A Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma
Phase: PHASE2
Conditions: Monoclonal Gammopathy, Smoldering Multiple Myeloma
Sponsor: Dana-Farber Cancer Institute



Protocol #: 17-212
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SCHEMA

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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS......................................................7
1.
OBJECTIVES....................................................................................................................11
1.1
Overview of Study Design.....................................................................................13
1.2
Number of Patients ................................................................................................13
1.3
Duration of Study...................................................................................................13
1.4
Primary Objectives.................................................................................................13
1.5
Secondary Objectives.............................................................................................13
2.
BACKGROUND ...............................................................................................................14
2.1
Multiple Myeloma .................................................................................................14
2.2
Risks of progression in MGUS..............................................................................15
2.3
MGUS and SMM consistently precede multiple myeloma ...................................16
2.4
Molecular studies in MGUS and SMM .................................................................16
2.5
Definition of SMM and MM. ................................................................................18
2.6
Daratumumab.........................................................................................................18
2.7
Trial Rationale .......................................................................................................21
2.8
Correlative Studies Background ............................................................................22
3.
PARTICIPANT SELECTION...........................................................................................24
3.1
Eligibility Criteria..................................................................................................24
3.2
Exclusion Criteria ..................................................................................................26
3.3
Prohibitions and Restrictions.................................................................................28
3.4
Inclusion of Women and Minorities ......................................................................28
4.
REGISTRATION PROCEDURES ...................................................................................28
4.1
General Guidelines for DF/HCC and DF/PCC Institutions...................................28
4.2
Registration Process for DF/HCC and DF/PCC Institutions .................................29
4.3
General Guidelines for Other Investigative Sites ..................................................29
4.4
Registration Process for Other Investigative Sites.................................................29
5.
TREATMENT PLAN........................................................................................................30
5.1
Treatment Regimen................................................................................................30
5.2
Agent Administration.............................................................................................30
6.
DOSE DELAYS ................................................................................................................36
6.1
Daratumumab Toxicity Management ....................................................................36
6.2
Daratumumab Delays.............................................................................................37
7.
TREATMENT COMPLIANCE ........................................................................................37
8.
CONCOMITANT THERAPY...........................................................................................38
8.1
Permitted Therapies ...............................................................................................38
8.2
Prohibited Therapies..............................................................................................38
8.3
Criteria for Taking a Participant Off Protocol Therapy.........................................38
8.4
Duration of Follow Up...........................................................................................39

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8.5
Criteria for Taking a Participant Off Study ...........................................................40
9.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40
9.1
Definitions..............................................................................................................40
9.2
Expected Toxicities................................................................................................42
9.3
Adverse Event Characteristics ...............................................................................43
9.4
Expedited Adverse Event Reporting......................................................................43
9.5
DF/HCC Expedited Reporting Guidelines.............................................................44
9.6
Expedited Reporting to the Food and Drug Administration (FDA) ......................45
9.7
Expedited Reporting to Janssen.............................................................................45
9.8
Adverse Events of Special Interest ........................................................................46
9.9
Expedited Reporting to Hospital Risk Management .............................................46
9.10
Routine Adverse Event Reporting .........................................................................46
9.11
Unlisted (Unexpected) Adverse Event/Reference Safety Information..................46
9.12
Special Reporting Situations..................................................................................46
9.13
SAEs, Adverse Events of Special Interest and Special Reporting Situations........47
9.14
Non-Serious AEs ...................................................................................................48
9.15
Product Quality Complaint (PQC).........................................................................48
9.16
Pregnancy...............................................................................................................49
10.
STUDY CALENDAR .......................................................................................................49
11.
PHARMACEUTICAL INFORMATION..........................................................................51
11.1
Daratumumab.........................................................................................................51
12.
BIOMARKER, CORRELATIVE, MRD ASSESSMENT, AND SPECIAL STUDIES...52
12.1
Minimal residual disease assessment (MRD)........................................................53
12.2
Correlative Studies.................................................................................................53
12.3
Bone Marrow Aspirate Samples............................................................................56
12.4
Peripheral Blood Samples......................................................................................57
13.
MEASUREMENT OF EFFECT........................................................................................58
13.1
Development of symptomatic disease ...................................................................58
13.2
Antitumor Effect....................................................................................................59
14.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................65
14.1
Data Reporting.......................................................................................................65
14.2
Data Safety Monitoring..........................................................................................65
15.
STATISTICAL CONSIDERATIONS. .............................................................................65
15.1
Study Design/Endpoints.........................................................................................66
15.2
Sample Size, Accrual Rate and Study Duration ....................................................66
15.3
Stratification Factors..............................................................................................67
15.4
Interim Monitoring Plan ........................................................................................67
15.5
Stopping Rule for Safety........................................................................................67
16.
PUBLICATION PLAN .....................................................................................................67

