.
STUDY EVALUATIONS .................................................................................................................... 51
9.1.
Study Procedures........................................................................................................................... 51
9.1.1.
Screening Phase ........................................................................................................................ 51
9.1.1.1.
Demographic Characteristics and Medical History.................................................................. 52
9.1.1.2.
Bone Marrow Biopsy, Serum and Urine Tests ........................................................................ 52
9.1.1.3.
Blood Typing/Indirect Coombs Testing ................................................................................... 52
9.1.2.
Treatment Phase ........................................................................................................................ 53
9.1.2.1.
Induction Therapy.................................................................................................................... 53
9.1.2.2.
Consolidation Stem Cell Therapy, if Eligible ........................................................................... 53
9.1.2.3.
Maintenance Therapy with Daratumumab .............................................................................. 53
9.1.2.4.
End of Treatment..................................................................................................................... 54
9.1.3.
Post-treatment Phase (Follow-Up) ............................................................................................. 54
9.2.
Efficacy Evaluations....................................................................................................................... 54
9.2.1.
SPEP, UPEP, and FLC Testing.................................................................................................. 55
9.2.2.
Serum Calcium ........................................................................................................................... 55
9.2.3.
Bone Marrow Examination.......................................................................................................... 56
9.2.4.
Assessment of Lytic Disease...................................................................................................... 56
9.2.5.
Documentation of Extramedullary Plasmacytomas.................................................................... 56
9.3.
Safety Evaluations ......................................................................................................................... 57
9.3.1.
Adverse Events........................................................................................................................... 57
9.3.2.
Clinical Laboratory Tests ............................................................................................................ 58
9.3.3.
Electrocardiogram (ECG) ........................................................................................................... 59
9.3.4.
Vital Signs................................................................................................................................... 59
9.3.5.
Physical Examination.................................................................................................................. 59
9.4.
Sample Collection and Handling.................................................................................................... 59
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 60
10.1.
Completion ..................................................................................................................................... 60
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 60
11.
STATISTICAL METHODS................................................................................................................. 61
11.1.
Subject Information ........................................................................................................................ 61
11.2.
Sample Size Determination ........................................................................................................... 62
11.3.
Efficacy Analyses ........................................................................................................................... 62
11.4.
Safety Analyses ............................................................................................................................. 62
11.5.
Interim Analysis.............................................................................................................................. 63
11.6.
Data Review Committee ................................................................................................................ 64
12.
ADVERSE EVENT REPORTING ...................................................................................................... 64
12.1.
Definitions ...................................................................................................................................... 64
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 64
12.1.2.
Attribution Definitions.................................................................................................................. 65
12.1.3.
Severity Criteria .......................................................................................................................... 66
12.2.
Special Reporting Situations.......................................................................................................... 66
12.3.
Procedures..................................................................................................................................... 67
12.3.1.
All Adverse Events...................................................................................................................... 67
12.3.2.
Serious Adverse Events ............................................................................................................. 68
12.3.3.
Pregnancy................................................................................................................................... 69
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 69
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 69
13.1.
Procedures..................................................................................................................................... 69
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 69
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14.
STUDY DRUG INFORMATION......................................................................................................... 70
14.1.
Physical Description of Study Drug(s) ........................................................................................... 70
14.2.
Packaging ...................................................................................................................................... 70
14.3.
Labeling.......................................................................................................................................... 70
14.4.
Preparation, Handling, and Storage............................................................................................... 70
14.5.
Drug Accountability ........................................................................................................................ 70
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 71
16.
ETHICAL ASPECTS ......................................................................................................................... 71
16.1.
Study-Specific Design Considerations........................................................................................... 71
16.2.
Regulatory Ethics Compliance....................................................................................................... 72
16.2.1.
Investigator Responsibilities ....................................................................................................... 72
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 72
16.2.3.
Informed Consent ....................................................................................................................... 73
16.2.4.
Privacy of Personal Data ............................................................................................................ 74
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 75
17.1.
Protocol Amendments.................................................................................................................... 75
17.2.
Regulatory Documentation ............................................................................................................ 75
17.2.1.
Regulatory Approval/Notification ................................................................................................ 75
17.2.2.
Required Prestudy Documentation............................................................................................. 75
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 76
17.4.
Source Documentation................................................................................................................... 77
17.5.
Case Report Form Completion ...................................................................................................... 78
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 78
17.7.
Record Retention ........................................................................................................................... 79
17.8.
Monitoring ...................................................................................................................................... 79
17.9.
Study Completion/Termination....................................................................................................... 80
17.9.1.
Study Completion/End of Study.................................................................................................. 80
17.9.2.
Study Termination....................................................................................................................... 80
17.10.
On-Site Audits ................................................................................................................................ 81
17.11.
Use of Information and Publication................................................................................................ 81
REFERENCES............................................................................................................................................ 83
INVESTIGATOR AGREEMENT ................................................................................................................. 93
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LIST OF ATTACHMENTS
Attachment 1:  Calculated and Measured Creatinine Clearance................................................................ 85
Attachment 2:  ECOG Performance Status Scale ...................................................................................... 86
Attachment 3:  Asthma Guidelines.............................................................................................................. 87
Attachment 4:  Serum Calcium Corrected for Albumin ............................................................................... 88
Attachment 5: IMWG Guidelines................................................................................................................. 89
Attachment 6:  Anticipated Events .............................................................................................................. 92
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Dosing Information for Dara-CyBorD by Cycle......................................................................... 34
Table 2:
Daratumumab Infusion Rates ................................................................................................... 42
Table 3:
Daratumumab Administration Schedule and Dose Delay Instructions..................................... 46
Table 4:
Recommended Dose Modification for Bortezomib-related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy ................................................................................. 47
Table 5:
Dexamethasone Dose Schedule .............................................................................................. 49
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 35
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
16 June 2016
Amendment 1
29 August 2016
Amendment 2
2 May 2017
         
Amendment INT-2 (2 May 2017)
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment is to end enrollment in the relapsed multiple myeloma arm, add 
a third interim safety analysis, and add several clarifications to entry criteria and assessments.
Edits and additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable Sections
Description of Changes
Rationale: Due to approval of daratumumab in combination with bortezomib and dexamethasone for the 
treatment of subjects with multiple myeloma after at least one prior line of therapy, subjects and physicians are 
not opting to enroll in the relapsed multiple myeloma arm of this study. Because of this, enrollment in the 
relapsed multiple myeloma arm is being stopped.
Synopsis, Overview of Study 
Design (second paragraph)
Synopsis, Statistical Methods
(third paragraph)
Approximately 100 subjects will be enrolled into this study with at least 40 
previously untreated multiple myeloma subjects. The relapsed multiple 
myeloma arm is closed to enrollment as of Amendment 2. 
To ensure that an adequate number of subjects in each cohort (previously 
untreated and relapsed) are enrolled, It is planned that at least 40 subjects will 
be enrolled in the previously untreated each disease cohort. As of 
Amendment 2, enrollment of subjects in the relapsed cohort is closed and 
expected not to exceed 15 subjects. No inferential statistics will be 
performed for the relapsed cohort. If the number of relapsed multiple 
myeloma subjects enrolled provides inadequate power, no statistical 
comparisons will be reported; rather, descriptive summaries will be reported.
3.1, Overview of Study Design 
Overview (first paragraph)
Approximately 100 subjects will be enrolled into this study with at least 40 
previously untreated multiple myeloma subjects. and at least 40 subjects with 
relapsed multiple myeloma following one prior line of therapy. Due to slow 
enrollment of and at least 40 subjects with relapsed multiple myeloma 
following one prior line of therapy, this cohort is closed to enrollment in 
Amendment 2.
4.1, Inclusion Criteria #4
Have previously untreated myeloma or relapsed myeloma (enrollment of 
subjects with relapsed myeloma closed in Amendment 2) with one prior line 
of therapy including….
11.2, Sample Size 
Determination (third 
paragraph)
If the number of relapsed multiple myeloma subjects enrolled provides 
inadequate power, no statistical comparisons will be reported; rather, 
descriptive summaries will be reported.
With the planned enrollment of 100 subjects, with a minimum of 40 newly 
diagnosed multiple myeloma subjects and at least 40 subjects with relapsed 
multiple myeloma following one prior line of therapy, at least 80% power will 
be achieved to detect an absolute 20% increase in each of these the untreated
cohorts at the 5% 1-sided significance level. In Amendment 2, enrollment of 
subjects in the relapsed cohort is closed and expected not to exceed 15 
subjects. No inferential statistics will be performed for the relapsed cohort.
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11.3, Efficacy Analyses
(second paragraph)
The proportion of subjects will be analyzed using a normal approximation to 
the binomial distribution comparing the observed proportion to a reference of 
0.60 for previously untreated subjects. and a reference value of 0.30 for 
relapsed subjects.
Rationale: Text regarding 1 additional interim safety analysis after at least 50 subjects complete Cycle 1 of study 
treatment (or discontinue before the end of Cycle 1) was added in order to evaluate infusion-related reactions 
during Cycle 1.
Synopsis, Statistical Methods
(last paragraph)
Two Three interim safety analyses are planned. The first interim safety 
analysis will occur after the first at least 20 subjects are treated for at least 1 
cycle of study treatment (or discontinue before the end of Cycle 1) , and the 
second will occur after at least 50 subjects are treated for at least 4 cycles. The 
second interim safety analysis will occur after at least 50 subjects complete 
cycle 1 of study treatment (or discontinue before the end of Cycle 1) with a 
focus on infusion related reactions during cycle 1. The third interim safety 
analysis will occur after at least 50 subjects are treated for at least 4 cycles 
(or discontinue before the end of Cycle 4).
3.1, Overview of Study Design
(ninth paragraph)
An Internal Data Monitoring Review Committee will review interim data at 23 
predetermined interim safety analyses. The first safety analysis will occur after 
at least 20 subjects are treated for at least 1 cycle of study treatment (or 
discontinue before the end of Cycle 1), and the second will occur after at least 
50 subjects are treated for at least 4 cycles. The second interim safety 
analysis will occur after at least 50 subjects complete Cycle 1 of study 
treatment (or discontinue before the end of Cycle 1) with a focus on 
infusion related reactions during Cycle 1. The third interim safety analysis 
will occur after at least 50 subjects are treated for at least 4 cycles (or 
discontinue before the end of Cycle 4).
11.5, Interim Analysis (first 
paragraph)
Two Three interim safety analyses are planned for the main study. The interim 
safety analyses will occur after the first 20 subjects are treated for at least 1 
cycle of study treatment (or discontinue before the end of Cycle 1), and the 
second will occur after at least 50 subjects are treated for at least 4 cycles. The 
first interim safety analysis will occur after at least 20 subjects are treated 
for at least 1 cycle of study treatment (or discontinue before the end of 
Cycle 1). The second interim safety analysis will occur after at least 50 
subjects complete Cycle 1 of study treatment (or discontinue before the 
end of Cycle 1) with a focus on infusion-related reactions during Cycle 1. 
The third interim safety analysis will occur after at least 50 subjects are 
treated for at least 4 cycles (or discontinue before the end of Cycle 4).
Rationale: Introductory text was added regarding the recent marketing approvals for daratumumab, and results 
for Study MMY3004, daratumumab in combination with bortezomib and dexamethasone.
1, Introduction (second 
paragraph)
Daratumumab by intravenous (IV) injection is approved in the United 
States (US), European Union, and other countries for the treatment of 
patients with multiple myeloma who have received at least 3 prior lines of 
therapy including a proteasome inhibitor (PI) and an immunomodulatory 
agent (IMiD) or who are double-refractory to a PI and an IMiD. On 21 
November 2016, the US Food and Drug Administration (FDA) approved 
daratumumab in combination with lenalidomide and dexamethasone, or 
bortezomib and dexamethasone, for the treatment of patients with 
multiple myeloma who have received at least one prior therapy.
1.1.2.2, Studies of 
Daratumumab in Combination 
with Other Backbone 
Chemotherapy Regimens in 
Relapsed/Refractory Multiple 
Myeloma (second, third 
paragraphs)
In Study MMY3004, daratumumab in combination with bortezomib and 
dexamethasone (DVd), the primary analysis showed a significant 
improvement in PFS for subjects in the DVd group, compared with the 
bortezomib/dexamethasone (Vd) group.  This represents a 61% reduction 
in the risk of disease progression or death for the DVd group compared 
with the Vd group.  The 12-month PFS rate was 61% for the DVd group 
and 27% for the Vd group.
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Among 243 DVd-treated subjects, the most common AEs were 
thrombocytopenia (60%), peripheral sensory neuropathy (49%), diarrhea 
(34%), upper respiratory tract infection (30%), anemia (28%), and cough 
(27%). SAEs were reported in 49% of subjects, with the most common 
being pneumonia (9%); anemia, bronchitis, thrombocytopenia, atrial 
fibrillation, and upper respiratory tract infection (each in 3%); and 
pyrexia (2%).  Deaths were reported in 14 subjects; 12 deaths were due to 
AEs and 2 were due to disease progression.  The safety profile for DVd was 
similar to that for the Vd comparator group.
Rationale: The entry criterion defining multiple myeloma was edited slightly for clarity.  Positron emission 
tomography (PET)/computed tomography (CT) fusion studies were removed for assessing lytic bone disease and 
extramedullary plasmacytomas since this method is unlikely to be used.
4.1, Inclusion Criteria #2
Have documented multiple myeloma as defined by the IMWG 2015 criteria 
below:

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or 
extramedullary plasmacytoma* and any one or more of the 
following CRAB (calcium level, renal dysfunction, anemia, and 
destructive bone lesions) features and myeloma defining events.
Myeloma-defining events: In addition, the subject must meet one 
of the criteria in either 2a or 2b.  

a. 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 min 
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, or
CT (computed tomography)**, or 
positron emission tomography (PET)-CT. 
-
b.  Any one or more of the following:
o
Clonal bone marrow plasma cell percentage* ≥60%
o
Involved:uninvolved serum FLC ratio*** >100
o
>1 focal lesions on MRI (magnetic resonance imaging) 
studies; Each focal lesion must be 5 mm or more in size.
Rationale: The exclusion criterion for human immunodeficiency virus and hepatitis was clarified, with additional 
assessments for hepatitis C reactivation.
4.2, Exclusion Criteria, #6
Time and Events Schedule 
(Laboratory assessments/
footnote j)
Subjects who completed treatment for hepatitis C at least 6 months prior 
to screening and have no detectable circulating hepatitis C virus (HCV) by 
hepatitis C RNA polymerase chain reaction (PCR) at screening, may 
participate in the study. Such subjects will be required to undergo regular 
assessment for HCV reactivation during their participation in the study.
Subjects who test positive for HCV at any time during these assessments 
will be withdrawn from the study.
HCV viral load to be assessed only for subjects who completed treatment 
for hepatitis C at least 6 months prior to screening and have no detectable 
circulating HCV at screening. Such subjects will be required to undergo 
regular assessment for HCV reactivation through 6 months after their last 
daratumumab administration.  Subjects who test positive for HCV at any 
time during these assessments will be withdrawn from the study. [To be 
checked every 3 months through 6 months after their last daratumumab 
administration]
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9.3.2, Clinical Laboratory 
Tests
10.2 Discontinuation of Study 
Treatment (sixth bullet)
10.2 Withdrawal From the 
Study (third bullet)
Hepatitis C viral load testing by hepatitis C RNA PCR – for reactivation of 
HCV for any subjects who had prior, treated hepatitis C and no detectable 
circulating HCV at study entry.

A subject with a history of HCV who completed treatment at least 6 
months prior to screening, who does not agree to undergo regular 
assessment for HCV reactivation during their participation in the 
study.

Had a history of HCV and completed treatment at least 6 months 
prior to screening but test positive for HCV at any time during the 
regular assessments
Rationale: An item was added to the exclusion criterion for prior multiple myeloma treatment, for completeness.
4.2, Exclusion Criterion #2
Diagnosed or treated for malignancy other than multiple myeloma, except:

Adequately treated non-melanoma skin cancer, lentigo maligna or 
in situ malignancies (eg, cervical, breast) without evidence of 
disease
Rationale:  Wording regarding spirometry/FEV1 testing was clarified. 
Time and Events Schedule 
row; 
and footnote f
Pulmonary functions testing Spirometry (FEV1)
For subjects with chronic obstructive pulmonary disease or asthma, FEV1 
should be measuredPulmonary function testing (spirometry) is required 
only for subjects with chronic obstructive pulmonary disease or asthma. 
FEV1 should be measured.
Rationale:  Text was corrected regarding enrollment of previously untreated subjects since this may not be
accurate.
3.2, Study Design Rationale
Since the total subject population will likely consist of at least 50% previously 
untreated subjects who may undergo consolidation therapy with an autologous 
transplant, The duration of follow-up needs to will be at least 36 months to 
capture median long-term outcomes such as progression-free survival.
Rationale:  Clarification was made regarding language for “study drug” and “study treatment”, and dose 
adjustments due to change in weight.
6, Dosage and Administration
In this protocol, the term “study drug” refers to daratumumab, and 
“study treatment” refers to Dara-CyBorD. In this study, daratumumab is the 
study drug. The CyBorD medications are considered standard of care and will 
be commercially available drugs. 
If a subject’s weight changes by more than 10% after C1D1, the dose of 
daratumumab and the other weight-based treatments (cyclophosphamide, 
bortezomib) will be re-calculated. Otherwise, dose modification of 
daratumumab is not permitted (see Section 6.2, Dose Delay and 
Modification).
Rationale: Correction was made for duration to withhold the daratumumab dose.
Table 3: Daratumumab 
Administration Schedule and 
Dose Delay Instructions for 
Cycles 7+
Dose Held: >7 >14 days (if induction or maintenance)
Rationale:  Correction was made to dexamethasone dose administration for Cycle 2. 
6.1.4.1, Preinfusion 
Medication; Dexamethasone 
3. Cycle 2 Day 1, 8, 15, and 22: dexamethasone 40 mg IV
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Rationale: Clarification was made regarding cyclophosphamide dose modifications.
6.4, Cyclophosphamide (first 
paragraph)
Cyclophosphamide will be given as 300 mg/m2 on Days 1, 8, 15 and 22 of each 
cycle (continuous) by mouth (PO), for up to 8 cycles. Dose modification may 
be made due to myelotoxicity (excluding anemia) and cystitis during any 
treatment cycle.
Rationale: Rescreening is allowed once and corresponding instructions were added.
9.1.1, Screening Phase
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 rescreening must sign 
a new ICF and will then be assigned a new screening number.
Rationale: Wording for the bone marrow aspirate at screening was clarified. 
9.2.3, Bone Marrow 
Examination
A reasonable attempt to obtain a fresh bone marrow aspirate is required 
at screening. A fresh bone marrow aspirate at screening is required, if at all 
possible.
Rationale:  Wording about laboratory results prior to dosing was clarified.
Time and Events Schedule, 
footnote j;
9.3.2, Clinical Laboratory 
Tests
Results of local hematology and chemistry tests must be evaluated before each 
study drug administration Day 1 of each cycle to guide treatment decisions, but 
do not need to be reported in the eCRF unless they result in a dose delay.
Rationale:  Clarifications were made for safety event reporting.
12.3.1, All Adverse Events 
(first paragraph)
(New second paragraph)
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 last dose of study treatment   completion of the subject's 
last study-related procedure, which may include contact for follow-up of safety.
Serious adverse events, including those spontaneously reported to the 
investigator within 30 days after the last dose of study treatmentdrug, must be 
reported using the Serious Adverse Event Form.
During the stem cell mobilization and transplantation procedures (in 
eligible subjects), adverse events related to stem cell mobilization and 
transplantation do not need to be reported in the CRF; however, any 
toxicity related to study treatment will continue to be reported.
Rationale: The “Data Monitoring Committee” is now referred to as the Data Review Committee to align with 
current Sponsor conventions. 
Changed everywhere relevant.
Rationale:  An Anticipated Event Review Committee was erroneously referred to in the previous version of the 
protocol and this is being deleted as there is no need for this committee.
Attachment 6, Anticipated 
Events
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform 
reviews of pre-specified anticipated events at an aggregate level. The ARC is a 
safety committee within the sponsor’s organization that is independent of the 
sponsor’s study team. The ARC 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 drug.
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
11
Approved, Date: 2 May 2017
Amendment INT-1 (29 August 2016)
This amendment is not considered substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to add clarifications for a few 
of the assessments being done in this study.  
Edits and additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable Section(s)
Description of Change(s)
Rationale:  The inclusion criterion pertaining to diagnosis of multiple myeloma is being edited to align with the 
most recent IMWG criteria.
4.1, Inclusion Criteria; 
#2 (first sentence and 
bullet related to bone 
lesions)
1.
Have documented multiple myeloma as defined by the IMWG 2015 criteria 
below:
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or 
extramedullary plasmacytoma* and any one or more of the following CRAB 
(calcium level, renal dysfunction, anemia, and destructive bone lesions) 
features and myeloma defining events:

Myeloma defining events:

Evidence of end organ damage that can be attributed to the underlying 
plasma cell proliferative disorder, specifically:
o
Bone lesions: one or more osteolytic lesions…. If bone marrow 
has <10% clonal plasma cells, more than one bone lesion is 
required to distinguish from solitary plasmacytoma with 
minimal marrow involvement
Rationale: The details for recording daratumumab administration are being simplified. 
7 Treatment Compliance
Daratumumab will be administered as an IV infusion by qualified study-site 
personnel and the details of each administration will be recorded in the case 
report form (CRF) (including date, start and stop times of the IV infusion, 
volume infused, and weight of IV infusion bag, including the infusion line, 
before and after the completion of the IV infusion). 
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
12
Approved, Date: 2 May 2017
Rationale: The FISH testing is being corrected to note that it is only being done at screening (for risk 
stratification analyses whereby patients will be grouped by high, intermediate, or standard risk for time to 
progression analyses).
The exploratory objective based on FISH results is being corrected to reflect the most important genetic 
biomarkers.
Treatment and Events 
Schedule; Sections 
9.1.1.2 Bone Marrow 
Biopsy, Serum and 
Urine Tests; 9.1.2.3 
Maintenance Therapy 
with Daratumumab; 
and 9.1.3 Post-
treatment Phase 
(Follow-Up)
Exploratory Objective 
(Synopsis; 
Sections 
2.1.1 Objectives; 2.1.2 
Endpoints) 
FISH was removed as an assessment to be done any time after screening.
An exploratory objective is to evaluate the clinical efficacy of Dara-CyBorD in 
molecular subgroups, including: del17p, del13, t(4;14), t(11;14), t(14;16) t(14;20), 
gain of 1q, del1p, hypodiploid status.
Rationale:  A clarification is being made for the hematology and chemistry laboratory tests to make it clear they 
are to be done both locally and centrally except at screening (where are to be done centrally, to determine 
eligibility). Further, creatinine clearance was added to the serum chemistry panel, for clarity.
Time 
and 
Events 
Schedule; 
Section 9.1.2.3,  
Maintenance Therapy 
with Daratumumab 
(second paragraph); 
Section 9.3.2, Clinical 
Laboratory Tests 
(second and fifth 
paragraphs)
The rows for Hematology and Chemistries (laboratory tests) were combined, and now 
clarify that these are to be done by both the Central Laboratory and Local Laboratory.  
Footnotes were corrected accordingly.
On Day 1 of every therapy cycle, a physical examination, vital signs, weight, ECOG 
performance status, and laboratory tests (central and local assessment of hematology, 
chemistry, and local assessment of pregnancy [with urine sample] if applicable) 
should be performed.
Tests being performed by the central laboratory include the hematology and 
chemistry tests listed below and serum pregnancy testing…..
Results of local hematology and chemistry tests must be evaluated before each 
study drug administration to guide treatment decisions, but do not need to be 
reported in the eCRF unless they result in a dose delay.
Creatinine clearance (added to assessments under Serum Chemistry Panel).
Rationale: Corrections are being made to delete karyotyping from the assessments to be done in an effort to limit 
the assessments only to those needed.   
Time 
and 
Events 
Schedule; 
Sections 
9.1.1.2, Bone Marrow 
Biopsy, 
Serum 
and 
Urine Tests; 9.1.2.3, 
Maintenance 
Therapy 
with Daratumumab
karyotype (deleted)
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
13
Approved, Date: 2 May 2017
Rationale:  Corrections are being made to clarify that karyotyping is not being performed (as stated above), and 
to note quantitative immunoglobulin assessment is not part of the biopsy procedure.
Section 
9.1.3, 
Post-
treatment 
Phase 
(Follow-Up)
Once the end of treatment visit has occurred, subjects will be asked to return to the 
study site every 12 weeks so that, if suspected CR, suspected sCR, or PD, bone 
marrow biopsy with Flow cytometry, quantitative Ig, karyotype and myeloma FISH 
panel can be performed. Quantitative Ig will also be measured.
Rationale:  The procedure for assessing baseline creatinine clearance is being clarified.
4.2, Exclusion Criteria, 
#10 
for 
creatinine 
clearance

Creatinine clearance ≤20 mL/min; please note that the creatinine clearance 
can be either measured by 24-hour urine study, or estimated using a validated 
equation, such as the Modification of Diet in Renal Disease, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-epi), or Cockcroft-Gault; see 
Attachment 1
Rationale:  Details regarding testing of bone marrow samples are being clarified.
9.2.3, Bone Marrow 
Examination
Bone marrow aspirate or biopsy will be performed at Screening for clinical 
characterization (morphology, immunohistochemistry [IHC], or immunofluorescence 
or 2- to 4-color flow cytometry, and cytogenetics),…. Additional bone marrow 
aspirates or biopsies (or both) will be performed to confirm sCR, CR, or disease 
progression (only one analysis is required, with either IHC or immunofluorescence or 
2- to 4- color flow cytometry included in the analysis).
Rationale:  Details for daratumumab compliance reporting are being corrected. 
7 TREATMENT 
COMPLIANCE
Daratumumab will be administered as an IV infusion by qualified study-site personnel 
and the details of each administration will be recorded in the case report form (CRF)
(including date, start and stop times of the IV infusion, volume infused, and weight of 
IV infusion bag, including the infusion line, before and after the completion of the IV 
infusion).
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
14
Approved, Date: 2 May 2017
SYNOPSIS
Study Title: Daratumumab plus Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) in 
Previously Untreated and Relapsed Subjects with Multiple Myeloma 
BACKGROUND
Daratumumab (JNJ-54767414) is a first-in-class, fully human immunoglobulin G (IgG)1monoclonal
antibody that binds with high affinity to CD38-expressing malignant cells, inducing tumor cell death 
through diverse mechanisms of immune-mediated actions (complement dependent cytotoxicity, 
antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cell phagocytosis), as well as 
induction of apoptosis and modulation of CD38 enzyme activities. CD38 is overexpressed on myeloma 
cells, but is expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues 
of non-hematopoietic origin, making it a relevant target for the treatment of multiple myeloma.
High response rates have been noted in subjects with previously untreated multiple myeloma when treated 
with the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD), now a standard 
of care. Due to the safety, tolerability, and response profile for daratumumab, its combination with 
CyBorD has the potential to bring higher response rates. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective
The primary objective is to evaluate complete response + very good partial response (CR+VGPR) rate 
following 4 cycles of induction therapy with daratumumab plus CyBorD (Dara-CyBorD), in previously 
untreated subjects, and in relapsed subjects with multiple myeloma, as defined by the International 
Myeloma Working Group (IMWG) criteria. 
Secondary Objectives
The secondary objectives are to evaluate, in previously untreated subjects and in relapsed subjects with 
multiple myeloma:

Overall response rate (CR+VGPR+partial response [PR], ORR)

Following 4 cycles of Dara-CyBorD induction therapy

At the end of 4 to 8 cycles of Dara-CyBorD induction therapy

Post-transplant (in subjects who undergo high dose therapy and autologous stem cell 
transplantation)

At the end of 12 cycles of daratumumab maintenance therapy

Time to VGPR or better

Time to PR or better

Progression-free survival (PFS) rate: at 1 year and 3 years

Overall survival (OS) rate: at 1 year and 3 years

Safety and tolerability of Dara-CyBorD

Safety profile of split-dose initial infusions of daratumumab administered as 8 mg/kg on Cycle 1 
Day 1 (C1D1) and cycle 1 Day 2 (C1D2)
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Clinical Protocol 54767414MMY2012 Amendment 2
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Approved, Date: 2 May 2017
Exploratory Objective
An exploratory objective is to evaluate the clinical efficacy of Dara-CyBorD in molecular subgroups, 
including: del17p, del13, t(4;14), t(11;14), t(14;16).
Endpoints
Primary Endpoint
The primary endpoint is the proportion of subjects achieving CR+VGPR response following 4 cycles of 
induction therapy with Dara-CyBorD, in previously untreated subjects and in relapsed subjects with 
multiple myeloma, as defined by the IMWG criteria.
Secondary Endpoints
The secondary efficacy endpoints include:

ORR - the proportion of subjects achieving CR+VGPR+PR response following 4 cycles of induction 
therapy with Dara-CyBorD, in previously untreated subjects, and in relapsed subjects with multiple 
myeloma, as defined by the IMWG criteria at the following timepoints:

Following 4 cycles of induction therapy

At the end of Dara-CyBorD induction therapy

Post–transplant (in subjects who undergo high dose therapy and autologous stem cell 
transplantation)

At the end of all (12 cycles) maintenance therapy  

Time to VGPR or better - the duration from the date of start of induction therapy to the date of initial 
documentation of VGPR or better, which was confirmed by a repeated measurement as required by 
the IMWG criteria*

Time to PR or better - the duration from the date of start of induction therapy to the date of initial 
documentation of PR or better, which was confirmed by a repeated measurement as required by the 
IMWG criteria*

Duration of response - defined as the duration from the date of initial documentation of a response 
(PR or better) according to the IMWG criteria to the date of first documented evidence of 
progressive disease according to the IMWG criteria

PFS - defined as the duration from the date of start of induction therapy to the date of first 
documented evidence of progressive disease or death, whichever comes first. PFS rate at 1 year and 
3 years will be estimated.

OS measured from the date of start of induction therapy to the date of the subject’s death. OS rate at
1 year and 3 years will be estimated.
The safety endpoints are:

Safety and tolerability of the combination of Dara-CyBorD as assessed by the incidence of adverse 
events and laboratory test abnormalities

Infusion reaction profile of split-dose infusions of daratumumab administered as 8 mg/kg on C1D1 
and C1D2 by tabulating the incidence of infusion-related reactions by System-Organ Class and 
Preferred Term
* Predefined data censoring rules will be applied for time to event analyses.
NCT02951819


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Clinical Protocol 54767414MMY2012 Amendment 2
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Approved, Date: 2 May 2017
Exploratory Endpoint
Clinical efficacy of Dara-CyBorD in high-risk molecular subgroups including: del17p, del13, t(4;14), 
t(11;14), t(14;16).
Hypothesis
The primary hypothesis of this study is that CR+VGPR rate following 4 cycles of induction therapy with
Dara-CyBorD in previously untreated subjects is higher than 60%, and in relapsed subjects with multiple 
myeloma is higher than 30%, as defined by the IMWG criteria.
OVERVIEW OF STUDY DESIGN
This is a multicenter, single-arm, open-label, Phase 2 study evaluating the combination of daratumumab 
and oral cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) in subjects with previously 
untreated multiple myeloma, irrespective of eligibility for high-dose chemotherapy (HDT) and autologous 
stem cell transplant (ASCT), or relapsed multiple myeloma following one prior line of therapy. Relapsed 
multiple myeloma following one line of therapy is defined as having achieved at least a PR with first-line 
therapy before progression.
Approximately 100 subjects will be enrolled into this study, with at least 40 previously untreated multiple 
myeloma subjects. The relapsed multiple myeloma arm is closed to enrollment as of Amendment 2.
Treatment phases consist of induction therapy with 4 to 8 cycles of Dara-CyBorD (this range allows for 
local standard of care and physician discretion), consolidation therapy with HDT/ASCT for eligible 
subjects, and maintenance therapy. Following induction and/or consolidation therapy with ASCT, 
subjects will receive maintenance therapy with daratumumab alone for 12 cycles (of 28 days each), or
until disease progression (whichever occurs first). The follow-up period for each subject, after completion 
of maintenance therapy with daratumumab, will continue through 36 months following the start of 
induction therapy. 
Throughout the study, subjects will be monitored closely for adverse events, laboratory abnormalities, and 
clinical response. Disease response and progression will be based on assessments from IMWG 
Guidelines. Efficacy assessments include: M-protein measurements (serum and urine), immunofixation
(serum and urine), serum free light chains, serum calcium corrected for albumin, serum immunoglobulins, 
examination of bone marrow aspirate or biopsy, and skeletal survey/documentation of extramedullary 
plasmacytomas. 
A Data Review Committee will be commissioned for this study.
SUBJECT POPULATION
Participants in this study are to be at least 18 years of age and have documented multiple myeloma, 
measurable disease, previously untreated myeloma or relapsed myeloma with one prior line of therapy, 
and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
DOSAGE AND ADMINISTRATION
Approximately 100 subjects will be assigned to receive Dara-CyBorD as induction on a 28-day cycle 
length. All subjects will receive 4 to 8 cycles of oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 
22; subcutaneous (SC) bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or intravenous (IV) 
dexamethasone 40 mg weekly. Subjects will concurrently receive daratumumab on 28-day cycles.  The 
initial dose of daratumumab will be given as a “split dose” of 8 mg/kg IV on C1D1 and C1D2. Starting 
Cycle 1 Day 8 through the completion of Cycle 2, daratumumab will be given weekly at 16 mg/kg IV. 
For Cycle 3 to Cycle 6, subjects will receive daratumumab 16 mg/kg IV once every 2 weeks. From 
Cycle 7 on, subjects will receive daratumumab 16 mg/kg IV once every 4 weeks, whether in the last 
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
17
Approved, Date: 2 May 2017
induction cycles with CyBorD, or alone during the maintenance phase. All eligible subjects are to receive 
12 cycles of maintenance therapy with daratumumab monotherapy, given on 28-day cycles.
The induction regimen is the same dose, schedule and cycle length for all subjects in both study 
populations (previously untreated myeloma or relapsed myeloma with one prior line of therapy), although 
the number of induction cycles may vary from 4 to 8, based on local standard of care and physician 
discretion. Regardless of the number of induction cycles given, all subjects will receive maintenance 
therapy with daratumumab 16 mg/kg on Day 1 of a 28-day cycle for 12 cycles.
EFFICACY EVALUATIONS
Disease response and progression will be assessed based on IMWG Guidelines. Daratumumab detection 
on serum immunofixation (IFE) has been demonstrated in subjects treated with 16 mg/kg, and may 
interfere with the traditional IMWG criteria of negative serum IFE for CR or stringent CR (sCR). To 
mitigate this interference, the sponsor has developed a reflex assay that utilizes anti-idiotype antibody to 
bind daratumumab and confirm its interference on IFE. For all subjects with VGPR and a negative 
M-protein by serum M-protein quantitation by electrophoresis (SPEP), reflex IFE testing will be 
performed to confirm the presence of daratumumab on IFE. In addition, for subjects who have an SPEP 
≤0.2 g/dL and detectable IgG kappa myeloma during the study, reflex testing will also be performed to 
determine whether the para-protein identified on SPEP/IFE is monoclonal daratumumab or the subject’s 
endogenous myeloma protein.
Disease evaluations must be performed on Day 1 of each cycle during the induction phase with Dara-
CyBorD. Disease evaluation should be performed following ASCT, on Day 1 of the first maintenance 
cycle dose, for subjects who undergo ASCT. For all subjects, disease evaluation will be done on Day 1 of 
the maintenance phase with daratumumab and then on Day 1 of every other cycle (approximately every 
56 days) or, if there are concerns for relapse, sooner.
SAFETY EVALUATIONS
Safety evaluations will include adverse event monitoring, clinical laboratory testing (hematology and 
serum chemistry), pregnancy testing, electrocardiogram monitoring, vital sign measurements, physical 
examinations, and ECOG performance status. 
Since daratumumab interferes with the indirect antiglobulin test (IAT), subjects will receive a subject
identification wallet card for the study that includes the blood profile (ABO, Rh, and IAT) determined 
before the first infusion of daratumumab along with information on the IAT interference for healthcare 
providers/blood banks.
STATISTICAL METHODS
The historical CR+VGPR rate after 4 cycles of CyBorD induction therapy is 60% in previously untreated 
multiple myeloma subjects.17 Thirty-three (33) enrolled subjects will provide 80% power at a 5% 1-sided 
significance level to detect an absolute 20% increase over 60% with Dara-CyBorD. 
The historical CR+VGPR rate after 4 cycles of CyBorD induction therapy is 30% in previously relapsed 
multiple myeloma subjects.20 Thirty-five (35) enrolled subjects will provide 80% power at a 5% 1-sided 
significance level to detect an absolute 20% increase over 30% with Dara-CyBorD.
It is planned that at least 40 subjects will be enrolled in the previously untreated cohort. As of
Amendment 2, enrollment of subjects in the relapsed cohort is closed and expected not to exceed 15 
subjects. No inferential statistics will be performed for the relapsed cohort. 
The primary analysis will be performed after all enrolled subjects have completed 4 cycles of induction 
therapy disease evaluation, or have been discontinued from study treatment by this timepoint. A final data 
cutoff and analysis, to update secondary endpoints and safety, will occur at the end of study when all 
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
18
Approved, Date: 2 May 2017
subjects have completed 36 months of follow-up after the start of induction therapy (on Cycle 1 Day 1 
[C1D1]), or until death or withdrawal of consent for study participation, whichever occurs first.
Response to study treatment and progressive disease will be evaluated by a validated computer algorithm 
to calculate IMWG response. The primary endpoint, rate of CR+VGPR achieved after 4 cycles of 
induction therapy for previously untreated and relapsed subjects, will be tabulated. Other binary 
endpoints, including overall CR, sCR, ORR, VGPR or better rate following induction, consolidation, and 
maintenance will be analyzed similarly. Time-to-event efficacy endpoints, including duration of CR, sCR, 
time to progression, PFS, and OS, will be descriptively summarized using the Kaplan-Meier method.
The CR+VGPR rate and its 2-sided 95% confidence interval will be provided. Other binary endpoints, 
including overall CR, sCR, ORR, VGPR or better rate following induction, consolidation, and 
maintenance will be analyzed similarly. Time-to-event efficacy endpoints, including duration of CR, sCR, 
time to progression, PFS, and OS, will be descriptively summarized using the Kaplan-Meier method.
For safety, treatment-emergent adverse events will be analyzed as the percentage of subjects who 
experience at least 1 occurrence of the given event. 
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated for 
each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled 
time point. Change from baseline to the worst adverse event grade experienced by the subject during the 
study will be provided as shift tables.
Descriptive statistics of vital signs and electrocardiogram results, and changes from baseline will be 
summarized at each scheduled time point and the percentage of subjects with values beyond clinically 
important limits will be summarized.
An internal Data Review Committee will be established to review the interim data. Three interim 
safety analyses are planned. The first interim safety analysis will occur after  at least 20 subjects 
are treated for at least 1 cycle of study treatment (or discontinue before the end of Cycle 1). The 
second interim safety analysis will occur after at least 50 subjects complete cycle 1 of study 
treatment (or discontinue before the end of Cycle 1) with a focus on infusion related reactions 
during cycle 1. The third interim safety analysis will occur after at least 50 subjects are treated 
for at least 4 cycles (or discontinue before the end of Cycle 4).
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JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
19
Approved, Date: 2 May 2017
TIME AND EVENTS SCHEDULE
Study procedures
Screening 
phase
(up to 28 
days)
Inductiona
(4 to 8 28-day cycles of Dara-
CyBorD)
+/-
HDT/
ASCTb
Maintenance Therapya
(12 months; 
approximately 12 cycles
of daratumumab)
EOTc
Follow-up: 
Through 36 months 
after Cycle1Day1d
Informed consente
X
Eligibility criteria
X
Medical history and demographics
X
Physical examination
X
Prior to dose on Day 1 of each cycle
Prior to dose on Day 1 of 
each cycle
X
ECOG performance status
X
Day 1 of each cycle 
Day 1 of each cycle
X
Spirometry (FEV1)f
X
Height
X
Weightg
X
Prior to dose on Day 1 of each cycle
Prior to dose on Day 1 of 
each cycle
Vital signsh
X
Prior to and after each dose 
Prior to and after each dose
Screening serology tests
X
12-lead ECG
X
Myeloma FISH panel
X
Blood type/indirect coombs testi
X
C1D1 only
Clinical Laboratory Assessments 
Hematology and Chemistries j (to be 
performed at central laboratory and local 
laboratory)
X (central 
laboratory 
only)
Prior to dose on Day 1 of each cycle
Prior to dose on Day 1 of 
each cycle
X
Hepatitis C viral load testing j
X
Every 3 months
Every 3 months
Serum pregnancy test (done at central 
laboratory)
Within 28 days before first dose on C1D1. 
Urine pregnancy test (done at local 
laboratory)
Within 24 hours before first dose on C1D1 and 
prior to dose on Day 1 of each cycle
Prior to dose on Day 1 of 
each cycle
Disease Evaluation (to be performed at the central laboratory)
Bone marrow biopsy w/ Flow cytometry
X
At suspected CR, suspected sCR, or 
PD
At suspected CR, suspected sCR, or PD
SPEPk
X
Day 1 of each cycle
Day 1 of every other cycle
Q12wks until PD
Serum quantitative immunoglobulinsl
X
Day 1 of each cycle
Day 1 of every other cycle
Q12wks until PD
24-hour urine (UPEP)m
X
Day 1 of each cycle
Day 1 of every other cycle
Q12wks until PD
Beta-2 microglobulin
X
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
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Approved, Date: 2 May 2017
Study procedures
Screening 
phase
(up to 28 
days)
Inductiona
(4 to 8 28-day cycles of Dara-
CyBorD)
+/-
HDT/
ASCTb
Maintenance Therapya
(12 months; 
approximately 12 cycles
of daratumumab)
EOTc
Follow-up: 
Through 36 months 
after Cycle1Day1d
Albumin (central laboratory)
X
Imaging
Chest x-rayn
X
Assessment of lytic lesions
X
As clinically indicated, using the 
same methodology as used at 
screening
As clinically indicated, using the same methodology as used at 
screening
Extramedullary plasmacytomaso
X
To be performed/evaluated locally 
every 4 weeks (by physical exam) 
for subjects with a history of 
plasmacytomas or as clinically 
indicated until confirmed CR or PD. 
If assessment can only be performed 
radiologically, may be done every 12 
weeks.
To be performed/evaluated locally every 4 weeks (by physical 
exam) for subjects with a history of plasmacytomas or as 
clinically indicated until confirmed CR or PD. If assessment 
can only be performed radiologically, may be done every 12 
weeks.
Drug Administration
Daratumumab
8 mg/kg IV on C1D1, C1D2; 
16 mg/kg IV on Cycle 1, Days 8, 15, 
22; 
Cycle 2, Days 1, 8, 15, 22; Cycles 3-
6, Days 1,15; Cycles 7-8, Day 1
16 mg/kg IV Day 1 of each 
cycle; can be administered 
within 14 days of planned 
date
Cyclophosphamide
300 mg/m2 PO, Days 1, 8, 15, 22 of 
each cycle
Bortezomib
1.5 mg/m2 SC Days 1, 8, 15 of each 
cycle
Dexamethasone
C1D1 and C1D2: 20 mg IV; C1Day 
3, 4 mg PO.
C1 Days 8, 15, and 22: 20 mg IV; 
C1 Days 9, 16, and 23: 20 mg PO.
C2 Days 1, 8, 15, and 22: 40 mg 
IV/PO.
C3-8 (if with CyBorD), Days 1, 8, 
15, and 22: 40 mg IV/PO
Day 1: 12 mg IV/PO
NCT02951819