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17.
REFERENCES ..................................................................................................................68
APPENDIX A: PERFORMANCE STATUS CRITERIA.............................................................74
APPENDIX B: SPECIMEN COLLECTION SCHEDULE ..........................................................75
APPENDIX C: SPECIMEN REQUISITION................................................................................76
APPENDIX D: DANA-FARBER/ HARVARD CANCER CENTER MULTI-CENTER 
OVERSIGHT PLAN AND DATA SAFETY MONITORING PLAN..............................77
1.
INTRODUCTION .............................................................................................................79
1.1
Purpose...................................................................................................................79
1.2
Multi-Center Data and Safety Monitoring Plan Definitions ..................................79
2.
GENERAL ROLES AND RESPONSIBILITIES..............................................................80
2.1
DF/HCC Sponsor...................................................................................................80
2.2
Coordinating Center...............................................................................................81
2.3
Participating Institution..........................................................................................81
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................82
3.1
Protocol Distribution..............................................................................................82
3.2
Protocol Revisions and Closures............................................................................82
3.3
Informed Consent Requirements ...........................................................................83
3.4
IRB Documentation ...............................................................................................83
3.5
IRB Re-Approval...................................................................................................83
3.6
Participant Confidentiality and Authorization Statement ......................................83
3.7
DF/HCC Multi-Center Protocol Registration Policy .............................................84
3.8
DF/HCC Protocol Case Number............................................................................85
3.9
Safety Assessments and Toxicity Monitoring........................................................86
3.10
Data Management ..................................................................................................87
4.
REQUISITIONING INVESTIGATIONAL DRUG..........................................................87
5.
MONITORING: QUALITY CONTROL..........................................................................88
5.1
Ongoing Monitoring of Protocol Compliance .......................................................88
5.2
Monitoring Reports................................................................................................89
5.3
Accrual Monitoring................................................................................................89
6.
AUDITING: QUALITY ASSURANCE ...........................................................................89
6.1
DF/HCC Internal Audits........................................................................................89
6.2
Audit Notifications.................................................................................................89
6.3
Audit Reports.........................................................................................................89
6.4
Participating Institution Performance ....................................................................90
APPENDIX E: INVESTIGATIONAL PRODUCT MANAGEMENT PLAN .............................91
APPENDIX F: RAPID DARATUMUMAB INFUSION GUIDELINE ....................................100

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APPENDIX G: Subject safety Card ...........................................................................................103
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Common abbreviations used in oncology protocols are provided below. Program-specific or 
protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable. Abbreviations that are retained should not be changed.
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
Ara-C
Cytarabine
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
area under the plasma concentration versus time curve from zero 
to 24 hours
area under the plasma concentration versus time curve from zero 
to infinity
area under the plasma concentration versus time curve from zero 
to next dose
BCRP
breast cancer resistance protein
βhCG
beta-human chorionic gonadotropin
BID
bis in die; twice a day
BM
bone marrow
BSA
body surface area
BUN
blood urea nitrogen
BZD
Benzodiazepines
CBC
complete blood count
CFR
Code of Federal Regulations
AUCτ
AUCinf
AUC24 hr

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Abbreviation
Term
CL
clearance, IV dosing
CLP
plasma clearance
CLTotal
total clearance
Cmax
single-dose maximum (peak) concentration
CNS
central nervous system
CO2
carbon dioxide
CR
complete remission
CRM
continual reassessment method
CRP
C-reactive protein
CSF-1R
colony-stimulating factor 1 receptor
CT
computed tomography
Ctrough
single-dose end of dosing interval (trough) concentration
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DME
drug metabolizing enzymes
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EOS
End of Study (visit)
EOT
End of Treatment (visit)
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor 
GMP
Good Manufacturing Practice

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Abbreviation
Term
Hb
Hemoglobin
Hct
Hematocrit
HDPE
high-density polyethylene
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
Ki
inhibition constant
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
LFT
liver function test(s)
MedDRA
Medical Dictionary for Regulatory Activities 
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
MUGA
multiple gated acquisition (scan)
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NPO
nothing by mouth
NYHA
New York Heart Association
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
Pgp
P-glycoprotein
NCI CTCAE