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2012 Amendment 2
21
Approved, Date: 2 May 2017
Study procedures
Screening 
phase
(up to 28 
days)
Inductiona
(4 to 8 28-day cycles of Dara-
CyBorD)
+/-
HDT/
ASCTb
Maintenance Therapya
(12 months; 
approximately 12 cycles
of daratumumab)
EOTc
Follow-up: 
Through 36 months 
after Cycle1Day1d
Ongoing Subject review
Concomitant medications
Continuous from the time of signing of ICF until 30 days after last dose of any component of the study treatment in the maintenance phase
Adverse event monitoring
Continuous from the time of signing of ICF until 30 days after last dose of any component of the study treatment in the maintenance phase
ASCT = autologous stem cell transplantation; C = cycle; CR = complete response; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
end-of-treatment; FISH = fluorescence in situ hybridization; FLC = free light chain; HDT = high-dose chemotherapy; 
ICF = informed consent form; IV = intravenous; PD = progressive disease; PO = oral; Q12wks = every 12 weeks; sCR = stringent CR; SPEP = serum M-protein quantitation 
by electrophoresis; UPEP = M-protein quantitation by electrophoresis.
a) Induction cycles are 28 days in duration. Maintenance therapy cycles are 28 days in duration. See Table 3 for acceptable dosing windows for daratumumab. 
b) Stem cell mobilization, HDT, and ASCT will be performed according to institutional standards. 
c) Subjects will receive study treatment through completion of the maintenance phase, or until confirmed disease progression, discontinuation of study treatment due to 
an unacceptable drug toxicity, or other reasons. Unless a subject withdraws consent for study participation, or is lost to follow-up, an EOT visit is to be scheduled 30 
days after the last dose of all components of the study treatment have been discontinued, or as soon as possible before the start of next-line therapy. The EOT visit 
should be performed 30 days after all other study treatment is permanently discontinued.
d) Subjects will be followed through 36 months after the start of induction therapy, or until death, withdrawal of consent for study participation, or the end of study 
definition is met. 
e) Must be signed before any study-related procedures are performed.
f) Pulmonary function testing (spirometry) is required only for subjects with chronic obstructive pulmonary disease or asthma. FEV1 should be measured. 
g) If a subject’s weight changes by more than 10% from C1D1, the dose of all study treatments will be re-calculated.
h) Temperature and respiratory rate; and pulse/heart rate and blood pressure measured in sitting position. For all infusions except C1D1 and C1D2, measured 
immediately before the start of and at the end of daratumumab infusion. For C1D1 and C1D2 only: immediately before the start of daratumumab infusion; at 0.5, 1, 
1.5, 2, and 3.5 hours after the start of the infusion and then every 2 hours through duration of infusion; at end of infusion; and 0.5 and 1 hour after the end of the 
infusion. For all other daratumumab infusions, vital signs should be measured before the start of infusion and at the end of the infusion.
i)
To be performed prior to dosing with daratumumab. For C1D1, there is no need to repeat the tests if they have been performed within the past 3 days. Does not need 
to be performed on C1D1 if no blood transfusions between screening and C1D1. A wallet card with the subject’s blood type will be provided to subjects.
j)
Results of local hematology and chemistry tests must be evaluated before Day 1 of each cycle to guide treatment decisions, but do not need to be reported in the 
eCRF unless they result in a dose delay. HCV viral load to be assessed only for subjects who completed treatment for hepatitis C at least 6 months prior to screening 
and have no detectable circulating HCV at screening. Such subjects will be required to undergo regular assessment for HCV reactivation through 6 months after their 
last daratumumab administration.  Subjects who test positive for HCV at any time during these assessments will be withdrawn from the study. Hematology and 
chemistry panels: see Section 9.3.2. 
k) Serum IFE and serum FLC assay will be performed at screening and thereafter when a CR or sCR is suspected (when SPEP or UPEP is 0 or nonquantifiable) or 
maintained. For subjects with light chain multiple myeloma, serum FLC assay will be performed routinely.
l)
All subject’s samples will be tested for IgG, IgA, and IgM. Subjects with IgE or IgD myeloma will have samples tested for IgE or IgD.
m) Urine IFE test will be performed at screening and thereafter when a CR or sCR is suspected (when SPEP UPEP are 0 or nonquantifiable) or maintained. 
n) To be done locally; acceptable for screening if performed as part of standard of care within 28 days before C1D1.
o) For subjects with history of plasmacytoma; assessed by physical exam or radiologic imaging, repeat assessment on C1D1 if not done within 14 days prior to C1D1. 
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ABBREVIATIONS
ADCC
antibody-dependent cell mediated cytotoxicity
ADCP
antibody-dependent cell phagocytosis
AE
adverse event
ALT
alanine aminotransferase
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
BSA
body surface area
C
Cycle
CDC
complement dependent cytotoxicity
C1D1, C1D2
Cycle 1 Day 1, Cycle 2 Day 2
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CT
computed tomography
CyBorD
cyclophosphamide, bortezomib, and dexamethasone
D
Day; dexamethasone
Dara-CyBorD
daratumumab with cyclophosphamide, bortezomib, and dexamethasone
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EOT
end of treatment
FEV1
forced expiratory volume in 1 second
FDA
United States Food and Drug Administration
FISH
fluorescence in situ hybridization
FLC
free light chain
GCP
Good Clinical Practice
HCV
HDT
hepatitis C virus
high-dose chemotherapy
IAT
Indirect Antiglobulin Test
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFE
immunofixation
Ig
immunoglobulin
IHC
immunohistochemistry
IMID
immunomodulatory drug
IMWG
International Myeloma Working Group
IRB
Institutional Review Board
IRR
infusion-related reaction
ISS
International Staging System
IV
Intravenous
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
M-protein
Monoclonal immunoglobulin (protein)
MRI
Magnetic Resonance Imaging
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
nCR
near complete response
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PI
proteasome inhibitor
PO
Oral
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PQC
Product Quality Complaint
PR
partial response
Q12wks
every 12 weeks
RBC
red blood cell(s)
Rd
lenalidomide + dexamethasone
SC
subcutaneous
sCR
stringent complete response
SPEP
serum M-protein quantitation by electrophoresis
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
UPEP
24-hour urine test M-protein quantitation by electrophoresis
US
United States
VGPR
very good partial response
WBC
white blood cell(s)
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1.
INTRODUCTION
Daratumumab (JNJ-54767414) is a first-in-class, fully human immunoglobulin G (IgG)1
monoclonal antibody that binds with high affinity to CD38-expressing malignant cells, inducing 
tumor cell death through diverse mechanisms of immune-mediated actions (complement 
dependent cytotoxicity [CDC], antibody-dependent cell-mediated cytotoxicity [ADCC], and 
antibody-dependent cell phagocytosis [ADCP]), as well as induction of apoptosis and 
modulation of CD38 enzyme activities. CD38 is overexpressed on myeloma cells, but is 
expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues of 
non-hematopoietic origin, making it a relevant target for the treatment of multiple myeloma.
Daratumumab by intravenous (IV) injection is approved in the United States (US), European 
Union (EU), and other countries for the treatment of patients with multiple myeloma who have 
received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an 
immunomodulatory agent (IMiD) or who are double-refractory to a PI and an IMiD. On 21
November 2016, the US Food and Drug Administration (FDA) approved daratumumab in 
combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the 
treatment of patients with multiple myeloma who have received at least one prior therapy.
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator’s Brochure for daratumumab. 
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.
Background
Multiple myeloma, a malignant disorder of the plasma cells, is characterized by uncontrolled and 
progressive proliferation of a plasma cell clone. Patients with multiple myeloma produce a 
monoclonal protein, also known as paraprotein (comprising monoclonal protein [M-protein] and 
free light chain [FLC]), which is an Ig or a fragment of one that has lost its function. The 
proliferation of myeloma cells causes displacement of the normal bone marrow. Normal Ig levels 
are compromised, leading to susceptibility to infections. Hypercalcemia, renal insufficiency or 
failure, and neurological complications are frequently reported side effects of the disease.13
There are numerous treatment options for subjects with previously untreated multiple myeloma.  
A treating physician selects a regimen based not only upon age, performance status, comorbidity, 
and aggressiveness of the disease, but also their personal understanding of and comfort level 
with myeloma regimens. The agents included in a regimen may include corticosteroids, DNA 
alkylators (oral melphalan, oral or intravenous cyclophosphamide, bendamustine), proteasome 
inhibitors (PIs: bortezomib), immunomodulatory drugs (IMiDs: thalidomide, lenalidomide, and 
pomalidomide), monoclonal antibodies (daratumumab and elotuzumab), and high-dose 
chemotherapy (HDT, typically melphalan) with stem cell support. In the past, newly diagnosed 
subjects with multiple myeloma were categorized into 2 subpopulations based on transplant 
eligibility. Using this characterization younger subjects typically received an induction regimen 
avoiding oral melphalan followed by consolidation treatment with HDT and autologous stem cell 
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transplantation (ASCT). For those not considered suitable for HDT and ASCT, regimens
typically included an alkylating agent (oral melphalan) and a PI or IMiD in combination with 
corticosteroids. 
This stratification remained unchallenged until the FIRST trial which randomized newly 
diagnosed transplant-ineligible subjects to 1 of 3 therapeutic options: melphalan, prednisone, and 
thalidomide for 12 months; lenalidomide and dexamethasone (Rd) for 18 months; or continuous 
Rd until progression.1 The median progression-free survival for the continuous Rd arm, Rd for 
18 months, and the melphalan, prednisone, and thalidomide arm were 25.5 months, 20.7 months, 
and 21.2 months, respectively. Therefore, in current practice even newly diagnosed transplant-
ineligible patients are treated with regimens omitting oral melphalan and are thus eligible for 
clinical trials exploring non-melphalan based approaches.
1.1.1.
Nonclinical Studies
Based on preclinical data, daratumumab may utilize multiple effector cell functions, resulting in 
immune-mediated killing of tumor cells. In ex vivo experiments utilizing human bone marrow 
stromal cells co-cultured with primary multiple myeloma cells, CDC, ADCC, and ADCP have 
all been shown to lead to multiple myeloma cell lysis. The precise role of some or all of these 
effector functions in reducing tumor burden is unknown.3,12
The binding of daratumumab to CD38 on the surface of tumor cells and engagement/ligation of 
the Fc domains of bound antibodies led to multiple biologic effects, including CDC, ADCC, 
ADCP, tumor cell apoptosis, and modulation of CD38 enzymatic activity in patient-derived cells 
and cell lines expressing human CD38. The in vivo efficacy of daratumumab was investigated by 
engrafting Daudi-luc lymphoma cells into severe combined immunodeficiency mice by 
intravenous (IV) injection, followed by treatment with daratumumab either immediately 
(preventive) or after the tumor was established (therapeutic). Treatment with daratumumab 
effectively reduced growth of human lymphoma cells in severe combined immunodeficiency 
mice, both in the preventive setting and in the therapeutic setting. In the preventive setting, the 
estimated half maximal effective concentration was calculated to be 0.065 µg/kg of body weight. 
When daratumumab was administered to mice bearing established disease, therapeutic activity 
was observed at a dose as low as 10 µg per mouse, corresponding to approximately 0.5 mg/kg 
body weight (see Investigator Brochure for details). 
Importantly, daratumumab-induced ADCC and CDC do not appear to be affected by the 
presence of bone marrow stromal cells, indicating that daratumumab can effectively induce the 
killing of multiple myeloma tumor cells in a tumor-preserving bone marrow microenvironment. 
In vivo studies have shown that daratumumab is highly active and interrupts xenograft tumor 
growth at low doses. 
In toxicology studies in chimpanzees, the major observed toxicities were infusion reactions and 
thrombocytopenia. Infusion reactions occurred during the first, but not subsequent, daratumumab 
infusions. Milder infusion reactions were observed after implementation of a 10 mg pre-dose 
24 hours prior to the first infusion. The binding of daratumumab is 15-fold higher for 
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chimpanzee platelets than for human platelets, suggesting that thrombocytopenia may have 
limited clinical relevance. In cynomolgus monkeys treated with another anti-CD38 antibody, a 
decrease in red blood parameters was observed. The other anti-CD38 antibody binds strongly to 
cynomolgus monkey red blood cells, while daratumumab shows only a low level of binding to 
human red blood cells. This suggests that the anemia observed in the cynomolgus monkey has
limited clinical relevance in patients. The effect on platelets and red blood cells in monkeys was 
reversible as daratumumab was cleared.
1.1.2.
Clinical Studies
1.1.2.1.
Single-agent Studies of Daratumumab in Relapsed/Refractory 
Multiple Myeloma
The GEN501 study had a 2-part design that investigated the safety and tolerability of 
daratumumab. Part 1 included the first-in-human study of daratumumab as part of a dose-
escalation study. Part 2 of the study was a dose-expansion phase which investigated the 8 and 
16 mg/kg dose of daratumumab with a primary endpoint of safety and secondary endpoints 
including pharmacokinetics and response. The median age of subjects was 64 years, with a 
median of 4 prior lines of therapy, 76% received prior ASCT, and 79% were refractory to the last 
line of therapy. In Part 1 of the study no maximum tolerated dose was found and the most 
common adverse events in Part 2 of the study was the occurrence of infusion-related reactions in 
71% of subjects which were most commonly Grade 1-2 and dependent on the rate of infusion. 
Grade 3-4 adverse events included pneumonia and thrombocytopenia in >5% of subjects. The 
overall response rate (ORR) in Part 2 on the study was 36% in the cohort which was 
administered 16 mg/kg of daratumumab and 10% in the cohort administered 8 mg/kg of 
daratumumab.9
The MMY2002 study is an open-label, Phase 2, multicenter trial in subjects with 
relapsed/refractory myeloma who had previously received at least 3 lines of therapy or were 
refractory to both a PI and an IMiD. In Part 1 of the study, subjects were randomized 1:1 to 
receive 8 or 16 mg/kg of daratumumab and the dose that appeared most effective was to be 
evaluated further in the second part of the study. At the first interim analysis, the 18 subjects 
randomized to the 8 mg/kg dose cohort had an ORR of 11.1%, therefore, this dose was 
determined to be suboptimal. An additional 25 subjects were enrolled in the 16 mg/kg dose 
cohort and following a second interim analysis, the 16 mg/kg dose was selected to be studied in 
Part 2 of the study which included an additional 65 subjects. The median age was 63.5 years with 
45% of subjects aged 65 years or older, and 11% >75 years. The median time from diagnosis 
was 4.8 years (1.1 – 23.8 years), with subjects having a median of 5 prior lines of therapy. All 
subjects had prior exposure to a PI and an IMiD with 95% being refractory to both a PI and an 
IMiD, and 80% received prior ASCT. In total, 106 subjects were treated with 16 mg/kg of 
daratumumab which resulted in an ORR of 29.2% including 3 subjects (2.8%) experiencing a 
stringent complete response (CR) and 10 subjects (9.4%) attaining very good partial response 
(VGPR). The median time to response was 1 month and the median duration of response was 7.4 
months. Grade 3 or higher adverse effects included anemia (24%), thrombocytopenia (19%), 
neutropenia (12%), fatigue (3%) and back pain (3%). The most common adverse effect was 
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infusion-related reactions which occurred in 42% of subjects and were mostly Grade 1-2,
however, 5% of subjects had a Grade 3 infusion-related reaction.10
The clinical efficacy of the 148 subjects treated with single agent daratumumab 16 mg/kg in the 
GEN501 and MMY2002 trials were studied by Usmani et al.20 The ORR was 31% with 2% 
stringent complete response (sCR), 1% CR, and 11% VGPR. The 1-year overall survival (OS) 
was 69% and the median OS was 19.9 months in this cohort of relapsed/refractory subjects.
1.1.2.2.
Studies of Daratumumab in Combination with Other Backbone 
Chemotherapy Regimens in Relapsed/Refractory Multiple Myeloma 
There are 7 ongoing and planned studies of daratumumab in combination with other backbone 
chemotherapy regimens in subjects, including 4 in subjects with relapsed or refractory multiple 
myeloma (the Phase 1 Study MMY1001, the Phase 1/2 Study GEN503, and the Phase 3 Studies 
MMY3003, MMY3004) and 3 in subjects with newly diagnosed multiple myeloma (MMY3006, 
MMY3007, and MMY3008). 
In Study MMY3004, daratumumab in combination with bortezomib and dexamethasone (DVd), 
the primary analysis showed a significant improvement in PFS for subjects in the DVd group, 
compared with the bortezomib/dexamethasone (Vd) group.  This represents a 61% reduction in 
the risk of disease progression or death for the DVd group compared with the Vd group.  The 12-
month PFS rate was 61% for the DVd grup and 27% for the Vd group.
Among 243 DVd-treated subjects, the most common AEs were thrombocytopenia (60%), 
peripheral sensory neuropathy (49%), diarrhea (34%), upper respiratory tract infection (30%), 
anemia (28%), and cough (27%). SAEs were reported in 49% of subjects, with the most common 
being pneumonia (9%); anemia, bronchitis, thrombocytopenia, atrial fibrillation, and upper 
respiratory tract infection (each in 3%); and pyrexia (2%).  Deaths were reported in 14 subjects; 
12 deaths were due to AEs and 2 were due to disease progression.  The safety profile for DVd 
was similar to that for the Vd comparator group.
1.1.2.3.
Combination Therapy: Bortezomib, Cyclophosphamide, and 
Dexamethasone
Prior to the era of the novel first generation (bortezomib and lenalidomide) anti-myeloma agents, 
the standard of care in many institutions was combination chemotherapy with vincristine, 
doxorubicin and dexamethasone, which was able to induce a partial response in 63% of subjects 
with 6% in CR/near CR (nCR).6 Bortezomib is the first PI to have been approved by the US 
Food and Drug Administration (FDA) for multiple myeloma and other hematological 
malignancies (in 2008) and represented a breakthrough in the management of patients with 
multiple myeloma. Bortezomib was initially dosed at 1.3 mg/m2 administered intravenously on a 
twice weekly schedule and 21-day cycle length in combination with corticosteroids. Subsequent 
studies revealed that subcutaneous administration and weekly dosing was equivalent to the 
intravenous twice weekly dosing, and the cycle length increased to 28 days.5,11
Another critical element in the evolution of our understanding in the optimal dosing and 
administration of the combination of bortezomib and dexamethasone was the results of the 
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Eastern Cooperative Oncology Group (ECOG) E4A03 study which evaluated high-dose versus 
low-dose dexamethasone in combination with lenalidomide.15 This pivotal study addressed the 
contributions of higher doses of dexamethasone, which was a legacy component of myeloma 
therapy in the era prior to the first generation anti-myeloma agents. At that time, dexamethasone 
likely represented one of the most active anti-myeloma agents, even in regimens including multi-
agent chemotherapy using alkylators, anthracyclines, and plant-based vinca alkyloids. Therefore, 
the corticosteroid dose was probably critical in the era prior to the first-generation anti-myeloma 
agents, as obtaining a response was challenging in itself. However, in the era of first-
(bortezomib, 
lenalidomide), 
second-
(carfilzomib, 
pomalidomide), 
and 
now 
third-
(daratumumab, elotuzumab, ixazomib) generation anti-myeloma agents the role of 
corticosteroids may be more limited and its role in toxicity more scrutinized. The ECOG E4A03 
study confirmed that higher doses of corticosteroids did, in fact, decrease survival in myeloma as 
compared to a lower dose of corticosteroids, mainly due to the higher incidence of serious 
infections in the control (higher dose corticosteroids) arm.
Following the FDA approval of bortezomib, the results of several clinical studies were 
published, describing the use of alkylators or non-cycle specific inhibitors such as 
cyclophosphamide and the anthracyclines. Although bortezomib was being included in the 
“Total Therapy 3” VTD-PACE study,22 Kropff et al.7 initially described the results of the 
combination of bortezomib, cyclophosphamide, and “intermediate-dose dexamethasone” in 
relapsed myeloma.7 Fifty-four subjects were treated with 8 cycles of bortezomib 1.3 mg/m2 on 
days 1, 4, 8, and 11 given intravenously, cyclophosphamide 50 mg per day continuous given 
orally (PO), and dexamethasone 20 mg on the day of bortezomib and then the following day 
(total 40 mg). This induction was followed by three 5-week cycles of bortezomib 1.3 mg/m2. The 
population was unique in that 67% of subjects had either 1-2 lines of prior therapy, however, 
only 30% had prior therapy with thalidomide; 20% had no prior autologous transplant but 80% 
had at least one prior autologous transplant. Grade 3-4 adverse events that occurred in at least 
9-10% of subjects consisted of myelosuppression (leukopenia and thrombocytopenia), infections 
(including herpes zoster), peripheral neuropathy and fatigue. The ORR was 90% including 66% 
with a partial response (PR) and an impressive 16% with a CR.
Reece et al. presented the Canadian experience in a Phase 1/2 study of 37 subjects with 
relapsed/refractory multiple myeloma.16 The Phase 1 portion of the study included 6 dosing 
levels where the maximum dose of bortezomib was 1.5 mg/m2 given intravenously weekly 
(days 1, 8, and 15), cyclophosphamide 300 mg/m2 given continuously, and prednisone 100 mg 
given every 2 days. There was no maximum tolerated dose of the regimen, thus the Phase 2
portion of the study utilized the above dosing and schedule for 13 subjects in total. A total of 14
Grade 3-4 adverse events were reported that comprised
nausea/vomiting, diarrhea, 
myelosuppression, hypokalemia, hypophosphatemia community acquired pneumonia, increased 
AST/ALT, and varicella zoster. The ORR was 85% and included CR in 54% of subjects who 
were, for the most part, treatment naive to the first generation anti-myeloma agents.
Reeder et al described the Mayo Scottsdale experience using the combination of bortezomib, 
cyclophosphamide and dexamethasone in a Phase 2 study of 33 newly diagnosed subjects with 
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myeloma.17 The regimen consisted of bortezomib 1.3 mg/m2 given intravenously on days 1, 4, 8, 
and 11, cyclophosphamide 300 mg/m2 given on days 1, 8, 15, and 22, and dexamethasone 40 mg 
on days 1-4, 9-12, and 17-20 all in a 28-day cycle. Dose modification was allowed only after 
Cycle 1 in anticipation of the most likely adverse events, eg, myelosuppression and cystitis due 
to cyclophosphamide, and peripheral neuropathy due to bortezomib. The statistical design of the 
study utilized the historical response rates from the studies using lenalidomide and 
dexamethasone and sought to improve the VGPR to >45% which would be supportive of an 
additional future study. The median age of the population was 60 years, 30% were International 
Staging System (ISS) III, and on Fluorescence In Situ Hybridization (FISH) panel 13% had 
deletion 17p and 18% had t(4;14). By intention-to-treat criteria the ORR was 88% with 61% 
achieving a >VGPR, however, 28 patients completed the 4 planned cycles and their ORR was 
96%, among whom 71% had a >VGPR. 
The authors commented that as compared to the Mayo experience with lenalidomide plus 
dexamethasone the depth of response using bortezomib, cyclophosphamide and dexamethasone 
resulted in significantly higher depths of response (>VGPR of 61% as compared to 44%). All 
subjects were able to mobilize and collect stem cells using either cytokine alone or chemo-
mobilization. Five subjects did not complete the planned 4 cycles of therapy due to: disease 
progression in 1 patient, adverse effects in 3 patients, and 1 due to unrelated complications from 
surgery. Grade 3 and 4 adverse events occurred in 48% and 13% of subjects, respectively. 
Grade 3-4 adverse events were due to myelosuppression (50%: anemia 12%, neutropenia 13%, 
and thrombocytopenia 25%). Dose reductions of bortezomib were required in 27% of subjects
due to peripheral neuropathy and in 21% of subjects due to myelotoxicity secondary to 
cyclophosphamide. However, consistent with the discussion above, 33% of subjects required a 
dose reduction of dexamethasone due to toxicities.
Reeder et al. updated their experience in unison with the Canadian group studying weekly 
bortezomib in 30 newly diagnosed subjects with myeloma.18 The control regimen was the 
previously studied twice weekly (days 1, 4, 8, 11) bortezomib regimen.  In addition, there was an 
evaluation of the combination of bortezomib 1.5 mg/m2 given intravenously but weekly on days 
1, 8, 15, and 22, cyclophosphamide as in the control regimen and dexamethasone with Cycles 1-
2 using the control regimen and Cycles 3-4 using once weekly 40 mg of dexamethasone. The 
ORR of 63 subjects treated with the 2 regimens (twice weekly bortezomib and once weekly 
bortezomib) was 90% and >VGPR in 60% and 41% in a CR/nCR. The toxicity profile of once 
weekly bortezomib was better than that of the control regimen and fewer dose reductions were 
needed of both bortezomib and dexamethasone. Long-term follow-up revealed that 49 subjects
(78%) had an autologous stem cell transplant following the planned 4 cycles of therapy with only 
29% receiving some form of maintenance therapy.19 The median PFS for the entire cohort of 63 
subjects was 40 months, with a 5-year PFS rate of 42% and an OS rate of 70%. The ORR was 
similar between standard- and high-risk subjects, however, the median PFS was significantly 
shorter in the high-risk population (27.6 versus 55.7 months) and this impacted the 5-year OS 
rate (54% versus 81%).
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1.2.
Overall Rationale for the Study
The clinical studies described above indicate that the combination of cyclophosphamide, 
bortezomib, and dexamethasone (CyBorD) is a highly active regimen for subjects with 
previously untreated and relapsed multiple myeloma. Category 1 recommendations by the 
National Comprehensive Cancer Network (NCCN) for induction regimens for previously 
untreated patients with multiple myeloma include bortezomib and dexamethasone; lenalidomide 
and dexamethasone; bortezomib, doxorubicin and dexamethasone; bortezomib, thalidomide and 
dexamethasone; 
and 
bortezomib, 
lenalidomide 
and 
dexamethasone
(http://www.cancertherapyadvisor.com/multiple-myeloma/multiple-myeloma-treatment-
regimens/article/218209/). 
The 
combination 
of 
bortezomib, 
cyclophosphamide 
and 
dexamethasone is not currently a Category 1 recommendation; however, it offers an ideal 
platform for study in combination with daratumumab. As compared to combinations including 
intravenous doxorubicin the addition of oral cyclophosphamide has no significant cardiac 
toxicity. Combinations containing IMiDs have the potential to cause additional renal failure in 
those subjects who present with renal disease either secondary to myeloma or as an underlying 
co-morbidity which, in addition, may cause unexpected myelotoxicity due to the erratic renal 
clearance of IMiDs.
The potential benefit of combining daratumumab with multi-drug chemotherapy regimens was 
evaluated in fresh tumor cells from subjects with multiple myeloma.21 Lysis of primary tumor 
cells was measured directly in bone marrow mononuclear cell isolates obtained from subjects
with multiple myeloma. Synergistic tumor cell lysis was demonstrated when daratumumab was 
combined with lenalidomide and/or bortezomib, even in samples from subjects who were 
refractory to lenalidomide and bortezomib treatment. Treatment of bone marrow mononuclear 
cell isolates with lenalidomide or bortezomib resulted in 10% and 18% lysis, respectively. When 
daratumumab was added to either lenalidomide or bortezomib, a 2-fold increase in lysis was 
observed compared with lenalidomide or bortezomib alone.
Thus, preliminary studies have shown that daratumumab can be added to multiple myeloma 
treatment regimens with acceptable tolerability and evidence of additional clinical activity.
We have described the high response rates which patients with previously untreated myeloma 
experience with the combination of CyBorD. Due to the tolerability and response profile for 
daratumumab, its combination with CyBorD has the potential to be the standard of care in 
myeloma. The broad allowance of 4 to 8 cycles of induction therapy is based on local standard of 
care and physician discretion for treating the subjects in this study. The primary endpoint is 
being evaluated after 4 weeks of induction therapy since historically, CyBorD and other 
induction regimens have been evaluated after 4 cycles.
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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective is to evaluate complete response + very good partial response 
(CR+VGPR) rate following 4 cycles of induction therapy of daratumumab plus CyBorD (Dara-
CyBorD), in previously untreated subjects, and in relapsed subjects with multiple myeloma, as 
defined by the International Myeloma Working Group (IMWG) criteria. 
Secondary Objectives
The secondary objectives are to evaluate, in previously untreated subjects and in relapsed 
subjects with multiple myeloma:

Overall response rate (CR+VGPR+partial response [PR], ORR) 

Following 4 cycles of Dara-CyBorD induction therapy

At the end of 4 to 8 cycles of Dara-CyBorD induction therapy

Post-transplant (in subjects who undergo high dose therapy and autologous stem cell 
transplantation)

At the end of 12 cycles of daratumumab maintenance therapy

Time to VGPR or better

Time to PR or better

Progression-free survival (PFS) rate: at 1 year and 3 years

Overall survival (OS) rate: at 1 year and 3 years

Safety and tolerability of Dara-CyBorD 

Safety profile of split-dose initial infusions of daratumumab administered as 8 mg/kg on 
Cycle 1 Day 1 (C1D1) and Cycle 1 Day 2 (C1D2).
Exploratory Objectives
An exploratory objective is to evaluate the clinical efficacy of Dara-CyBorD in molecular 
subgroups, including: del17p, del13, t(4;14), t(11;14), t(14;16).
2.1.2.
Endpoints
Primary Endpoint
The primary endpoint is the proportion of subjects achieving CR+VGPR response following 4 
cycles of induction therapy with Dara-CyBorD, in previously untreated subjects, and in relapsed 
subjects with multiple myeloma, as defined by the IMWG criteria.
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Secondary Endpoints
The secondary efficacy endpoints include:

ORR - the proportion of subjects achieving CR+VGPR+PR response following 4 cycles of 
induction therapy of Dara-CyBorD, in previously untreated subjects, and in relapsed 
subjects with multiple myeloma, as defined by the IMWG criteria at the following 
timepoints:

Following 4 cycles of induction therapy

At the end of Dara-CyBorD induction therapy

Post–transplant (in subjects who undergo high dose therapy and autologous stem cell 
transplantation)

At the end of all (12 cycles) maintenance therapy  

Time to VGPR or better - the duration from the date of start of induction therapy to the date 
of initial documentation of VGPR or better, which was confirmed by a repeated 
measurement as required by the IMWG criteria.* 

Time to PR or better - the duration from the date of start of induction therapy to the date of 
initial documentation of PR or better, which was confirmed by a repeated measurement as 
required by the IMWG criteria.*

Duration of response - the duration from the date of initial documentation of a response (PR 
or better) according to the IMWG criteria to the date of first documented evidence of 
progressive disease according to the IMWG criteria.

PFS - the duration from the date of start of induction therapy to the date of first documented 
evidence of progressive disease or death, whichever comes first. PFS rate at 1 year and 3 
years will be estimated.

OS measured from the date of start of induction therapy to the date of the subject’s death. 
OS rate at 1 year and 3 years will be estimated.

Safety and tolerability of the combination of Dara-CyBorD as assessed by the incidence of 
adverse events and laboratory test abnormalities.

Infusion reaction profile of split-dose infusions of daratumumab administered as 8 mg/kg 
on C1D1 and C1D2 by tabulating incidence of IRRs by System-Organ Class and Preferred 
Term.
* Predefined data censoring rules will be applied for time to event analyses.
Exploratory Endpoints
Clinical efficacy with Dara-CyBorD in high-risk molecular subgroups including: del17p, del13, 
t(4;14), t(11;14), t(14;16).
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
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2.2.
Hypothesis
The primary hypothesis of this study is that CR+VGPR rate following 4 cycles of induction 
therapy of Dara-CyBorD in previously untreated subjects is higher than 60%, and in relapsed 
subjects is higher than 30%, as defined by the IMWG criteria.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, single-arm, Phase 2 study, evaluating the combination of Dara-CyBorD in 
subjects with previously untreated multiple myeloma irrespective of eligibility for HDT and 
ASCT and subjects with relapsed multiple myeloma following one prior line of therapy. 
Approximately 100 subjects will be enrolled into this study with at least 40 previously untreated
multiple myeloma subjects. Due to slow enrollment of  subjects with relapsed multiple myeloma 
following one prior line of therapy, this cohort is closed to enrollment in Amendment 2.
Treatment phases consist of induction therapy with 4 to 8 cycles of Dara-CyBorD, consolidation 
therapy with HDT/ASCT for eligible subjects, and maintenance therapy (Figure 1). Following 
induction and/or consolidation therapy with ASCT, subjects will receive maintenance therapy 
with daratumumab alone for twelve 28-day cycles or until disease progression (whichever occurs 
first). Maintenance therapy for subjects who have ASCT should begin approximately 90 days 
after ASCT. Follow-up for all subjects will continue up until 36 months after the start of 
induction therapy (C1D1). 
Approximately 100 subjects will be assigned to receive Dara-CyBorD as induction on a 28-day 
cycle length. All subjects will receive 4 to 8 cycles of oral cyclophosphamide 300 mg/m2 on 
Days 1, 8, 15, and 22; subcutaneous (SC) bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral 
or IV dexamethasone 40 mg weekly. Subjects will concurrently receive daratumumab on 28-day 
cycles (Table 1). The initial dose of daratumumab will be given as a split dose, at a dose of 
8 mg/kg IV on consecutive days (C1D1 and C1D2). Starting Cycle 1 Day 8 through the 
completion of Cycle 2, daratumumab will be given weekly at 16 mg/kg IV. For Cycle 3 to 
Cycle 6, subjects will receive daratumumab 16 mg/kg IV once every 2 weeks. From Cycle 7 
onward, subjects will receive daratumumab 16 mg/kg IV once every 4 weeks, whether in the last 
induction cycles with CyBorD, or alone during the maintenance phase. Regardless of the number 
of induction cycles given, all eligible subjects are to receive 12 cycles of maintenance therapy 
with daratumumab 16 mg/kg IV monotherapy, given on 28-day cycles.
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Table 1:
Dosing Information for Dara-CyBorD by Cycle
Cycle 1
Cycle 2
Cycles 
3 to 6
Cycles 
7 to 8
Maintenance 
cycles  
Drug (dose)
Day 1
Day 
2
Day 8
Day 15
Day 22
Daratumumab (8 
mg/kg IV, Cycle 1 
Days 1 and 2; 16 
mg/kg IV, all others)
X
X
X
X
X
Day 1, 
8, 15, 
22
Day 1, 
15
Day 1
Day 1
Bortezomib (1.5 
mg/m2)
X
X
X
Up to 4 to 8 cycles, Days 
1, 8, 15
--
Cyclophosphamide 
(300 mg/m2)
X
X
X
X
Up to 4 to 8 cycles, Days 
1, 8, 15, 22
--
Dexamethasonea
X
X
X
X
X
Up to 4 to 8 cycles, Days 
1, 8, 15, 22
Day 1
a: See dexamethasone dosing table (Table 5)
No daratumumab dose modification (increase or decrease) will be permitted. Protocol-specified 
dose delays for daratumumab have been included in this protocol (refer to Section 6.2.1) and will 
be implemented as necessary. Subjects will be evaluated for toxicity before each dose of 
daratumumab is administered, as well as the occurrence of infusion-related reactions (refer to 
Section 6.1.5). Doses may be held based on the severity of and recovery from a previous toxicity. 
Dose adjustments and delays of cyclophosphamide, bortezomib, and corticosteroids will be 
permitted (refer to Sections 6.3 – 6.5).
Throughout the study, subjects will be monitored closely for adverse events, laboratory 
abnormalities, and clinical response, as specified in the Time and Events Schedule. The National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 4.03) 
will be used to grade toxicity throughout the study.
Disease response and progression will be based on assessments from IMWG Guidelines
(see Attachment 5).4,8 Efficacy assessments include: M-protein measurements (serum and urine), 
IFE
(serum and urine), serum FLC, serum calcium corrected for albumin, serum 
immunoglobulins, 
examination 
of 
bone marrow 
aspirate 
or 
biopsy, 
and 
skeletal 
survey/documentation of extramedullary plasmacytomas. 
The primary study endpoint will be the CR+VGPR rate following 4 cycles of induction therapy 
with Dara-CyBorD, in previously untreated subjects and in relapsed subjects with multiple 
myeloma, as defined by the IMWG criteria. Secondary endpoints include ORR after 4 cycles of 
induction, at end of induction, after ASCT (if applicable) and at end of maintenance therapy;
time to response (VGPR and PR); duration of response; the PFS rate and OS rates at 
1 and 3 years; and the safety profile of Dara-CyBorD as well as of split dose infusions of 
daratumumab on C1D1 and C1D2.
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An Internal Data Review Committee will review interim data at 3 predetermined interim safety 
analyses. The first safety analysis will occur after at least 20 subjects are treated for at least 1 
cycle of study treatment (or discontinue before the end of Cycle 1). The second interim safety 
analysis will occur after at least 50 subjects complete Cycle 1 of study treatment (or discontinue 
before the end of Cycle 1) with a focus on infusion related reactions during Cycle 1. The third 
interim safety analysis will occur after at least 50 subjects are treated for at least 4 cycles (or 
discontinue before the end of Cycle 4).
A diagram of the study design is provided below.
Figure 1:
Schematic Overview of the Study
3.2.
Study Design Rationale
The present study is designed to evaluate the combination of Dara-CyBorD in subjects with 
previously untreated multiple myeloma and in subjects with relapsed multiple myeloma 
following only one line of therapy. The duration of induction therapy is generously broad due to 
the variability of physician preferences in the community oncology setting. It is anticipated that 
the median number of induction cycles will be 6 and, from this assumption, we anticipated 
approximately 12 months of maintenance therapy with daratumumab. The duration of follow-up 
will be at least 36 months to capture median long-term outcomes such as progression-free 
survival.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before enrollment.
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 should consult with the appropriate sponsor representative before enrolling a subject 
in the study.
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4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.    Be at least 18 years of age. 
2.
Have documented multiple myeloma as defined by the IMWG 2015 criteria below:
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
plasmacytoma.* 
In addition, the subject must meet one of the criteria in either 2a or 2b.  
a. 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 min 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, or CT
(computed tomography) **. 
b.  Any one or more of the following:
o
Clonal bone marrow plasma cell percentage* ≥60%
o
Involved:uninvolved serum FLC ratio*** >100
o
>1 focal lesions on MRI (magnetic resonance imaging) studies; Each focal 
lesion must be 5 mm or more in size.
*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. 
**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. 
***These values are based on the serum Freelite assay (The Binding Site Group, 
Birmingham, UK). The involved FLC must be ≥100 mg/L. 
3.
Have measurable 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

Immunoglobulins A, D, E or M multiple myeloma: serum M-protein level ≥0.5 g/dL or 
urine M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in the urine: serum Ig FLC 
≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
4.
Have previously untreated myeloma or relapsed myeloma (enrollment of subjects with 
relapsed myeloma closed in Amendment 2) with one prior line of therapy including an 
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induction regimen which may be followed by autologous stem cell transplantation and 
single agent maintenance therapy. For previously untreated subjects an emergency course of 
steroids (defined as no greater than 40 mg of dexamethasone, or equivalent per day for a 
maximum of 4 days) is permitted. In addition, radiation therapy is permitted prior to study 
entry, during screening, and during Cycles 1-2 of study treatment as needed for lytic bone 
disease.
5.
Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 
2 (refer to Attachment 2).
6.
Before C1D1, a woman must be either:

Not of childbearing potential: premenarchal; postmenopausal (>45 years of age with 
amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and 
a serum follicle stimulating hormone level >40 IU/L or mIU/mL]); permanently 
sterilized (eg, bilateral tubal occlusion [which includes tubal ligation procedures as 
consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy); or otherwise be incapable of pregnancy,

Of childbearing potential and practicing a highly effective method of birth control for 
4 weeks before initiating study treatment that is consistent with local regulations 
regarding the use of birth control methods for subjects participating in clinical studies: 
eg, established use of oral, injected or implanted hormonal methods of contraception; 
placement of an intrauterine device or intrauterine system; barrier methods: condom 
with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner 
sterilization (the vasectomized partner should be the sole partner for that subject); true 
abstinence (when this is in line with the preferred and usual lifestyle of the subject) 
Note: If the childbearing potential changes after start of the study (eg, woman who is 
not heterosexually active becomes active, premenarchal woman experiences menarche) 
a woman must begin a highly effective method of birth control, as described above.
7.
A woman of childbearing potential must have 2 negative serum (β human chorionic 
gonadotropin) or urine pregnancy tests during screening, the first one within 28 days prior to 
the first dose of study drug and the second within 24 hours prior to the first dose of study 
drug.
8.
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must 
also not donate sperm during the study and for 3 months after receiving the last dose of 
study drug.
9.
Subjects must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol and referenced in the informed consent form (ICF).
10. Each subject (or their legally acceptable representative) must sign an ICF indicating that he 
or she understands the purpose of and procedures required for the study and are willing to 
participate in the study. 
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4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Refractory to any PI or the combination of PI and IMiD agents (such as lenalidomide), 
defined as failure to respond or progression within 60 days of the end of PI therapy
2.
Diagnosed or treated for malignancy other than multiple myeloma, except:

Malignancy treated with curative intent and with no known active disease present for ≥5 
years before enrollment

Adequately treated non-melanoma skin cancer, lentigo maligna or in situ malignancies
(eg., cervical, breast) without evidence of disease
3.
Exhibiting clinical signs of or has a known history of meningeal or central nervous system 
involvement by multiple myeloma
4.
Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 
second (FEV1) <50% of predicted normal 
(Note that FEV1 testing is required for subjects suspected of having chronic obstructive 
pulmonary disease and subjects must be excluded if FEV1 <50% of predicted normal.)
5.
Has known moderate or severe persistent asthma within the past 2 years (see Attachment 3), 
or currently has uncontrolled asthma of any classification
(Note that subjects who currently have controlled intermittent asthma or controlled mild 
persistent asthma are allowed in the study.)
6.
Is known to be seropositive for human immunodeficiency virus, known to have hepatitis B 
surface antigen positivity, or known to have a history of hepatitis C. Subjects who 
completed treatment for hepatitis C at least 6 months prior to screening and have no 
detectable circulating hepatitis C virus (HCV) by hepatitis C RNA polymerase chain 
reaction (PCR) at screening, may participate in the study. Such subjects will be required to 
undergo regular assessment for HCV reactivation during their participation in the study.
Subjects who test positive for HCV at any time during these assessments will be withdrawn 
from the study.   
7.
Has any concurrent medical condition or disease (eg, active systemic infection) that is likely 
to interfere with study procedures or results, or that in the opinion of the investigator would 
constitute a hazard for participating in this study 
8.
Has clinically significant cardiac disease, including:

Myocardial infarction within 6 months before C1D1, or unstable or uncontrolled 
disease/condition related to or affecting cardiac function (eg, unstable angina, 
congestive heart failure, New York Heart Association Class III-IV)

Uncontrolled cardiac arrhythmia (NCI-CTCAE Version 4.03 Grade 2 or higher) or 
clinically significant electrocardiogram (ECG) abnormalities 
9.
Screening 12-lead ECG shows a baseline QT interval (QTc) >470 msec.
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10. Has any of the following laboratory test results during the screening phase:

Absolute neutrophil count ≤1.0 × 109/L; (granulocyte colony stimulating factor use is 
permitted)

Hemoglobin level ≤7.5 g/dL (≤5 mmol/L); blood transfusions to maintain hemoglobin 
>7.5 are acceptable

Platelet count <75 × 109/L for subjects in whom <50% of bone marrow nucleated cells 
are plasma cells; otherwise platelet count <50 × 109/L; no platelet transfusions in the 
past 7 days are allowed

Alanine aminotransferase (ALT) level ≥2.5 × upper limit of normal (ULN)

Aspartate aminotransferase (AST) level ≥2.5 × ULN

Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin 
2 × ULN)

Creatinine clearance ≤20 mL/min estimated using Cockcroft-Gault; see Attachment 1

Corrected serum calcium >14.0 mg/dL (>3.5 mmol/L) or free ionized calcium 
>6.5 mg/dL (>1.6 mmol/L); see Attachment 4
11. Has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human 
proteins, daratumumab or its excipients (refer to Investigator's Brochure), or known 
sensitivity to mammalian-derived products
12. Has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential), 
Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and/or skin changes), or amyloid light-chain 
amyloidosis
13. Is known or suspected of not being able 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
14. Has a contraindication to the use of oral cyclophosphamide, bortezomib, or corticosteroids 
per local prescribing information
15. Has received an investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 4 weeks before C1D1 (except for investigational anti-
myeloma agents, which cannot be taken within 2 weeks before C1D1)
16. Is a woman who is pregnant or breast-feeding or planning to become pregnant while 
enrolled in this study or within 6 months after the last dose of study drug
17. Has any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments
18. Has had major surgery within 2 weeks before C1D1, or will not have 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.  (Note: subjects
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with planned surgical procedures to be conducted under local anesthesia may participate. 
Kyphoplasty is not considered a major surgery.) 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before C1D1 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.
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.
Agree to follow the contraceptive requirements as noted in the inclusion criteria
In addition, during the study and for 3 months after receiving the last dose of 
daratumumab, a woman must agree not to donate eggs (ova, oocytes) for the purposes 
of assisted reproduction. Women of reproductive potential should use effective 
contraception during and for 3 months after cessation of daratumumab treatment.
5.
TREATMENT ALLOCATION AND BLINDING
As this is an open-label study, blinding procedures are not applicable.
Subjects who are entered in the study will be registered at Screening. To initiate sponsor 
registration, study sites will use the interactive web response system (IWRS). After the 
investigator has verified that all eligibility criteria have been met, the subject will be assigned by 
IWRS to receive study drug. All subjects will receive the same treatment regimen, single-agent 
daratumumab.
The IWRS will also be used to assign study drug for the subject throughout the study, per the 
Time & Events schedule. The requestor will use his or her own user identification and personal 
identification number when contacting the IWRS, and will then give the relevant subject details 
to uniquely identify the subject. Details on the use of IWRS will be provided in the IWRS 
manual.
6.
DOSAGE AND ADMINISTRATION
Study site personnel will instruct subjects on how to store pre- and post-infusion medications for 
at-home use as indicated for this protocol. In this protocol, the term “study drug” refers to 
daratumumab, and “study treatment” refers to Dara-CyBorD. The CyBorD medications are 
considered standard of care and will be commercially available drugs. 
If a subject’s weight changes by more than 10% after C1D1, the dose of daratumumab and the 
other weight-based treatments (cyclophosphamide, bortezomib) will be re-calculated. Otherwise, 
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dose modification of daratumumab is not permitted (see Section 6.2, Dose Delay and 
Modification).
6.1.
Daratumumab 
6.1.1.
Preparation
Infusion solution will be prepared as a 500-mL dilution of daratumumab in sterile, pyrogen-free 
0.9% NaCl (Table 2). Preparation of infusion bags should be done on the day of the planned 
infusion. Daratumumab must be administered as an IV infusion given through a well-functioning 
IV catheter by using an infusion pump. The study drug must be filtered by using an inline filter 
(0.2 μM) during the infusion. Manuals with detailed descriptions for preparation and 
administration of daratumumab will be supplied to each pharmacy and site.
6.1.2.
Treatment Schedule and Administration
Daratumumab will be administered in 28-day cycles. The initial dose of daratumumab will be 
given as a split dose, at a dose of 8 mg/kg IV on consecutive days on C1D1 and C1D2. Starting 
Cycle 1 Day 8 through the completion of Cycle 2, daratumumab will be given weekly at 
16 mg/kg IV. For Cycle 3 to Cycle 6, subjects will receive daratumumab 16 mg/kg IV 
once every 2 weeks. From Cycle 7 onward, subjects will receive daratumumab 16 mg/kg IV 
once every 4 weeks, whether in the last induction cycles with CyBorD, or alone during the 
maintenance phase. All eligible subjects are to receive 12 cycles of maintenance therapy with 
daratumumab monotherapy, given on 28-day cycles.
Each subject’s dose will be calculated based on the subject’s weight rounded to the nearest 
kilogram. The dose of daratumumab will remain constant throughout the study, unless the 
subject’s weight changes more than 10% from baseline. Subjects will receive preinfusion 
medications and postinfusion medications as outlined in Sections 6.1.4.1 and 6.1.4.2, 
respectively. All infusions will be planned as outpatient visits.
Subjects who have an ASCT will be eligible for maintenance daratumumab beginning 
approximately 90 days following the re-infusion of autologous stem cells (Day 0). Subjects will 
receive daratumumab post-ASCT once every 4 weeks until they complete a total of 12 cycles of 
maintenance therapy with daratumumab, or have disease progression, whichever comes first.
Every effort should be made to keep subjects on the planned dosing schedule. Day 1 of each 
cycle of daratumumab should correspond to Day 1 of each cycle of CyBorD while subjects are 
receiving CyBorD. However, doses given within the permitted windows (see Table 3) are 
allowed. All induction and maintenance cycles are 28 days. Delays in Day 1 of CyBorD should 
result in a corresponding delay in Day 1 of daratumumab for that cycle.
6.1.3.
Instructions for Preparing and Administering Daratumumab Infusions
The dilution volumes, initial infusion rates, and increment of infusion rates for the first, second, 
and subsequent doses in the absence of an infusion-related reaction >Grade 1 are provided in 
Table 2: Daratumumab Infusion Rates. The sponsor may modify the infusion rates or the 
preinfusion medications prospectively based upon the information collected to date from this and 
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other studies. Additional details for administration times and rates, as well as preinfusion 
medications, will be provided in the administration guidelines (study site investigational product 
and procedures manual).
Infusion rates will be administered as shown in Table 2. 
Table 2:
Daratumumab Infusion Rates
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum 
Infusion Rate
First infusion (C1D1, 
8 mg/kg)
500 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Second infusion
(C1D2, 8 mg/kg)a
500 mL
100 mL/hour
50 mL/hour 
every hour
200 mL/hour
Subsequent infusions
(16 mg/kg)b
500 mL
100 mL/hour
50 mL/hour 
every hour
200 mL/hour
a: Escalate only if there were no Grade 1 (mild) or greater infusion reactions during the first 3 hours of the first 
infusion.
b: Escalate only if there were no Grade 1 (mild) or greater infusion reactions during a final infusion rate of 
≥100 mL/hr in the first 2 infusions.
As noted in the Time and Events Schedule, vital signs should be monitored frequently on C1D1 
and C1D2, before, during, and after the first infusion of daratumumab (immediately before the 
start of daratumumab infusion; at 0.5, 1, 1.5, 2, and 3.5 hours after the start of the infusion and 
then every 2 hours through duration of infusion; at end of infusion; and 0.5 and 1 hour after the 
end of the infusion). For all other infusions, vital signs should be measured before the start of 
infusion and at the end of the infusion. If a subject experiences any 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.
For this study, any dose of daratumumab greater than 8 mg/kg on C1D1 and C1D2 and 16 mg/kg 
on all subsequent doses of daratumumab within a 24-hour time period will be considered an 
overdose.
6.1.4.
Guidelines for Prevention and Management of Infusion-related
Reactions
The recommended pre- and postinfusion medications listed in the following sections will be 
provided by the study sites. 
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6.1.4.1.
Preinfusion Medication
On daratumumab infusion days, subjects will receive the following medications approximately 
1 hour prior to daratumumab infusion; premedication up to 3 hours before the dose of 
daratumumab is permitted:

Dexamethasone (as listed in Table 5); doses may be give PO unless specified as IV:
1.
C1D1 and C1D2: dexamethasone 20 mg IV
2.
Cycle 1 Day 8, 15 and 22: dexamethasone 20 mg IV
3.
Cycle 2 Day 1, 8, 15, and 22: dexamethasone 40 mg
4.
Cycles 3-6 (if with CyBorD) Days 1, 8, 15, 22: dexamethasone 40 mg 
5.
Cycles 7-8 (if with CyBorD), Days 1, 8, 15, 22: dexamethasone 40 mg
6.
Maintenance cycles, Day 1: dexamethasone, 12 mg   

Paracetamol (acetaminophen) 650-1000 mg IV or PO

An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent). Avoid the use of IV 
promethazine  

Leukotriene inhibitor (optional): montelukast 10 mg PO or equivalent, as per investigator 
discretion
If necessary, all PO preinfusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken within 3 hours before the infusion.
6.1.4.2.
Postinfusion Medication
Postinfusion medications are listed below. 

Cycle 1 Day 3: dexamethasone (4 mg PO)

Cycle 1 Day 9, 16, 23: dexamethasone (20 mg PO)

No further post-infusion corticosteroids are needed following Cycle 1 if no delayed infusion 
reactions have occurred.  However, dexamethasone 4 mg PO for up to 2 days after each dose 
of daratumumab may be continued at the investigator’s discretion.
For subjects receiving daratumumab and who have a higher risk of respiratory complications (ie, 
subjects with mild asthma or subjects with chronic obstructive pulmonary disease who have an 
FEV1 <80% at screening or developed FEV1 <80% during the study without any medical 
history), the following postinfusion medications should be considered:

Antihistamine (diphenhydramine or equivalent medication)

Leukotriene inhibitor (montelukast or equivalent medication)

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
salbumatol ± inhaled corticosteroids for subjects with chronic obstructive pulmonary 
disease)
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In addition, hospitalization for monitoring for up to 2 nights after an infusion should be 
considered. If these subjects are not hospitalized, then a follow-up telephone call should be made 
to monitor their condition within 48 hours after all infusions. 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, antihistamines, and corticosteroids that are deemed necessary to provide 
adequate supportive care in the event that a bronchospasm occurs after subjects are released from 
the hospital/clinic. If an at-risk subject experiences no major infusion-related reactions, then 
postinfusion medications may be waived after Cycle 1, at the investigator’s discretion.
6.1.5.
Management of Infusion-related Reactions
Subjects should be carefully observed during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of an infusion-related reaction (IRR), and resources 
necessary for resuscitation must be available. Attention to staffing should be considered when 
multiple subjects will be dosed at the same time. 
For IRRs of any grade/severity, immediately interrupt the daratumumab infusion and manage 
symptoms. Management of IRRs may further require reduction in the rate of infusion, or 
discontinuation of daratumumab.

Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at 
no more than half the rate at which the reaction occurred. If the subject does not 
experience any further reaction symptoms, then infusion rate escalation may resume at 
increments and intervals as outlined in Table 2. 

Grade 3 (severe): If the intensity of the reaction decreases to Grade 2 or lower, then 
consider restarting the infusion at no more than half the rate at which the reaction 
occurred. If the subject does not experience additional symptoms, then resume infusion 
rate escalation at increments and intervals as outlined in Table 2. 
Immediately interrupt the daratumumab infusion in the renewed event of Grade 3 
symptoms. If the intensity decreases to Grade 2 or lower consider restarting the infusion 
as described above. Permanently discontinue daratumumab upon the third occurrence of a 
Grade 3 or greater infusion reaction.

Grade 4 (life threatening): Permanently discontinue daratumumab treatment.
6.2.
Dose Delay and Modification
Dose modification of daratumumab is not permitted. Dose delay is the primary method for 
managing daratumumab-related toxicities.
6.2.1.
Toxicity Management
Cycle Delays
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 
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previous dose(s). Toxicities are to be assessed according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. Dose delays will be 
made based on the toxicity experienced during the previous infusion or newly encountered on 
Day 1 of a new cycle. 
The study drug must be held if any of the following criteria below are met, to allow for recovery 
from toxicity, regardless of relationship to daratumumab.
The criteria for a dose delay are:

Grade 4 hematologic toxicity 

Grade 3 or higher thrombocytopenia 

Febrile neutropenia

Neutropenia with infection

Grade 3 or higher non-hematologic toxicities with the following exceptions: 

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

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 restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception of laryngeal edema, bronchospasm or febrile neutropenia, which 
must be fully recovered.
If daratumumab administration does not commence within the prespecified window (Table 3) of 
the scheduled administration date, then the dose will be considered a missed dose and it should 
be skipped. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
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Table 3:
Daratumumab Administration Schedule and Dose Delay Instructions
Cycles
Frequency
Dose Held
Dosing Re-start
1 and 2
(excluding 
C1D1 and 
C1D2 
which 
must be 
given as 
planned)
Weekly
>3 days
next planned weekly dosing date
3 to 6
Biweekly (q2wks)
>7 days
next planned biweekly dosing date
7+
Every 4 weeks 
>7 days (if 
induction or 
maintenance)
next planned every 4 weeks dosing date
Doses of daratumumab may be delayed as listed in Table 3. 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, if a within-cycle dose is delayed, then the dates of the subsequent within-cycle doses 
should not be adjusted.
A daratumumab dose that is held for more than the permitted time 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. Subjects whose 
dose was delayed for more than the prescribed duration, should have study treatment 
discontinued, unless, upon consultation with the sponsor and the review of safety and efficacy, 
continuation is agreed upon.
6.3.
Bortezomib
Bortezomib will be given as 1.5 mg/m2 subcutaneously on Days 1, 8, and 15 of each cycle, for 
up to 8 cycles (see Table 1). Dose modification may be made only after the first cycle is 
completed for the occurrence of peripheral neuropathy and myelotoxicity excluding anemia.
The amount (in mg) of bortezomib to be administered is based on body surface area (BSA) 
calculations using a standard nomogram or according to institutional policy, as follows:
Bortezomib dose (mg/m
2) × subject BSA (m
2)
2.5 mg/mL
= Total bortezomib volume (mL) to be administered
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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). Subjects
will receive 
1.5 mg/m2 bortezomib as an SC injection once weekly (Days 1, 8, and 15) during the 28-day 
induction. For subjects who experience injection-site reactions at the SC administration site, 
bortezomib may be administered by IV injection (see study site investigational product and 
procedures manual and bortezomib United States prescribing information). On daratumumab 
infusion days, bortezomib will be administered at the end of the daratumumab infusion.
6.3.1.
Dose Adjustments of Bortezomib
Dose adjustments should be based on the highest grade of toxicity that is ascribed to bortezomib.
Bortezomib should be withheld at the onset of any Grade 3 or 4 non-hematological or Grade 4 
hematological toxicity, excluding neuropathy as discussed in Table 4: Recommended Dose 
Modification for Bortezomib-related Neuropathic Pain and/or Peripheral Sensory or Motor 
Neuropathy. Once the symptoms of the toxicity have resolved, bortezomib may be reinitiated at a 
reduced dose as follows:

Starting dose: 1.5 mg/m2

Dose level -1: 1.3 mg/m2

Dose level -2: 1.0 mg/m2
Neurologic Toxicity
If the subject experiences peripheral neuropathy, then dose adjustments should be made 
according to the recommendations in Table 4.
Table 4:
Recommended Dose Modification for Bortezomib-related Neuropathic Pain and/or Peripheral 
Sensory or Motor Neuropathy
Gradea
Modification
1 (asymptomatic; loss of deep tendon reflexes or 
paresthesia) without pain or loss of function
No action
1 with pain or Grade 2 (moderate symptoms; limiting 
instrumental ADLb)
Reduce bortezomib to 1.3 mg/m2
2 with pain or Grade 3 (severe symptoms; limiting self-
care ADLc)
Withhold bortezomib treatment until symptoms of toxicity 
have resolved. When toxicity resolves, reinitiate with a 
reduced dose of bortezomib at 1.0 mg/m2 once per week
4 (life-threatening consequences; urgent intervention 
indicated)
Discontinue bortezomib
ADL = activities of daily living
a: Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v4.03.
b: Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc
c: Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
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6.4.
Cyclophosphamide
Cyclophosphamide will be given as 300 mg/m2 on Days 1, 8, 15 and 22 of each cycle 
(continuous) by mouth (PO), for up to 8 cycles. Dose modification may be made due to 
myelotoxicity (excluding anemia) and cystitis during any treatment cycle.
For Grade 3 hematologic toxicity and for Grade 1 or 2 cystitis: level-1, 300 mg/m2 on Days 1, 8, 
and 15; level-2, 300 mg/m2 Days 1 and 8; level-3, 300 mg/m2 Day 1. Grade 3 or 4 cystitis 
mandates discontinuation of cyclophosphamide.14
6.5.
Corticosteroids
The corticosteroid for pre- and post-daratumumab administration is dexamethasone. The route of 
administration of corticosteroids prior to infusion of daratumumab during Cycle 1 must be IV. 
During subsequent cycles the route of administration may be either IV or PO prior to infusion of 
daratumumab. Beginning in Cycle 2, post-infusion corticosteroids are optional and can be 
omitted at the discretion of the investigator if the subject experiences no delayed infusion 
reactions. Please refer to the table below for corticosteroid dosing. 
Dose modification of the corticosteroids is not advised during the first cycle of treatment. 
However, dose modifications may be made due to Grade 2 muscle weakness, Grade 3 GI 
toxicity, or any other Grade 3 toxicity believed to be due to corticosteroids. For such level of 
toxicity the dose of corticosteroids may be reduced by 50%.
Note: All corticosteroid doses may be given PO unless specified as IV.
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Table 5:
Dexamethasone Dose Schedule
Cycle/Timepoint
Day 1 (pre-
infusion)*
Day 1 of 
Week  
Day of Infusion +1 
Day (post-inf)
Day of Infusion +2 Days 
(post-inf)
Cycle 1 (Dara-
CyBorD)
Week 1 (Dara on 
Days 1 and 2)
20 D (IV)
--
20 D on C1D2 (IV)
Day 3:  4 D
Week 2
20 D (IV)
--
20 D
Week 3
20 D (IV)
--
20 D
Week 4
20 D (IV)
--
20 D
Cycle 2 (Dara-
CyBorD)
Week 1
40 D
--
None needed+
None needed+
Week 2
40 D
--
None needed+
None needed+
Week 3
40 D
--
None needed+
None needed+
Week 4
40 D
--
None needed+
None needed+
Cycles 3-6 (Dara-
CyBorD)**
Week 1
40 D
--
None needed+
None needed+
Week 2
--
40 D
None needed+
None needed+
Week 3
40 D
--
None needed+
None needed+
Week 4
--
40 D
None needed+
None needed+
Cycles 7-8 (Dara-
CyBorD)**
Week 1
40 D
None needed+
None needed+
Week 2
--
40 D
None needed+
None needed+
Week 3
--
40 D
None needed+
None needed+
Week 4
--
40 D
None needed+
None needed+
Daratumumab
Maintenance (Q28 
days for 12 
months; up to 12 
cycles) 
Week 1 of each 
cycle
12 D
--
None needed+
None needed+
IV – intravenous, D – Dexamethasone, Q28 – every 28
* Also on Day 2 for Cycle 1 only 
** Dara-CyBorD induction may be given for 4 to 8 cycles
+None needed unless subject experiences an infusion reaction
7.
TREATMENT COMPLIANCE
Daratumumab will be administered as an IV infusion by qualified study-site personnel and the 
details of each administration will be recorded in the case report form (CRF).
Oral cyclophosphamide is self-administered by the subject. The treating team is responsible for 
interviewing the subject at each visit in regards to the subject compliance with oral 
cyclophosphamide, but cyclophosphamide intake will not be recorded in a subject’s CRF.
Bortezomib is administered as an SC injection at the study-site by qualified members of the 
treating team. Bortezomib intake is to be recorded in a subject’s CRF.
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Dexamethasone will need to be administered intravenously during the first cycle of therapy and 
therefore compliance will be monitored by the members of the treating team. However, 
subsequent doses may be self-administered PO by the subject. There will be regular interviews 
by the study team to ensure compliance but corticosteroid intake will not be recorded in a 
subject’s CRF.
Drug supplies for each subject will be inventoried and accounted for.
8.
PRESTUDY AND CONCOMITANT THERAPY
Pre-study therapies administered up to 30 days before first dose of study drug must be recorded 
at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study drug until 30 days following completion of the last dose of study drug.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen, 
route of administration, and its indication. Modification of an effective preexisting therapy 
should not be made for the explicit purpose of entering a subject into the study.
Subjects must not have received an investigational drug (including investigational vaccines) or 
used an invasive investigational medical device within 4 weeks before C1D1 (except for 
investigational anti-myeloma agents, which cannot be taken within 2 weeks before C1D1).
Subjects with previously untreated myeloma may receive radiation therapy to control local 
complications of myeloma such as fracture and nerve impingement. Subjects may also receive a 
short course of steroids however, no more than 160 mg of dexamethasone or equivalent.
Subjects with relapsed myeloma may have received regimens containing lenalidomide, 
bortezomib, corticosteroids, or high-dose melphalan prior to autologous transplant amongst other 
regimens including conventional alkylators.
Subjects are expected not to receive multiple myeloma therapy during the follow-up period. 
However, if they do receive such therapy, they are to remain in follow-up and the therapy(ies) 
being received are to be reported in the CRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
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Additional Recommended Therapies

Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase, as 
per institutional guidelines.

Prevention of steroid induced gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are 
permitted per institutional guidelines, for example proton pump inhibitors (omeprazole or 
equivalent) or sucralfate, or H2 blockers (ranitidine or equivalent).

Other - Bisphosphonates
Due to the high risk of skeletal related complications in this subject population it is highly 
encouraged to prescribe appropriate bisphosphonates if subject agrees and the administration 
criteria allow.
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:

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 red blood cells.