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Abbreviation
Term
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
QD
quaque die; each day; once daily
QID
quater in die; 4 times a day
QOD
quaque altera die; every other day
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SC
Subcutaneous
SD
stable disease
SmPC
Summary of Product Characteristics
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
single-dose time to reach maximum (peak) concentration
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
Vz
volume of distribution in the terminal phase
WBC
white blood cell
WHO
World Health Organization

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1. OBJECTIVES
The concept of initiating therapy after end organ damage is analogous to initiating therapy after 
the development of metastatic cancer in solid tumors. Indeed, the concepts of screening, early 
detection and intervention are part of the major curative advances that have been achieved in solid 
tumors while metastatic cancer remains incurable in these same cancers. It is, therefore, not 
surprising that Multiple Myeloma remains incurable, in spite of all the advances in therapeutic 
interventions. Could it be because we are waiting too long – until metastatic myeloma occurs – to 
treat our patients? In such a condition, watchful waiting may actually be more harmful to the 
patient than early intervention.
The paradigm of therapy in Smoldering Multiple Myeloma (SMM) is changing as we develop 
better therapeutic agents that prevent end organ damage and improve survival of patients with 
Multiple Myeloma (MM)1-4. Indeed, recent studies of a phase III trial of lenalidomide and 
dexamethasone versus placebo showed improved response, progression free survival and overall 
survival in patients with high-risk smoldering MM compared to placebo control5. After a median 
follow-up of 40 months, the median time to progression was significantly longer in the treatment 
group than in the observation group (median not reached vs. 21 months; hazard ratio for 
progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001).
The current understanding is that transformation of MGUS/SMM to MM is likely due to a clonal 
evolution and clonal competition/selection that is Darwinian-like6,7 leading to expansion of 
“winner clones” that have a more proliferative advantage leading to disease progression8,9. Most 
studies defining this model in MM have been performed using samples of patients with MM or 
relapsed MM10,11,12.
However, even in patients with high-risk smoldering myeloma, there is significant clonal 
heterogeneity that may indicate that cure may not be achievable at this stage of the disease.
An important step in the progression of tumors is evasion and suppression of the host immune 
system. There is an active immune response during the early stages of tumor growth in MGUS, 
which controls the growth but does not fully eliminate the tumor clone. As tumor growth 
progresses to the stages of SMM and active MM, there is an associated cellular and humoral 
immune deficiencies13, indicating that the evolution of disease in MM is associated with an 
immunosuppressive milieu that fosters immune escape.
Smoldering Multiple Myeloma (SMM) is a heterogeneous disease entity that includes patients who 
have a disease burden that is higher than that in patients with MGUS but who are not yet 
symptomatic14. The term SMM was first described by Greipp and Kyle et al in 198015 and was 
followed by many other descriptions terming it indolent MM16, or Durie Salmon Stage I17. It was 
not until 2003 that the International Myeloma Working Group (IMWG) described the exact 
definition of this disease. SMM was defined as serum M-protein ≥3 g/dL and/or ≥10% monoclonal 
plasma cells in the bone marrow (BM), Table 118,19. While the incidence and prevalence of SMM 
in the population is not well defined, it has been estimated to represent approximately 8% to 20% 
of patients within the MM spectrum14.

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Most recently, the IMWG further re-defined the group of patients who meet criteria for treatment 
and included asymptomatic SMM patients who are likely going to have end-organ damage in the 
near future, previously defined as “ultra-high risk smoldering myeloma”. These include patients 
with bone marrow plasmacytosis ≥60% 20; an abnormal FLC-ratio ≥100 (involved kappa) or <0.01 
(involved lambda) 21: and/or 2 or more focal bone marrow lesions detected by functional imaging 
including PET-CT and/or MRI 22,23. These patients should therefore not be considered SMM 
anymore but rather re-defined as patients with myeloma-defining events that require therapy.
The overall risk of progression of SMM is 10% per year for the first 5 years and 3% per year for 
the next 5 years24. The most common factors used to stratify patients with SMM are the Mayo 
Clinic criteria24,25 and the Spanish PETHEMA criteria26. The Mayo Clinic criteria are based on the 
tumor burden defined by the serum protein level (by serum protein electrophoresis or light chain 
ratio) or by the percent bone marrow plasma cell involvement (see Table 2 )24,25, leading to risks 
of progression at 5 years of 25% for low risk, 51% for intermediate risk and 76% for high risk 
individuals who have 1, 2 or 3 risk factors respectively24,25. The risk stratification of the 
PETHEMA group is based on identifying the number of clonal plasma cells in the bone marrow 
by flow cytometry (≥95% ratio of abnormal neoplastic plasma cells to normal plasma cells) and 
reduction of uninvolved immunoglobulins, with 5 year-risk of progression being 4%, 46%, and 
72% for patients with 0, 1 or 2 risk factors, respectively26.
The paradigm of therapy in Smoldering Multiple Myeloma (SMM) is changing as we develop 
better therapeutic agents that prevent end organ damage and improve survival of patients with 
multiple myeloma (MM)1-3. Indeed, recent studies of a phase III trial of lenalidomide and 
dexamethasone versus placebo showed improved response, progression free survival and overall 
survival in patients with high risk smoldering MM compared to placebo control5.
Therefore, we hypothesize that a long therapeutic intervention with Daratumumab at the 
stage of high-risk MGUS and low-risk smoldering myeloma will lead to a complete 
eradication of the tumor clone and potential cure in a subset of these patients.
We will test this hypothesis by first examining the depth of response in these patients 
(primary objective) and by defining the number of patients in MRD negative disease during 
follow up every 6 months for up to 5 years (secondary objective).

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1.1
Overview of Study Design
This is a single-arm, phase II study using single agent daratumumab in patients with high-risk 
MGUS and low-risk smoldering multiple myeloma.
1.2
Number of Patients
A total of 50 eligible patients will be included on this study. Enrollment includes patients who 
receive the first day of therapy. Patients who are registered, but never start protocol therapy 
should be replaced.
1.3
Duration of Study
A treatment cycle is defined as 4 weeks in length. During Cycles 1 and 2, patients will receive 
daratumumab weekly. During cycles 3 through 6, daratumumab will be administered every 2 
weeks. During cycles 7 through 20, daratumumab will be administered every 4 weeks.
For information regarding dosing of daratumumab, please reference section 5.1. For information 
regarding dose modifications of daratumumab, please refer to section 6.0.
There is no maintenance therapy. Patients will be followed for up to five years after discontinuation 
of therapy.
1.4
Primary Objectives
•
To determine the proportion of patients who are in VGPR or better after twenty cycles of 
therapy with Daratumumab. This will be determined at the time of best overall response.
1.5
Secondary Objectives
•
To determine the number of patients, with VGPR or better, who are MRD negative 
disease at the completion of therapy and every 6 months after therapy for up to 5 years.
•
To assess duration of response.
•
To assess safety of the agent in this patient population.
•
To evaluate clonal heterogeneity in these patients using deep sequencing at the DNA and 
RNA level and determine association of genomic aberrations with response/progression 
to daratumumab and progression to SMM/MM.
•
To evaluate T cell response (flow cytometry, TCR sequencing, functional T cell status) in 
this patient population.
•
To assess changes in the immune microenvironment in high-risk MGUS and low-risk 
SMM patients over the course of the study; to assess these immune changes and 
association with progression to SMM or MM.
•
To examine the immunoglobulin sequence in MGUS and SMM patients to determine if 
common clonal sequences are noted among high-risk MGUS and low-risk SMM, and to 
evaluate whether common Ig sequences are associated with progression.