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
9.
STUDY EVALUATIONS
9.1.
Study Procedures
The Time and Events Schedule summarizes the frequency and timing of all measurements 
applicable to this study. Subject participation is to include a screening phase, an induction phase 
with Dara-CyBorD, optional ASCT consolidation therapy, a maintenance phase with 
daratumumab alone, an end-of-treatment visit and a post-treatment follow-up phase. 
9.1.1.
Screening Phase
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 rescreening 
must sign a new ICF and will then be assigned a new screening number.
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9.1.1.1.
Demographic Characteristics and Medical History
At the screening phase (within 28 days of C1D1/start of study drug administration), the 
following assessments will be done: height and weight, physical examination, ECOG 
performance status, vital signs, pulmonary function testing, screening serology, 12-lead 
electrocardiogram, blood typing (see Section 9.1.1.3), a chest x-ray, and pregnancy test (for 
female subjects).  Laboratory tests (hematology and chemistry [including beta-2 microglobulin]) 
will be done for baseline values.
A medical history will be taken, including recording of prior and concomitant medications. 
Demographic characteristics will be recorded. 
9.1.1.2.
Bone Marrow Biopsy, Serum and Urine Tests
Bone marrow biopsy with Flow cytometry, serum M-protein quantitation by electrophoresis 
(SPEP) and serum IFE, serum FLC, serum quantitative immunoglobulins, a 24-hour urine test 
for M-protein quantitation by electrophoresis (UPEP), and urine IFE will be performed. All 
subject’s samples will be tested for IgG, IgA, and IgM. Subjects with IgE or IgD myeloma will 
have samples tested for IgE or IgD. In addition, there will be a baseline assessment for lytic 
lesions and extramedullary plasmacytomas. Extramedullary plasmacytomas should be assessed 
for all subjects with a history of plasmacytomas or if clinically indicated, by clinical examination 
or radiologic imaging; a repeat assessment should be done on C1D1 if not done within 14 days 
prior to C1D1. The disease status tests listed here are explained further in Section 9.2.
9.1.1.3.
Blood Typing/Indirect Coombs Testing
Blood Type, Rh, and Indirect Antiglobulin Test (IAT) should be done before the first dose of 
daratumumab; there is no need to repeat the tests if they have been performed within the 3 days
prior to C1D1, and there is no need to perform these on C1D1 if there were no blood transfusions 
between screening and C1D1. Subject RBC phenotyping (standard or extended) is an alternative 
option to the IAT test, if locally required. Either method must be completed prior to first 
daratumumab infusion.
Daratumumab interferes with the 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 Antiglobulin [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 and Rh blood groups, and IAT or phenotyping) determined 
before the first infusion 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 
interference with IAT by treating reagent red blood cells with dithiothreitol.2
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Possible methods for blood banks to provide safe red blood cells (RBCs) for transfusion to 
subjects receiving daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) 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 emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
Daratumumab Investigator’s Brochure.
9.1.2.
Treatment Phase
Each treatment cycle is to be 28 days.
9.1.2.1.
Induction Therapy
During induction, drug administration and testing are to be performed as listed in the Time and 
Events Schedule. Vital signs will be monitored extensively on C1D1 and C1D2. 
A physical examination, vital signs, weight, ECOG performance status, urine pregnancy test (for 
pre-menopausal female subjects), and laboratory tests (hematology and chemistry); SPEP, 
quantitative Ig, and UPEP will be done on Day 1 of each 28-day cycle. 
9.1.2.2.
Consolidation Stem Cell Therapy, if Eligible
Eligible subjects may undergo stem cell collection, HDT and ASCT following 4-8 cycles of 
induction therapy. The criteria, testing and treatment for subjects undergoing an ASCT will be as 
per the standard operating procedures of the transplant center.
9.1.2.3.
Maintenance Therapy with Daratumumab
After the induction therapy cycles of Dara-CyBorD, and whether or not HDT/ASCT is 
performed, daratumumab alone will be given in 28-day cycles, for 12 cycles or a total of 16 to 20 
cycles (including the cycles of induction therapy).
On Day 1 of every therapy cycle, a physical examination, vital signs, weight, ECOG 
performance status, and laboratory tests (central and local assessment of hematology, chemistry,
and local assessment of pregnancy [with urine sample] if applicable) should be performed.
On Day 1 of every other cycle during maintenance therapy (every 56 days), SPEP, quantitative 
Ig, and UPEP should be performed. In addition, in case of suspected CR, suspected sCR, or 
progressive disease (PD), a bone marrow biopsy with Flow cytometry will be done.
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9.1.2.4.
End of Treatment
At the end of treatment visit, to be scheduled 30 days after the last dose, the following will be 
assessed: 
Physical examination, ECOG performance status, and laboratory tests (hematology and 
chemistry).
9.1.3.
Post-treatment Phase (Follow-Up)
Once the end of treatment visit has occurred, subjects will be asked to return to the study site 
every 12 weeks so that, if suspected CR, suspected sCR, or PD, bone marrow biopsy with Flow 
cytometry can be performed. Quantitative Ig will also be measured. 
Lytic lesions and extramedullary plasmacytomas will be assessed if clinically indicated until PD 
through Month 36. 
Subjects will be instructed that study drug (daratumumab) will not be made available to them 
after they have completed/discontinued study drug and that they should return to their primary 
physician to determine standard of care.
9.2.
Efficacy Evaluations
Disease response and progression will be assessed based on IMWG Guidelines
(see Attachment 5). Daratumumab detection on serum immunofixation has been demonstrated in 
subjects treated with 16 mg/kg, and may interfere with the traditional IMWG criteria of negative 
serum IFE for CR or sCR. To mitigate this interference, the sponsor has developed a reflex assay 
that utilizes anti-idiotype antibody to bind daratumumab and confirm its interference on IFE (see 
laboratory manual). For all subjects with VGPR and a negative M-protein by SPEP, reflex IFE 
testing will be performed to confirm the presence of daratumumab on IFE. In addition, for 
subjects who have an SPEP ≤0.2 g/dL and detectable IgG kappa myeloma during the study, 
reflex testing will also be performed to determine whether the para-protein identified on 
SPEP/IFE is monoclonal daratumumab or the subject’s endogenous myeloma protein.
Disease evaluations must be performed on Day 1 of every cycle during the induction phase with 
Dara-CyBorD. Disease evaluation should be performed following ASCT for subjects who 
undergo ASCT, on Day 1 of their first maintenance therapy cycle. During the maintenance phase 
with daratumumab monotherapy, disease evaluation may be done on Day 1 of every other cycle
(approximately every 56 days) or, if there are concerns for relapse, sooner. The scheduled 
disease assessment during any given phase may be done ±3 days of the due date. If treatment is 
delayed for any reason, then the disease evaluations must be performed according to schedule, 
regardless of any changes to the dosing regimen.
Disease evaluations scheduled for treatment days should be collected before study treatment is 
administered.
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Disease evaluations will be performed by a central laboratory (unless otherwise specified) 
according to the Time and Events Schedule until disease progression.  For quantitative Ig, 
M-protein, and IFE measurements in serum and 24-hour urine, the investigator will use results 
provided by the central laboratory. Subjects with positive serum IFE and confirmed 
daratumumab IFE interference, that meet all other clinical criteria for CR or sCR, will be 
considered CR/sCR. If a bone marrow biopsy is performed for suspected CR, suspected sCR, or 
PD, morphology and plasma cell clonality testing will be done at the central laboratory.
9.2.1.
SPEP, UPEP, and FLC Testing
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 per timepoint are required by the 
central laboratory to perform the following tests.
Serum M-protein quantitation by electrophoresis (SPEP), 24-hour urine M-protein quantitation 
by electrophoresis (UPEP), serum immunofixation at Screening and thereafter when a CR or 
sCR is suspected or maintained, urine immunofixation at Screening and thereafter when a CR or 
sCR is suspected or maintained, and a serum free light chain assay are to be performed as 
outlined in the T&E Schedule. Blood and 24-hour urine samples will be collected as specified in 
the Time and Events Schedule until the development of confirmed disease progression. 
After subjects have completed the 12 cycles of maintenance therapy with daratumumab, the 
timing of collection for SPEP and UPEP (and the timing of collection of FLC for subjects with 
light chain multiple myeloma) will change from every 4 weeks to every 12 weeks. Disease 
progression based on 1 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 tests and serum FLC assay will be performed at Screening and thereafter 
when a CR or sCR is suspected (when SPEP or UPEP are 0 or nonquantifiable) or maintained. 
However, for subjects with light chain multiple myeloma, serum FLC assay will be performed 
routinely. 
9.2.2.
Serum Calcium
Blood samples for calculating serum calcium corrected for albumin will be collected and 
analyzed centrally (as specified in the Time and Events Schedules) until the development of 
confirmed disease progression. Development of hypercalcemia (corrected serum calcium 
>11.5 mg/dL or 2.8 mM/L) can indicate disease progression or relapse if it is not attributable to 
any other cause (see disease response criteria). Calcium binds to albumin and only the unbound 
(free) calcium is biologically active; therefore, the serum calcium level must be adjusted for 
abnormal albumin levels (“corrected serum calcium”). The formula for adjustment is presented 
in Attachment 4.
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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 to be hypercalcemic for this study.
Blood samples for β2 microglobulin and albumin are to be collected at Screening, and will be 
analyzed by the central laboratory.
9.2.3.
Bone Marrow Examination
Bone marrow aspirate or biopsy will be performed at Screening for clinical characterization 
(morphology, immunohistochemistry [IHC], or immunofluorescence or flow cytometry, and 
cytogenetics), to perform molecular subtyping to monitor daratumumab activity in high-risk 
molecular subgroups. Good quality slides are required for morphological examination to 
determine plasma cell percentage in the bone marrow. Assessment by flow cytometry alone is 
not sufficient. Bone marrow examination for disease assessment will be performed centrally, and 
a portion of the bone marrow aspirate will be used for molecular subtyping. A reasonable attempt 
to obtain a fresh bone marrow aspirate is required at screening. Additional bone marrow 
aspirates or biopsies (or both) will be performed to confirm sCR, CR, or disease progression. 
9.2.4.
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 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 (MRI) or low-dose CT scan are acceptable methods 
for evaluation of bone disease, and may be included at the discretion of the investigator. If a 
radionuclide bone scan was used at Screening in addition to the complete skeletal survey, then 
both methods must be used to document disease status. These tests must be performed at the 
same time. However, a radionuclide bone scan does not replace a complete skeletal survey.
Sometimes subjects 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 more subtle, repeat 
imaging may be performed in 1 to 3 weeks per investigator discretion.
9.2.5.
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 
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contraindication to the use of intravenous contrast. Positron emission tomography scan 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. Assessment of measurable sites of extramedullary disease will be performed and 
evaluated locally every 4 weeks (by physical examination) 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. If assessment can only be performed 
radiologically, then evaluation of extramedullary plasmacytomas may be done every 12 weeks.
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. 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.
Safety Evaluations
Safety evaluations will include adverse event monitoring, clinical laboratory parameters 
(hematology and serum chemistry), pregnancy testing, electrocardiogram monitoring, vital sign 
measurements, physical examinations, and ECOG performance status. 
Since daratumumab interferes with the IAT, all subjects will receive a subject identification 
wallet card for the study that includes the blood profile (ABO, Rh, and IAT) determined before 
the first infusion of daratumumab along with information on the IAT interference for healthcare 
providers/blood banks.
Details regarding the Data Review Committee are provided in Section 11.6.
9.3.1.
Adverse Events
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF. Any clinically significant abnormalities persisting at the end of the 
study/early withdrawal will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule: adverse event monitoring, clinical laboratory 
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parameters (hematology and serum chemistry), pregnancy testing, electrocardiogram monitoring, 
vital sign measurements, physical examinations, and ECOG performance status.
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events
(AEs) are to be collected on the AE forms of the CRF from time of consent through 30 days after 
last daratumumab infusion. During the subsequent follow-up period, serious SAEs and AEs are 
to be reported if the investigator considers them to be causally related to daratumumab. Adverse 
events will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
9.3.2.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF. The laboratory reports must be filed 
with the source documents.
Tests being performed by the central laboratory include the hematology and chemistry tests 
listed below and serum pregnancy testing. Tests being performed by the central laboratory 
include, but are not limited to, the following:

Hematology Panel
-hemoglobin
-hematocrit
-RBC count
-platelet count
-white blood cell (WBC) count with differential
Note: A WBC evaluation may include any abnormal cells, which will then be reported by
the laboratory. A RBC evaluation may include abnormalities in the RBC count, RBC
parameters, or RBC morphology, which will then be reported by the laboratory.
In addition, any other abnormal cells in a blood smear will also be reported.

Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-lactic acid dehydrogenase (LDH)
-chloride
-uric acid
-bicarbonate
-calcium
-blood urea nitrogen (BUN)
- phosphate
-creatinine
-albumin
-creatinine clearance
-total protein
-glucose
-magnesium
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)
-total bilirubin
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Serum Pregnancy Testing [for women of childbearing potential only] at screening.
Serology (HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody) at screening.
Hepatitis C viral load testing by hepatitis C RNA PCR – for reactivation of HCV for any subjects 
who had prior, treated hepatitis C and no detectable circulating HCV at study entry.
Results of local hematology and chemistry tests must be evaluated before Day 1 of each cycle to 
guide treatment decisions, but do not need to be reported in the eCRF unless they result in a dose 
delay.
For women of childbearing potential, pregnancy testing (urine test) is to be done at the local 
laboratory within 24 hours of C1D1, and throughout the induction and maintenance phases as 
listed in the Time and Events Schedule.
9.3.3.
Electrocardiogram (ECG) 
During the collection of the screening ECG, 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 time point as ECG 
recording, the procedures should be performed in the following order: ECG(s), vital signs, blood 
draw.
9.3.4.
Vital Signs 
Oral temperature, pulse/heart rate, respiratory rate, blood pressure will be taken at the times 
shown in the Time and Events Schedule.
Blood pressure and pulse/heart rate measurements will be assessed with the subject in a seated
position with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 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).
9.3.5.
Physical Examination
A physical examination is to be done on Day 1 of each induction and maintenance therapy cycle.
9.4.
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Time and Events Schedule 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.
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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 assessments 
at the completion of the maintenance phase of therapy, including the end-of-treatment visit.
Subjects who prematurely discontinue study treatment for any reason before completion of the 
maintenance treatment phase will not be considered to have completed the study.
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if they have to discontinue
treatment before the end of the treatment regimen.
A subject’s study treatment must be discontinued if:

The investigator believes that for safety or tolerability reasons (eg, adverse event) it is in the
best interest of the subject to discontinue study treatment

The subject becomes pregnant

The subject (or the subject’s legally acceptable representative) withdraws consent for
administration of study treatment

The subject initiates treatment with a prohibited medication

The subject received concurrent (non-protocol) treatment for multiple myeloma

A subject with a history of HCV who completed treatment at least 6 months prior to 
screening, who does not agree to undergo regular assessment for HCV reactivation during 
their participation in the study

The subject experiences unacceptable toxicity, including reactions
described in
Section 6.1.5, Management of IRRs

The subject cannot tolerate bortezomib, cyclophosphamide or corticosteroids despite the 
appropriate dose reductions

The subject’s daratumumab dose is held for more than 28 days during induction cycles or if 
≥3 consecutive planned doses are missed for reasons other than toxicity

The subject experiences disease progression. Relapse from CR is not considered as disease
progression.
If a subject discontinues study treatment for any reason before the end of the
induction/consolidation phase or maintenance phase, end of treatment assessments should be 
obtained and post-treatment follow-up scheduled assessments should be continued through
36 months after the start of induction therapy.
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The primary reason for discontinuation of study treatment is to be recorded in the CRF. If study 
treatment is discontinued for a reason other than disease progression, then disease evaluations 
will continue to be performed as specified in the Time and Events Schedule.
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

Had a history of HCV and completed treatment at least 6 months prior to screening 
but test positive for HCV at any time during the regular assessments

Death

Sponsor terminates the study
If a subject withdraws from the study before the end of the induction or consolidation phase, end 
of treatment assessments should be obtained.
If a subject is 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 before completing the study, the reason for withdrawal is to be
documented in the CRF and in the source document. Study drug assigned to the withdrawn
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
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
Analysis of primary and secondary efficacy variables will be based on the response-evaluable 
population, which includes all enrolled subjects who have measurable disease, receive at least 1 
dose of study treatment, and have at least 1 efficacy evaluation assessment. All safety analyses 
will be based on the safety analysis set, which includes all enrolled subjects who receive at least 
1 dose of study treatment.
Continuous variables will be summarized using descriptive statistics such as mean, standard 
deviation, and range. Categorical variables will be summarized using frequency tables. For time-
to-event variables, the Kaplan-Meier method will be used for descriptive summaries.
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11.2.
Sample Size Determination
The historical CR+VGPR rate after 4 cycles of CyBorD induction therapy is 60% in previously 
untreated multiple myeloma subjects.17 Thirty-three (33) enrolled subjects will provide 
80% power at a 5% 1-sided significance level to detect an absolute 20% increase over 60% with 
Dara-CyBorD.
The historical CR+VGPR rate after 4 cycles of CyBorD induction therapy is 30% in previously 
relapsed multiple myeloma subjects. 20 Thirty-five (35) enrolled subjects will provide 80% power 
at a 5% 1-sided significance level to detect an absolute 20% increase over 30% with Dara-
CyBorD.
With the planned enrollment of 100 subjects, with a minimum of 40 newly diagnosed multiple 
myeloma subjects, at least 80% power will be achieved to detect an absolute 20% increase in the 
untreated cohort at the 5% 1-sided significance level. In Amendment 2, enrollment of subjects in 
the relapsed cohort is closed and expected not to exceed 15 subjects. No inferential statistics will 
be performed for the relapsed cohort.
11.3.
Efficacy Analyses 
The primary analysis will be performed after all enrolled subjects have completed 4 cycles of 
induction therapy disease evaluation or have been discontinued from study treatment by this time 
point. A final data cutoff and analysis, to update secondary endpoints and safety, will occur at 
the end of study when all subjects have completed follow-up at 36 months after the start of 
induction therapy, or until death or withdrawal of consent for study participation, whichever 
occurs first.
Response to study treatment and progressive disease will be evaluated by a validated computer 
algorithm to calculate IMWG response. The primary endpoint, rate of CR+VGPR achieved after 
4 cycles of induction therapy, for newly diagnosed and relapsed subjects will be tabulated. The 
proportion of subjects will be analyzed using a normal approximation to the binomial 
distribution comparing the observed proportion to a reference of 0.60 for previously untreated
subjects.
The CR+VGPR rate and its 2-sided 95% confidence interval will be provided. Other binary 
endpoints, including overall CR, sCR, ORR, VGPR or better rate following induction, 
consolidation, and maintenance will be analyzed similarly. 
Time-to-event efficacy endpoints, including duration of CR, sCR, time to progression, PFS, and 
OS, will be descriptively summarized using the Kaplan-Meier method.
11.4.
Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). 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 will be 
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included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. In addition, 
comparisons between treatment groups will be provided if appropriate.
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. These will be provided using the same formats as those used for 
adverse events.
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 time point. Changes from 
baseline results will be presented in pre- versus posttreatment cross-tabulations (with classes for 
below, within, and above normal ranges). A listing of subjects with any laboratory results outside 
the reference ranges will be provided. A listing of subjects with any markedly abnormal 
laboratory results will also be provided.
Parameters with predefined NCI-CTCAE version 4.03 toxicity grades will be summarized. 
Change from baseline to the worst adverse event grade experienced by the subject during the 
study will be provided as shift tables.
Electrocardiogram data will be summarized by vital signs parameters (temperature, pulse/heart 
rate and blood pressure (systolic and diastolic). Descriptive statistics will be calculated at 
baseline and for observed values and changes from baseline at each scheduled time point. 
Frequency tabulations of the abnormalities will be made.
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 
time point. The percentage of subjects with values beyond clinically important limits will be 
summarized.
11.5.
Interim Analysis
Three interim safety analyses are planned. The first interim safety analysis will occur after at 
least 20 subjects are treated for at least 1 cycle of study treatment (or discontinue before the end 
of Cycle 1). The second interim safety analysis will occur after at least 50 subjects complete 
Cycle 1 of study treatment (or discontinue before the end of Cycle 1) with a focus on infusion-
related reactions during Cycle 1. The third interim safety analysis will occur after at least 50 
subjects are treated for at least 4 cycles (or discontinue before the end of Cycle 4).
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A Data Review Committee will be established to review the interim data and formulate 
recommended decisions/actions in accordance with the objectives of the interim analysis (see 
Section 11.6). 
11.6.
Data Review Committee
An internal Data Review Committee will be established to monitor data on an ongoing basis to 
ensure the continuing safety of the subjects enrolled in the study. The committee will meet 
periodically to review interim safety data and will also perform the predetermined interim safety 
analysis as detailed in Section 11.5, Interim Analysis. After the review, the committee will make 
recommendations regarding the continuation of the study. The details will be provided in a 
separate committee charter.
The Data Review Committee will consist of at least 2 medical experts in the relevant therapeutic 
area and at least 1 statistician. The committee responsibilities, authorities, and procedures will be 
documented in its charter.
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 per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3, All Adverse Events, for time of last adverse event recording).
A list of Anticipated Events for daratumumab is included as Attachment 6.
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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 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
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 Brochure, and 
not included in the list of Anticipated Events included in this protocol (see Attachment 6).
For cyclophosphamide, bortezomib, and corticosteroids, the expectedness of an adverse event 
will be determined by whether or not it is listed in the respective prescribing information.
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.
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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).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
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

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. 
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12.3.
Procedures
12.3.1.
All Adverse Events
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 last dose of 
study treatment. Serious adverse events, including those spontaneously reported to the 
investigator within 30 days after the last dose of study treatment, must be reported using the 
Serious Adverse Event Form. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol.
During the stem cell mobilization and transplantation procedures (in eligible subjects), adverse 
events related to stem cell mobilization and transplantation do not need to be reported in the 
CRF; however, any toxicity related to study treatment will continue to be reported. 
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.
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
treatment, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). 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). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
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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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, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made 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 infusion of daratumumab, 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.
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12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious
adverse events and must be reported using the Serious Adverse Event Form. Any subject who
becomes pregnant during the study must be promptly withdrawn from the study and discontinue
further study treatment. The subject should be referred to a physician experienced in teratology
for evaluation and advice. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported as noted above. Follow-up information regarding 
the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
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 
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.
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Daratumumab
The daratumumab supplied for this study is a colorless to pale yellow liquid and sterile 
concentrate of 20 mg/mL as a liquid vial. It will be manufactured and provided under the 
responsibility of the sponsor. Refer to the Investigator’s Brochure for a list of excipients.
14.2.
Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 
20 mg/mL.
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
Daratumumab product must be stored in the original carton in a refrigerator at controlled 
temperatures ranging from 2°C to 8°C. Study drug must not be utilized after the expiry date 
printed on the label. The daratumumab product must be protected from light and must not be 
frozen. Daratumumab does not contain preservatives; therefore, any unused portion remaining in 
the vial must be discarded.
Refer to the pharmacy manual/study site investigational product and procedures manual 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, or used returned study drug for destruction, will be documented on the drug return form. 
When the study site is an authorized destruction unit and study drug supplies are destroyed on-
site, this must also be documented on the drug return form.
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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.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator’s Brochure for daratumumab

Study site investigational product and procedures manual

Laboratory manual

NCI-CTCAE Version 4.03

Interactive Web Response System (IWRS) Manual

Electronic Data Capture (eDC) Manual
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Based on the potential infusion reactions associated with administration of daratumumab, 
guidelines 
for
prevention 
and 
management 
of 
infusion 
reactions
are 
provided 
(see Sections 6.1.4 and 6.1.5). Based on the mode of action of daratumumab, a potential risk 
could be infection; therefore the protocol requires the review of hematological laboratory results 
prior to daratumumab infusion. CD38 is distributed in erythrocytes and platelets. A significant 
reduction of platelets was reported in an animal study. In a human clinical study (Study 
GEN501), thrombocytopenia was also reported. However, safety laboratory monitoring did not 
show a clinically meaningful reduction of platelets. No bleeding events were observed. Anemia 
was also reported in Study GEN501. Free hemoglobin was mildly elevated, but other parameters 
did not support hemolysis. 
Routine safety laboratory measurement of RBCs and platelets will be closely monitored in this 
study.
All subjects will be receiving standard of care (CyBorD) for multiple myeloma in this study.
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 
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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.
The total blood volume to be collected is considered to be acceptable for subjects participating in
a cancer clinical study and reasonable (eg, less than the standard blood donation 
[500 mL over 60 days]) over the time frame of the study.
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.
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 
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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 
study

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.
16.2.3.
Informed Consent
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 
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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. 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, which includes permission to obtain 
information about his or her survival status.
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.
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.
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.
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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.
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.
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 per 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 per local 
regulations) by the chairman or authorized designee.
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
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
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. In cases where the subject is not randomized into the study, the date seen and 
date of birth 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.
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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 following data will be recorded directly into the CRF and will be considered source data:

Race

History of nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of e-
cigarettes), cigars, chewing tobacco, patch, gum
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 or

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 eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in 
the CRF. Data in this system may be considered source documentation. 
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17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.  
All CRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the CRF are accurate 
and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
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 CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
CRF in English. The CRF 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 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.
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, 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 CRF 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 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.
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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 use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. 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. 
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Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. 
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last scheduled study assessment shown in the 
Time and Events Schedule for the last subject participating in the study. 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.
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
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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 exploratory research data, generated as a result of 
this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. 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 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 
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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 12 months of the availability of the final data (tables, 
listings, graphs), 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 Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
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.
Benboubker L, Dimopoulos MA, Dispenzieri A, et al for the FIRST Trial Team. Lenalidomide and 
dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014; 371:906-917.
2.
Chapuy C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility 
testing. Transfusion 2015;55:1545-1554.
3.
de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal 
antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol 2011;186:1840-
1848.
4.
Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. 
Leukemia 2006;20:1467–1473.
5.
Girnius SK, Lee S, Kambhampati S, et al. A Phase II trial of weekly bortezomib and dexamethasone in 
veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell 
transplantation. Brit J Haematol 2015;169;1:36-43.
6.
Harousseau JL, Attal M,  Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus 
doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly 
diagnosed multiple myeloma: Results of the IFM 2005-01 Phase III trial. J Clin Oncol 2010; 28:4621-4629.
7.
Kropff M, Bisping G, Schuck E, et al.  Bortezomib in combination with intermediate-dose dexamethasone and 
continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Brit J Haematol 2007;138:330-
337.
8.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple 
myeloma. Leukemia 2009;23:3-9.
9.
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple 
myeloma. N Engl J Med 2015; 373:1207-1219.
10.
Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory 
multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. The Lancet 2016;387:1551-1560.
11.
Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in 
patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. The Lancet Oncol 
2011;12:431-440.
12.
Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor 
activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 2015;7:311-321.
13.
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046-1060.
14.
Prescribing Information for Cyclophosphamide. Bayer Corporation. 2013. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdf. Accessed 07 June 
2016.
15.
Rajkumar SV, Jacobus S, Callander NS, et al.  Lenalidomide plus high-dose dexamethasone versus 
lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-
label randomised controlled trial. The Lancet Oncol 2010;11:29-37.
16.
Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and 
prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 2008;26:4777-4783.
17.
Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone (CyBorD) 
induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia
2009;23:1337-1341.
18.
Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with 
CyBorD in newly diagnosed multiple myeloma. Blood 2010; 115:3416-3417.
19.
Reeder CB, Reece DE, Kukreti V, et al. Long-term survival with cyclophosphamide, bortezomib and 
dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Brit J 
Haematol 2014;167:563-565.
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20.
Usmani SZ, Weiss B, Bahlis NJ, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily 
pretreated relapsed or refractory multiple myeloma. ASH Annual Meeting presentation, Dec 5-8, 2015.
21.
van der Veer MS, de Weers M, van Kessel B, et al. The therapeutic human CD38 antibody daratumumab 
improves the anti-myeloma effect of newly emerging multi-drug therapies. Blood Cancer Journal 2011;1, e41; 
doi:10.1038/bcj.2011.42; published online 28 October 2011.
22.
van Rhee F, Szymonifka J, Anaissie E, et al. Total Therapy 3 for multiple myeloma: prognostic implications of 
cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, 
and dexamethasone, relevant to all phases of therapy. Blood 2010; 116: 1220–1227.
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Attachment 1:  Calculated and Measured Creatinine Clearance
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault 
formula:
CrCl = (140 - age [in years]) x weight (kg)
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L), 
use the following formula to convert SI units to conventional (mg/dL) units (Manual of 
Laboratory & Diagnostic Tests, 2004):
•
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL)
Formula to measure creatinine clearance:
CrCl = UCr x Uvol
PCr x Tmin
Corrected CrCl = CrCl  x 1.73
BSA
Notes: UCr, Urine creatinine concentration; Uvol, Urine volume from 24hrs collection; PCr, plasma 
creatinine concentration; Tmin, collection time in minutes (24h x 60min); BSA, body surface area.
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Attachment 2: ECOG Performance Status Scale
Grade ECOG 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 selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
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Attachment 3:  Asthma Guidelines
Source: https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf Accessed 10 May 2016.
Components of
Severity
Classification of Asthma Severity
Intermittent
Persistent
Mild
Moderate
Severe
0-4
yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Impairment
Normal 
FEV1/FVC :
8-19 yr 85%
20-39 yr 80%
40-59 yr 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 time per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% 
Normal
N/A
60-80%
75-80%
60-80% 
Reduced 5%
N/A
< 60%
< 75%
< 60% 
Reduced
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 patients 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
oral 
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 4 or 5 
and
consider 
short 
course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: 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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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])
Source: http://www.globalrph.com/calcium.htm
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Attachment 5: IMWG Guidelines
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Attachment 6:  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: 

Amyloidosis

Anaemia

Bleeding

Bone diseases (ie, spinal cord compression, osteolytic lesions, fracture)

Hypercalcaemia

Hyperuricemia

Hyperviscosity syndrome

Infection (ie, pneumonia, herpes zoster, meningitis, septicaemia, endocarditis, osteomyelitis, 
cellulitis, pyelonephritis, urinary tract infection, haemophilus infections)

Neutropenia

Plasma cell myeloma recurrent 

Renal failure or insufficiency

Thrombocytopenia
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3, All Adverse Events. Any event that meets serious adverse event criteria will be 
reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities. However if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
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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INVESTIGATOR AGREEMENT
NCT02951819

SAP_001.pdf: 
1
Approved Date: 12 February 2018
Janssen Research & Development 
Statistical Analysis Plan
Daratumumab plus Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) 
in Previously Untreated and Relapsed Subjects with Multiple Myeloma  
Protocol 54767414MMY2012; Phase 2
JNJ-54767414  (daratumumab)
Authors: 
Date: 12 February 2018
Status:
Approved
Date:
12 February 2018
Prepared by:
Janssen Research & Development
Document No.:
EDMS-ERI-157307205
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.1.1.
Primary Objective ......................................................................................................................... 5
1.1.2.
Secondary Objectives................................................................................................................... 5
1.1.3.
Exploratory Objective.................................................................................................................... 5
1.2.
Trial Design ...................................................................................................................................... 5
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 6
1.4.
Sample Size Justification ................................................................................................................. 6
1.5.
Randomization and Blinding ............................................................................................................ 7
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 7
2.1.
Visit Windows................................................................................................................................... 7
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 7
2.3.
Analysis Sets.................................................................................................................................... 7
2.4.
Definition of Subgroups.................................................................................................................... 8
2.5.
Study Day and Relative Day ............................................................................................................ 9
2.6.
Baseline Measurement .................................................................................................................... 9
2.7.
Unique Lab value ............................................................................................................................. 9
2.8.
Imputation of Missing/Partial Dates ............................................................................................... 10
2.8.1.
Missing/Partial Adverse Event Onset Date................................................................................. 10
2.8.2.
Missing/Partial Adverse Event End Date.................................................................................... 10
2.8.3.
Partial Multiple Myeloma Diagnosis Date................................................................................... 11
2.8.4.
Partial Concomitant Medication Start/End Date ......................................................................... 11
2.9.
General Analysis Method............................................................................................................... 11
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE ............................................................... 12
3.1.
Interim Analysis.............................................................................................................................. 12
3.2.
Data Review Committee ................................................................................................................ 12
4.
SUBJECT INFORMATION................................................................................................................ 12
4.1.
Demographics and Baseline Characteristics ................................................................................. 12
4.2.
Disposition Information................................................................................................................... 13
4.3.
Extent of Exposure......................................................................................................................... 13
4.4.
Protocol Deviations ........................................................................................................................ 14
4.5.
Pre-study and Concomitant Therapies .......................................................................................... 14
5.
EFFICACY ......................................................................................................................................... 14
5.1.
Analysis Specifications................................................................................................................... 14
5.1.1.
Level of Significance................................................................................................................... 14
5.1.2.
Data Handling Rules................................................................................................................... 14
5.2.
Primary Efficacy Endpoint.............................................................................................................. 15
5.2.1.
Definition..................................................................................................................................... 15
5.2.2.
Analysis Methods........................................................................................................................ 15
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 15
5.3.1.
Progression-Free Survival .......................................................................................................... 15
5.3.1.1.
Definition.................................................................................................................................. 15
5.3.1.2.
Analysis Methods .................................................................................................................... 16
5.3.2.
Time to Disease Progression (TTP) ........................................................................................... 16
5.3.2.1.
Definition.................................................................................................................................. 16
5.3.2.2.
Analysis Methods .................................................................................................................... 16
5.3.3.
Overall Survival (OS).................................................................................................................. 17
5.3.3.1.
Definition.................................................................................................................................. 17
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5.3.3.2.
Analysis Methods .................................................................................................................... 17
5.3.4.
Overall Response Rate (ORR) ................................................................................................... 17
5.3.4.1.
Definition.................................................................................................................................. 17
5.3.4.2.
Analysis Methods .................................................................................................................... 17
5.3.5.
Duration of Response (DOR) ..................................................................................................... 17
5.3.5.1.
Definition.................................................................................................................................. 17
5.3.5.2.
Analysis Methods .................................................................................................................... 18
5.3.6.
Time to Response....................................................................................................................... 18
5.3.6.1.
Definitions................................................................................................................................ 18
5.3.6.2.
Analysis Methods .................................................................................................................... 18
5.4.
Subgroup Analyses........................................................................................................................ 18
6.
SAFETY............................................................................................................................................. 19
6.1.
Adverse Events .............................................................................................................................. 19
6.2.
Clinical Laboratory Tests................................................................................................................ 20
6.3.
Vital Signs and Physical Examination............................................................................................ 21
6.4.
ECOG Performance Status............................................................................................................ 22
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ABBREVIATIONS
AE
Adverse Event
ASCT
Autologous Stem Cell Transplantation
C1D1
Cycle 1 Day 1
C1D2
Cycle 1 Day 2
CTC
Common Toxicity Criteria
Dara-CyBorD
Daratumumab Plus Cyclophosphamide, Bortezomib And Dexamethasone 
DRC
Data Review Committee
DPS
Data Presentation Specification
ECG
Electrocardiogram 
eCRF
Electronic Case Report Form
HDT
High-Dose Chemotherapy
IMWG
International Myeloma Working Group
ISS 
International Staging System 
MedDRA
Medical Dictionary For Regulatory Activities
NCI-CTCAE
National Cancer Institute Common Terminology Criteria For Adverse Events
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
TEAEs
Treatment-Emergent Adverse Events
ULN
Upper Limit Normal
WHO
World Health Organization
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the planned analysis for study
protocol 54767414MMY2012:
Daratumumab plus Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) in 
Previously Untreated and Relapsed Subjects with Multiple Myeloma.
1.1.
Trial Objectives
1.1.1.
Primary Objective
The primary objective is to evaluate complete response + very good partial response 
(CR+VGPR) rate following 4 cycles of induction therapy of daratumumab plus CyBorD (Dara-
CyBorD), in previously untreated subjects, and in relapsed subjects with multiple myeloma, as 
defined by the International Myeloma Working Group (IMWG) criteria. 
1.1.2.
Secondary Objectives
The secondary objectives are to evaluate, in previously untreated subjects and in relapsed 
subjects with multiple myeloma:

Overall response rate (ORR including CR+VGPR+partial response [PR]) 

Following 4 cycles of Dara-CyBorD induction therapy

At the end of 4 to 8 cycles of Dara-CyBorD induction therapy

Post-transplant (in subjects who undergo high dose therapy and autologous stem cell 
transplantation)

At the end of 12 cycles of daratumumab maintenance therapy

Time to VGPR or better

Time to PR or better

Progression-free survival (PFS) rate: at 1 year and 3 years

Overall survival (OS) rate: at 1 year and 3 years

Safety and tolerability of Dara-CyBorD 

Safety profile of split-dose initial infusions of daratumumab administered as 8 mg/kg on 
Cycle 1 Day 1 (C1D1) and Cycle 1 Day 2 (C1D2).
1.1.3.
Exploratory Objective
An exploratory objective is to evaluate the clinical efficacy of Dara-CyBorD in molecular 
subgroups, including: del17p, del13, t(4;14), t(11;14), t(14;16).
1.2.
Trial Design
This is a multicenter, single-arm, Phase 2 study, evaluating the combination of Dara-CyBorD in 
subjects with previously untreated multiple myeloma irrespective of eligibility for HDT and 
ASCT and subjects with relapsed multiple myeloma following one prior line of therapy.  
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JNJ-54767414  (daratumumab)                         
                                                                 
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Approximately 100 subjects will be enrolled into this study with at least 40 previously untreated 
multiple myeloma subjects. Due to slow enrollment of subjects with relapsed multiple myeloma 
following one prior line of therapy, this cohort is closed to enrollment in Amendment 2 of the 
protocol.
Subjects will be assigned to receive Dara-CyBorD as induction on a 28-day cycle length. All 
subjects will receive 4 to 8 cycles of oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 
22; subcutaneous (SC) bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV 
dexamethasone 40 mg weekly. Subjects will concurrently receive daratumumab on 28-day cycles
(8 mg/kg IV on C1D1, C1D2;16 mg/kg IV on Cycle 1, Days 8, 15, 22; Cycle 2, Days 1, 8, 15, 
22; Cycles 3-6, Days 1,15; Cycles 7-8, Day 1; Maintenance, Day 1 for 12 cycles).
Treatment phases consist of induction therapy with 4 to 8 cycles of Dara-CyBorD, consolidation 
therapy with HDT/ASCT for eligible subjects, and maintenance therapy. Following induction 
and/or consolidation therapy with ASCT, subjects will receive maintenance therapy with 
daratumumab alone for twelve 28-day cycles or until disease progression (whichever occurs 
first). Maintenance therapy for subjects who have ASCT should begin approximately 90 days 
after ASCT. Follow-up for all subjects will continue up until 36 months after the start of 
induction therapy (Cycle 1 Day 1). 
Throughout the study, subjects will be monitored closely for adverse events, laboratory 
abnormalities, and clinical response, as specified in the Time and Events Schedule of the 
protocol. The National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE Version 4.03) will be used to grade toxicity throughout the study.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that CR+VGPR rate following 4 cycles of induction 
therapy of Dara-CyBorD in previously untreated subjects is higher than 60%, and in relapsed 
subjects is higher than 30%, as defined by the IMWG criteria. The hypotheses are as follow:
For previously untreated subjects:
H0: p  ≤  0.6       vs      HA : p  > 0.8
For relapsed subjects:
H0: p  ≤  0.3       vs      HA : p  > 0.5  ,
where p is the proportion of subjects with CR+VGPR.
1.4.
Sample Size Justification
The historical CR+VGPR rate after 4 cycles of CyBorD induction therapy is 60% in previously 
untreated multiple myeloma subjects. Thirty-three (33) enrolled subjects will provide 80% power 
at a 5% 1-sided significance level to detect an absolute 20% increase over 60% with Dara-
CyBorD.
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JNJ-54767414  (daratumumab)                         
                                                                 
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The historical CR+VGPR rate after 4 cycles of CyBorD induction therapy is 30% in previously 
relapsed multiple myeloma subjects. Thirty-five (35) enrolled subjects will provide 80% power 
at a 5% 1-sided significance level to detect an absolute 20% increase over 30% with Dara-
CyBorD.
With the planned enrollment of 100 subjects, with a minimum of 40 newly diagnosed multiple 
myeloma subjects, at least 80% power will be achieved to detect an absolute 20% increase in the 
untreated cohort at the 5% 1-sided significance level. In Amendment 2 of the study protocol, 
enrollment of subjects in the relapsed cohort is closed and expected not to exceed 15 subjects. 
No inferential statistics will be performed for the relapsed cohort.
1.5.
Randomization and Blinding
This is a single-arm study where all enrolled subjects will be treated with the same treatment 
combination of Dara-CyBorD.  There is no randomization and unblinding is not required.
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 particular cycle is 
defined as the date of the first scheduled dose of any component of the study treatment, and
the end date of a cycle is the start date of the next cycle minus 1. For the last cycle, the end
date is defined as the end of treatment visit date or the minimum of last study treatment
date plus 30 days or subsequent anti-myeloma 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.
2.2.
Pooling Algorithm for Analysis Centers
Data from participating centers in the study will be pooled together for analyses purpose.
2.3.
Analysis Sets
The following analysis sets are defined.

Full analysis set (FAS): is defined as enrolled subjects who have provided informed consent 
and met the study eligibility criteria.  Analyses of demographics, baseline characteristic and 
time-to-event variables (e.g., PFS and OS) will be based on this population.

Safety analysis set: is defined as enrolled subjects who received at least 1 dose (partial or 
complete)
of study treatment
(Daratumumab, Cyclophosphamide, Bortezomib or
Dexamethasone). This population will be used for all safety related analyses.
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Response-evaluable set: is defined as subjects who have measurable disease at baseline or 
screening visit. In addition, subjects must have received at least 1 administration of study 
treatment and have at least 1 post baseline disease assessment. Measurable disease is defined 
as follows: 

Serum M-protein level ≥1.0 g/dL or urine M protein level ≥200 mg/24 hours; or

Immunoglobulins A, D, E or M multiple myeloma: serum M-protein level ≥0.5 g/dL 
or urine M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in the urine: serum Ig FLC 
≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
Analyses of the primary endpoint of CR+VGPR response and secondary response-related 
endpoints such as ORR and duration of response will be based on this population. 
2.4.
Definition of Subgroups  
The following subgroup analyses may be performed for the newly diagnosed patients for
the primary endpoint, PFS, and OS, depending on the number of subjects in each subgroup as 
shown in Table 1.
Table 1: Subgroup Analyses of Efficacy Endpoints
Subgroup 
Definition 
Sex 
Male, Female 
Age 
<65 years, ≥65 years
Type of MM 
IgG, Non-IgG 
ECOG performance score 
0, ≥1 
Cytogeneticsa
high risk vs. standard risk 
a Includes: del17p, del13, t(4;14), t(14;16), and t(11;14).  High risk and 
standard risk defined below.
For each of the del17p, del13, t(4;14), t(14:16) and t(11;14), the cytogenetic abnormality finding 
for a subject can be classified into the following 3 groups:

Yes (abnormality): if there is any abnormality finding from FISH testing by bone marrow 
aspirate

No: there is no abnormality finding

Not done: the testing is not done.
For cytogenetics profile, two cytogenetic risk categories are defined as:

High risk: An abnormality finding in any of del17p, del13, t(4;14), and t(14;16).  

Standard risk: No abnormality findings in all of del17p, del13, t(4;14) and t(14;16).
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JNJ-54767414  (daratumumab)                         
                                                                 
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Additionally, patients who have consolidation therapy with HDT/ASCT after 4 to 8 cycles 
induction therapy of Dara-CyBorD is considered as a separate ASCT subgroup for analysis 
purpose.  
Given that enrollment in the relapsed group is stopped early, subgroup analyses will not be
performed for the relapsed group.
2.5.
Study Day and Relative Day
Study treatment refers to Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone
(Dara-CyBorD). Study drug refers to Daratumumab.  
Study treatment dosing date is the date on which a subject receives study treatment (partial or 
complete) and will be recorded in the study treatment administration dataset.
The first study treatment date is defined as the earliest date of non-zero dose of the following 
administration: Daratumumab, Cyclophosphamide, Bortezomib or Dexamethasone. The last 
study treatment date is defined as the latest date of non-zero dose of the 4 treatment 
administrations. 
Study Day 1 or Day 1 refers to the start of the first study treatment administration date. All 
efficacy and safety assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date < date of Day 1
A subject is considered as treated in a cycle if he/she receives any nonzero dose of 
Daratumumab, Cyclophosphamide, Bortezomib or Dexamethasone in that cycle.
2.6.
Baseline Measurement
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the 
first study treatment administration (including time if time is available, with exception of 
parameters associated with disease-related efficacy assessment such as SPEP, UPEP, kappa, 
lambda, kappa/lambda ratio, serum calcium, and albumin).
2.7.
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.
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JNJ-54767414  (daratumumab)                         
                                                                 
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2.8.
Imputation of Missing/Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations. For analysis and reporting purpose, missing or partial dates in adverse event (AE 
onset date; AE end date), and concomitant therapies (start date; end date) will be imputed.
Additional imputation rules may be specified in the data presentation specification (DPS).    
2.8.1.
Missing/Partial Adverse Event Onset Date
If the onset date of an adverse event is missing completely or partially, the following imputation 
rules will be used:

When month and year are present and the day is missing,

If the onset month and year are the same as the month and year of first study 
treatment, the day of first study treatment is imputed. If the imputed start date is later 
than end date, the day-component of the AE end date (possibly imputed) is imputed

If the onset month and year are not the same as the month and year of first study 
treatment, then the first day of the month is imputed

When only a year is present or no components of the onset date are present,

If the onset year is the same as the year of first study treatment. If AE end date is 
available and is prior to first study treatment, the day and month of AE end date are 
imputed. Otherwise, the day and month of first study treatment are imputed

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 date of first study treatment is imputed as the 
onset date.
No imputation will be done for partial or missing AE onset time.
2.8.2.
Missing/Partial Adverse Event End Date
If the end date of an adverse event is missing completely or partially, the following imputation 
rules will be used:

If month and year are present and the day of the month is missing, the last day of the month 
is imputed.

If only a year is present, the 31st of December is used.
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JNJ-54767414  (daratumumab)                         
                                                                 
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
If the imputed date is later than the date of death (if available), the date of death will be used 
as the imputed date instead.
No imputation will be done for partial or missing AE end time.
2.8.3.
Partial Multiple Myeloma Diagnosis Date
For partial date of original multiple myeloma diagnosis, the following imputation rules will apply:

If only the day is missing, set day=15 and pick minimum of imputed date, date of collection 
and date of randomization.

If both the day and month are missing, set to January 1 and pick minimum of imputed date, 
date of collection and date of randomization.

If year is missing, no imputation will be applied.
2.8.4.
Partial Concomitant Medication Start/End Date
In case of partially missing concomitant medication start/end dates, the following imputation 
rules will be applied. If the date is completely missing, no imputation will be performed.

If only the day is missing, the 15th day of the month will be used

If both the day and month are missing, the 30th of June will be used
If the medication was taken prior to study start, and the imputed start date is after first treatment 
date, further adjust the imputed start date as the day prior to first dosing date; if the medication 
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 end date so that it 
is on or after first dosing date.
2.9.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as mean, 
standard deviation (SD), median and range (maximum and minimum). Categorical variables will 
be summarized using frequency and percentage.  For time-to-event variables including PFS, OS, 
etc., Kaplan-Meier method will be used for descriptive summaries and KM plots.
Summary tabulations for baseline characteristics, safety parameters including AEs and lab will
be presented for newly diagnosed subjects, relapsed subjects and all subjects combined as side-
by-side columns.  For efficacy parameters, summary tabulations will be presented for newly 
diagnosed subjects and relapsed subjects only (no display for all subjects). 
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JNJ-54767414  (daratumumab)                         
                                                                 
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3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE 
3.1.
Interim Analysis
There is no interim efficacy analysis planned for this study.  However, three interim safety 
analyses are planned. The first interim safety analysis will occur after at least 20 subjects are 
treated for at least 1 cycle of study treatment (or discontinue before the end of Cycle 1). The 
second interim safety analysis will occur after at least 50 subjects complete cycle 1 of study 
treatment (or discontinue before the end of Cycle 1) with a focus on infusion related reactions 
during cycle 1. The third interim safety analysis will occur after at least 50 subjects are treated 
for at least 4 cycles (or discontinue before the end of Cycle 4).  A separate SAP was prepared 
that outlines the interim safety analyses. 
All three planned interim safety analyses have
completed.
3.2.
Data Review Committee
An internal Data Review Committee will be established to monitor data on an ongoing basis to 
ensure the continuing safety of the subjects enrolled in the study. The committee will meet 
periodically to review interim safety data and will also perform the predetermined interim safety 
review as detailed in Section 3.1, Interim Analysis. After the review, the committee will make 
recommendations regarding the continuation of the study. The details will be provided in a 
separate committee charter.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
The following parameters will be summarized using full analysis set:

Demographic and baseline characteristic variables: age (continuous), age category (< 65 
years, 65 to < 75 years, and ≥75 years), sex, ethnicity, race, weight (kg), height (cm), and 
ECOG performance status (0, 1, 2) 

Baseline disease characteristics: type of myeloma (IgA, IgD, IgE, IgG, IgM, light chain, 
biclonal, Serum free light chain only), ISS staging (I, II, III), cytogenetics profile (del17p, 
del13, t(4;14), t(11;14), t(14;16)), time since initial diagnosis (years), Line of prior therapy 
(0, 1), number of lytic bone lesions (None, 1-3, 4-10, more than 10), presence of diffuse 
myeloma-related osteopenia (Yes, No), number extramedullary plasmacytomas (0, ≥1), 
bone marrow % plasma cells (10, 10 – 30, >30), 

Disease related laboratory values: hemoglobin (g/L), hemoglobin category (< 80 g/L, 80 –
100 g/L, >100 g/L), platelets (giga/L), platelets category (< 75, ≥ 75), calcium (mmol/L), 
calcium category (>ULN, ≤ ULN), corrected calcium (mmol/L), corrected calcium 
category ((> ULN, ≤ ULN), creatinine(umol/L), creatinine category ((> ULN, ≤ ULN), 
creatinine clearance (mL/min), creatinine clearance category (> 60 mL/min, 30 -  60 
mL/min,  < 30 mL/min), beta2 microglobulin (mg/L), beta2 microglobulin category (< 3.5 
mg/L, 3.5 – < 5.5 mg/L, ≥ 5.5 mg/L) , albumin (g/L), and albumin category (< 35 g/L,  ≥ 
35 g/L)

Baseline laboratory tests: Summary statistics as well as frequencies of CTC toxicity grade 
will be provided for the following parameters:
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JNJ-54767414  (daratumumab)                         
                                                                 
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o
Hematology: white blood cell (WBC) count, platelets (giga/L), lymphocytes, 
neutrophils, red blood cell (RBC) count, hematocrit. 
o
Serum chemistry: potassium, total bilirubin, Aspartate Aminotransferase (AST), 
Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), ionized calcium.

General ongoing medical history by body system as reported on eCRF. A listing will be 
generated for ongoing medical history.

The incidence of subjects receiving radiotherapy, systemic therapy, or palliative 
supportive care for second primary malignancy will be provided.

Baseline vital signs: pulse, systolic blood pressure, and diastolic blood pressure.

Baseline ECG overall interpretation: normal, abnormal and clinically significant, or
abnormal and not clinically significant.
4.2.
Disposition Information
The number of subjects (%) who discontinued study treatment will be summarized using the full 
analysis set, together with reasons of discontinuation reported on eCRF. The number of subjects 
who discontinued from study and the reported reasons on eCRF will be presented similarly.  
An overview of subject disposition in the study will be provided too. The overview
includes a summary of total number of subjects who are enrolled into each treatment
group, the number (%) of subjects who entered into each treatment phase, and their status 
(completed, DC and on-going) in each phase (induction, ASCT, maintenance, and follow-up)
will be provided. 
4.3.
Extent of Exposure
Extent of exposure to study treatments will be summarized based on the full analysis set
including the following:

The number and percentage of subjects treated within each cycle. 

Duration of study treatment, defined as the number of months from the date of the first 
administration of study treatment to the date of the last dose.

The duration of Daratumumab infusion (hours) for first infusion, second infusion, and 
subsequent infusions

Total dose administered overall for Daratumumab (mg/kg), Cyclophosphamide (mg/m2), 
Bortezomib (mg/m2), or Dexamethasone (mg).

Dose intensity for each treatment, which is calculated as the sum of total doses (mg/kg, or 
mg/m2, or mg) received in all cycles divided by the number of treatment cycles.

Relative dose intensity (%), which is defined as the ratio of the total actually received dose 
and total planned dose. Total planned dose is calculated as the sum of planned dose level 
over the number of recorded infusions or dose administrations (zero & non-zero dosing
records included).

Number of subjects with cycle delay, dose skipped (not administered), adjusted, and 
stopped for Daratumumab, Bortezomib, and Dexamethasone and dose reduced for 
Cyclophosphamide, as well as the respective reasons.
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JNJ-54767414  (daratumumab)                         
                                                                 
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4.4.
Protocol Deviations
The incidence of major protocol deviations will be summarized based on the full analysis set. A 
listing of all major protocol deviations will be provided.
4.5.
Pre-study and Concomitant Therapies
Pre-study therapies are therapies administered up to 30 days before first dose of study treatment. 
Concomitant therapies are therapies recorded throughout the study beginning with start of the 
first dose of study drug until 30 days following completion of the last dose of study drug.
Medications will be summarized by World Health Organization (WHO) drug therapeutic class 
and generic medication name using the full analysis set.  Pre- and post-infusion medications will 
also be summarized separately.  This will be provided using the full analysis set.
Additionally, number of subjects who received HDT/ASCT after 4 to 8 cycles of induction 
therapy with Dara-CyBorD will be summarized, and their stem cell yield will be summarized.
5.
EFFICACY
The primary analysis will be performed after all enrolled subjects have completed 4 cycles of
induction therapy, disease evaluation or have been discontinued from study treatment by this 
time point. A final data analysis, to update secondary endpoints and safety, will occur at the end 
of study when all subjects have completed follow-up at 36 months after the start of
induction therapy, or until death or withdrawal of consent for study participation, whichever
occurs first.
Response to study treatment and progressive disease will be evaluated by a validated computer 
algorithm to calculate IMWG response.  As a sensitivity analysis, investigator assessments of 
response and disease progression using the IMWG response criteria will also be performed.
All response related efficacy analyses will be based on the Response-evaluable set and time to 
events including PFS, time to disease progression (TTP), OS and time to response analyses will 
be based on the full analysis set.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The primary hypothesis is to be tested at a 1-sided 0.05 significance level for the previously 
untreated subjects.  All 95% confidence interval presented will be 2-sided.  
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
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JNJ-54767414  (daratumumab)                         
                                                                 
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5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary endpoint is the proportion of subjects achieving either a complete response (CR) 
or a very good partial response (VGPR), [CR+VGPR], following 4 cycles of induction therapy 
with Dara-CyBorD, as determined by the validated computer algorithm using the IMWG 
criteria.
5.2.2.
Analysis Methods 
The number and percentage of subjects with [CR+VGPR] response achieved after 4 cycles of 
induction therapy will be tabulated. The proportion of [CR+VGPR] response will be compared 
to a reference value of 0.6 at a 1-sided 0.05 significance level using a normal approximation to 
the binomial distribution for the previously untreated subjects. In Amendment 2 of the study 
protocol, enrollment of subjects in the relapsed cohort is closed and expected not to exceed 15 
subjects. No inferential statistics will be performed for the relapsed subjects.  In addition, a 2-
sided 95% confidence interval for [CR+VGPR] will be provided. 
A sensitivity analysis of [CR+VGPR] rate after 4 cycles of induction therapy based on 
investigator assessment according to the IMWG response criteria will be performed.
5.3.
Secondary Efficacy Endpoints
5.3.1.
Progression-Free Survival
5.3.1.1.
Definition
PFS is defined as the duration from the date of first dose (start of induction) to the date of 
first documented evidence of progressive disease based on the computerized algorithm 
according to the IMWG response criteria or death due to any cause, whichever occurs first.
Subjects who start subsequent antimyeloma 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 subjects are lost
to follow-up. Subjects who have not progressed and are still alive at the cutoff date for analysis
will be censored at the last disease assessment. Subjects without any post-baseline disease
assessment will be censored at the first dose date.
Determination of dates of PFS event and dates for censoring is summarized in Table 2
as follows.
Table 2:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
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JNJ-54767414  (daratumumab)                         
                                                                 
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Disease progression prior to start of
subsequent antimyeloma therapy
Earliest date that indicates disease progression
PFS event
Death prior to start of subsequent
antimyeloma therapy
Date of death
PFS event
No post-baseline disease assessment
First dose date
Censored
Other (e.g., withdrawal of consent to study
participation, lost to follow-up, start of
subsequent antimyeloma therapy etc.)
Date of last disease assessment prior to
withdrawal of consent to study
participation, lost to follow-up, or 
subsequent antimyeloma treatment
Censored
5.3.1.2.
Analysis Methods
Kaplan-Meier method will be used to estimate the distribution of PFS. The estimated median
PFS with 95% CI will be provided. In addition, the number and percentage of subjects who
had a PFS event or were censored will be reported. In addition, 1, 2, and 3-years PFS rates
with 95% CI will be estimated by Kaplan-Meier method. Kaplan-Meier PFS curves will also
be generated.
A sensitivity analysis of PFS, in which progressive disease is based on investigator assessment 
according to the IMWG response criteria, will be performed in a similar manner as described
above.
5.3.2.
Time to Disease Progression (TTP)
5.3.2.1.
Definition
TTP is defined as the time between the date of first dose (start of induction) and the date of
first documented evidence of confirmed PD, as defined in the IMWG response criteria.
Subjects who start subsequent antimyeloma therapies for multiple myeloma without disease
progression will be censored at the last disease assessment before the start of subsequent
therapies. Subjects who withdraw consent to study or are lost to follow-up or die without
disease progression will be censored at the last disease assessment. Subjects who have not
progressed at the cutoff date for analysis will be censored at the last disease assessment.
Subjects without any post-baseline disease assessment will be censored at the first dose date.
5.3.2.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 5.3.1 for PFS analysis.  
A sensitivity analysis of TTP, in which progressive disease is based on investigator
assessment according to the IMWG response criteria, will be performed in a similar manner.
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JNJ-54767414  (daratumumab)                         
                                                                 
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5.3.3.
Overall Survival (OS)
5.3.3.1.
Definition
Overall survival (OS) is measured from the date of first dose (start of induction) to the date of 
death due to any cause. Subjects who withdraw consent from the study or are lost to follow-up 
will be censored at the time of withdrawal or lost to follow-up. Subjects who are still alive at the 
cutoff date for the analysis will be censored at the last known date of alive. The date of last 
known alive will be determined by the maximum collection/assessment date from among 
selected data domains within the clinical database.
5.3.3.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 5.3.1 for PFS analysis.
5.3.4.
Overall Response Rate (ORR)
5.3.4.1.
Definition
ORR is defined as the proportion of subjects who achieve a partial response or better (i.e., PR, 
VGPR, CR or sCR), according to IMWG response criteria.
5.3.4.2.
Analysis Methods
Analysis of ORR will be based on the Response-evaluable set defined in Section 2.3.  The 
number and percentage of subjects in the following response categories will be presented: 
stringent complete response (sCR), complete response (CR), sCR+CR, very good partial
response (VGPR), partial response (PR), overall response (sCR+CR+VGPR+PR), minimal 
response (MR), overall response + MR (sCR, CR, VGPR, PR, and MR), stable disease (SD), 
progressive disease (PD), and not evaluable (NE). The corresponding 95% CI for each response 
category will also be provided. Analysis of ORR will be presented at the following time points:

Following 4 cycles of induction therapy

At the end of Dara-CyBorD induction therapy

Post–transplant (in subjects who undergo high dose therapy and autologous stem cell 
transplantation)

At the end of 12-cycles maintenance therapy  
A sensitivity analysis of overall response rate, in which disease response is based on investigator 
assessment according to the IMWG response criteria, will be performed in a similar manner.
5.3.5.
Duration of Response (DOR)
5.3.5.1.
Definition
Duration of response is defined for subjects with a confirmed response (PR or better) as the 
duration from the date of initial documentation of a response (PR or better) according to the 
IMWG criteria to the date of first documented evidence of progressive disease according to the 
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JNJ-54767414  (daratumumab)                         
                                                                 
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IMWG criteria or death due to progressive disease.  Responders without disease progression
will be censored at the censoring time point for TTP.  
5.3.5.2.
Analysis Methods
Analysis of DOR will be based on subjects who achieved a confirmed response of PR or
better. Median DOR with 95% CI will be estimated based on the Kaplan-Meier method.  
Kaplan-Meier estimates will be generated and Kaplan-Meier curves for the duration of response
will be produced.
A sensitivity analysis of DOR, in which disease response and progression are based on 
investigator assessment according to the IMWG response criteria, will be performed in a similar 
manner.
5.3.6.
Time to Response 
5.3.6.1.
Definitions
Time to VGPR or better response (based on the computerized algorithm) is defined as the
duration from the date of first dose (start of induction) to the date of initial documentation of 
VGPR or better, which was confirmed by a repeated measurement as required by the IMWG 
criteria.  Subjects without confirmed response (VGPR or better) will be censored at the
censoring date for TTP.
Time to PR or better response (based on the computerized algorithm) is defined as the duration 
from the date of first dose (start of induction) to the date of initial documentation of PR or 
better, which was confirmed by a repeated measurement as required by the IMWG criteria.  
Subjects without confirmed response (PR or better) will be censored at the censoring date for 
TTP.
5.3.6.2.
Analysis Methods
Kaplan-Meier method will be used to estimate the cumulative distribution function of
response over time using the full analysis set. Median time to response with 95% CI will be
tabulated.  Similar analyses will be conducted for time to VGPR or better response and
time to PR or better response. Kaplan-Meier estimates and curves for both time to response 
variables will be provided.  
In addition, for subjects who achieve a confirmed response, descriptive statistics (n,
mean, standard deviation, median, range) will also be provided to summarize time to VGPR 
and time to PR or better response.
A sensitivity analysis of time to response based on investigator assessment according to the 
IMWG response criteria will be performed.
5.4.
Subgroup Analyses
Subgroup analyses of the primary and selected secondary efficacy endpoints will be performed 
based on pre-specified subgroups defined in Section 2.4 in the newly diagnosed subject group.  
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Descriptive summaries and forest plot for the computer algorithm assessed response rate 
[CR+VGPR] will be provided for the subgroups specified in Section 2.4 for the previously 
untreated subjects.  The subgroup analyses will be performed if there is adequate number of 
subjects in each subgroup.
The computer algorithm assessed PFS and OS will also be analyzed similarly for the subgroups 
using the methods described in section 5.3.1.2.
Additionally, the efficacy endpoint of best response will be summarized for subjects who 
received ASCT after 4-8 cycles of induction therapy.
6.
SAFETY
Safety evaluation will include adverse events (AEs), death, clinical laboratory tests (hematology 
and serum chemistry), vital signs, physical exam findings, and ECOG performance status. Safety 
analyses will be performed based on the safety analysis set.  
6.1.
Adverse Events
AEs will be monitored throughout the study. All 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 electronic case report forms (eCRF) by investigators to identify adverse events will 
be coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. Unless otherwise specified, at each level of subject summarization in 
reporting the incidence of the AE, a subject is counted once if one or more events were recorded.   
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs), which are
defined as any AE that occurs after the first administration of study treatment (e.g., 
Daratumumab, Cyclophosphamide, Bortezomib, or Dexamethasone) through 30 days after the 
last study treatment administration or the day prior to start of subsequent therapy, whichever is 
earlier, or any AE that is considered reasonably related to 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 reasonably related to study treatment by the investigator. 
The incidence of TEAEs will be summarized overall, by MedDRA system organ class (SOC) 
and preferred term, by maximum toxicity grade, and by relationship to study treatment 
administration. Specifically, the following AE summaries will be presented: 

A summary of TEAEs will be provided and will include the number and percentage 
(incidence) of subjects with any AE, subjects with any toxicity grade 3 or higher AE, 
subjects with any treatment-related AE, subjects with any toxicity grade 3 or higher 
treatment-related AE, subjects with any SAE, subjects with any treatment-related SAE, 
subjects with any AEs leading to study treatment discontinuation, subjects with any 
treatment-related AE leading to study treatment discontinuation, and subjects with any 
AE with outcome of death.
  

Incidence of TEAEs by SOC, preferred term and toxicity grade (1-4)
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Incidence of TEAEs by SOC, preferred term and toxicity grade (1-2 and 3-4)

Incidence of toxicity grade 3 TEAEs, by SOC, preferred term and toxicity grade (3 and 
4)

Study Treatment-Related Adverse Events  

Incidence of Treatment-Related TEAEs by SOC, preferred term and toxicity grade (1-
4)

Incidence of TEAEs related to daratumumab by SOC, preferred term and toxicity 
grade (1-4)

Serious Adverse Events 

Incidence of treatment-emergent SAEs, by SOC and preferred term

Incidence of treatment-emergent SAEs related to daratumumab by SOC and preferred 
term

Infusion-related reaction

Infusion-related reactions (IRR) reported with daratumumab will be summarized by 
SOC and preferred term and maximum toxicity grade. Subjects with any infusion 
reactions associated with daratumumab will also be listed. The list will include 
subject ID, MedDRA preferred term/verbatim, study day of event, toxicity grade, 
relationship to study treatment, action taken with study treatment and outcome.

Incidence of TEAEs leading to any study treatment discontinuation (Daratumumab, 
Cyclophosphamide, Bortezomib, or Dexamethasone) by SOC, preferred term and toxicity 
grade will be provided.  For subjects who discontinued any study treatment due to AEs, a 
list including subject ID, preferred term/verbatim term, study day of AE, AE toxicity 
grade, relationship to study treatment, action taken with study treatment and outcome will 
be provided.

Incidence of TEAEs leading to any treatment cycle delays or dose modifications of at 
least one of the study treatments (Daratumumab, Cyclophosphamide, Bortezomib, or
Dexamethasone) by SOC, preferred term and toxicity grade will be summarized.  Dose 
modifications include dose skipping (not administered) or dose adjustment or dose 
stopped (applicable to Daratumumab, Bortezomib, or Dexamethasone).

Deaths: The number of subjects who died during study and within 30 days of last dose 
will be summarized. The primary cause of death recorded on eCRF page will also be 
summarized. A listing of subjects whose primary cause of death is at least one AE during 
the study will be provided

Secondary malignancy: A listing of subjects who reported second primary malignancies
during the study will 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.
6.2.
Clinical Laboratory Tests
The evaluation of clinical laboratory tests will focus on the following selected laboratory 
analytes:
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JNJ-54767414  (daratumumab)                         
                                                                 
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Hematology:
- hemoglobin
- platelet count
- neutrophils and lymphocytes
- white blood cell (WBC) count with absolute 
- red blood cell (RBC) count 
Chemistry: 
- sodium
- total bilirubin
- potassium
- alkaline phosphatase
- creatinine and creatinine clearance
- uric acid
- glucose 
- calcium and albumin-adjusted calcium
- aspartate aminotransferase (AST)
- phosphate
- alanine aminotransferase (ALT)
- albumin
- chloride
- bicarbonate
- blood urea nitrogen (BUN)
- gamma-glutamyltransferase (GGT)
- lactic acid dehydrogenase (LDH)
- total protein
- magnesium
Descriptive statistics (mean, standard deviation (SD), median, and range) will be used to 
summarize observed laboratory values and their change from baseline at each scheduled visit 
during the study.  Line plot of mean with standard error for each laboratory analyte over time will 
be displayed for hemoglobin, neutrophils, lymphocytes, platelets, WBC, AST, ALT, and 
creatinine.
The worst toxicity grade in hematology and chemistry during treatment will be summarized by 
toxicity grade. Shift tables from baseline to worst toxicity grade during the study will be 
provided for laboratory parameters listed above. These tables will summarize the number of 
subjects with each baseline CTC grade and changes to the maximum CTC grade. 
A listing of subjects with any laboratory results outside the reference ranges (any grade 3 and 
above laboratory results) will be provided. 
6.3.
Vital Signs and Physical Examination
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
time point.
Physical examination with abnormal findings as well as those reported to be clinically significant 
will be summarized by body system and time point.
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JNJ-54767414  (daratumumab)                         
                                                                 
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6.4.
ECOG Performance Status
Frequencies of ECOG performance status (0, 1, 2, >2) over time will be summarized. In addition, 
shift from baseline to worst score during treatment may be provided.
NCT02951819


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12Feb2018, 20:03:35 PM, UTC
Document Approval
 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18Feb2018, 16:24:12 PM, UTC
Document Approval
NCT02951819