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•
To assess the rate of secondary hematologic malignancies
2. BACKGROUND
2.1
Multiple Myeloma
Multiple myeloma is a plasma cell neoplasm characterized by multifocal proliferation of clonal, 
long-lived plasma cells associated with an overproduction of monoclonal gammaglobulin 31. In 
2010 the International Myeloma Working Group (IMWG) defined monoclonal gammopathy of 
undetermined significance (MGUS) by the presence of serum M-protein < 3 g/dL, clonal plasma 
cell population in the bone marrow < 10%, and the absence of end-organ damage such as 
hypercalcemia (serum calcium ≥ 11 mg/dL), renal insufficiency (serum creatinine > 2 mg/dL), 
anemia (hemoglobin value below the lower limit of normal by more than 2 g/dL or hemoglobin 
value < 10 g/dL) and lytic bone lesions (CRAB features) that can be attributed to the plasma cell 
proliferative disorder 32. Smoldering multiple myeloma was defined by the presence of serum M- 
protein ≥ 3 g/dL or urinary monoclonal protein ≥500 mg/dL and/or clonal bone marrow plasma 
cells 10-60% and the absence of CRAB features clinically.
In a large population based study in Olmsted County, MN, Kyle et al. analyzed serum samples of 
more than 75% of residents, 50 years or older, within the county 33. They identified MGUS in 694 
of 21,463 patients tested (3.2%). While the overall prevalence was noted to be 3.2% (95 % CI, 3.0 
to 3.5), there was a significant age dependent increase in both sexes with the prevalence among 
persons 80 years of age or older 4 times as high as among those 50-59 years of age. Age-adjusted 
rates were higher in men (4.0 %, 95% C.I., 3.5 to 4.4) than in women (2.7%, 95% C.I., 2.4 to 3.0). 
In a subsequent study on a majority of the same patients from Olmsted County, Dispenzieri, et al, 
used the free light chain assay (FREELITE) and showed that 0.8% of people older than 50 years 
had light chain-MGUS. The total MGUS prevalence including the light chain-MGUS cases was 
noted at 4.2% (95% C.I., 3.9 to 4.5%) 34. A limitation of both these studies was that 97.3% of the 
residents of Olmsted County were white.
For SMM patients a M-protein ≥ 3 g/dL, a FLC ratio outside the range of 0.125 to 8, and ≥ 10% 
plasma cells in the bone marrow are considered as adverse factors in this model 24,25. The 5-year 
rate of progression in patients with 1, 2 and 3 risk factors was 25%, 51% and 76% respectively. 
The time to progression with these risk factors was 10, 5.1 and 1.9 years respectively. Recently 
Rajkumar et al have proposed that SMM with >60% plasma cells progress to multiple myeloma 
within 2 years in 95% cases and should be treated at diagnosis even in the absence of symptoms
20.

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Table 1: Definitions currently available for MGUS and smoldering myeloma
International Myeloma Working Group criteria, 2010 version32
MGUS

Serum M protein <3 g/dL

Clonal bone marrow plasma cells <10%

Absence of myeloma defining events and amyloidosis
SMM

Serum M protein >3 g/dL

and/or clonal bone marrow plasma cells 10% - 60%

or urinary monoclonal protein ≥500 mg per 24 hours

or FLC ratio < 0.125 or > 8

or ≥ 95% abnormal plasma cells in the bone marrow

or immunoparesis of one or more immunoglobulins

Absence of myeloma defining events and amyloidosis
MM

Clonal bone marrow plasma cells ≥10% and/or biopsy proven 
plasmacytoma

Presence of serum and/or urinary monoclonal protein at any level

Evidence of end organ damage that can be attributed to the underlying 
plasma cell proliferative disorder (CRAB criteria)
o
Hypercalcemia: Serum calcium >0.25 mmol/L above upper limit 
of normal or > 2.75 mmol/L (> 1 mg/dL above upper limit of 
normal)
o
Renal insufficiency: Serum creatinine > 173 μmol/L (>2 mg/dL)
o
Anemia: Normochromic, normocytic with a hemoglobin value of
>2 g/dL below the lower limit of normal or a hemoglobin value
<10 g/dL
o
Bone lesions: Lytic lesions, or osteoporosis with compression 
fractures

Or any MYELOMA DEFINING EVENTS (MDE) as follows:
o
Clonal bone marrow plasma cell percentage*> 60%20
o
An abnormal FLC-ratio ≥100 (involved kappa) or <0.01 (involved 
lambda)21>1 or more focal lesions on MRI or PET-CT studies(≥22,
23
2.2
Risks of progression in MGUS
The Mayo Clinic criteria are primarily based on the levels of serum protein markers (serum protein 
electrophoresis [SPEP] with immunofixation and FLC assay). In a retrospective study of 1148 
patients diagnosed with MGUS with long-term follow-up, M-protein > 1.5 g/dL, non-IgM MGUS, 
and a sFLC ratio < 0.26 or > 1.65 were independent risk factors for progression. At 20 years, 
patients with no risk factors had a 5% risk of progression compared with 21%, 37%, and 58% for 
patients with 1, 2, or 3 risk factors, respectively71.

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In contrast, the risk stratification scheme of the PETHEMA Study Group has focused on the use 
of multiparameter flow cytometry of the BM to quantify the ratio of abnormal, neoplastic plasma 
cells (aPCs) to normal plasma cells. At 5 years of follow-up, patients with MGUS with neither ≥ 
95% aPCs nor DNA aneuploidy were found to have a very small, 2% risk of progression compared 
with a 10% risk for patients with one risk factor and a comparatively high 46% risk of progression 
at 5 years for patients with both72.
Table 2: Risk stratification of smoldering MM criteria is defined below:
Model
Risk Factors
No. of Risk 
Factors
5-year 
progression
%
Relative Risk
1
25
1
2
51
2.0
3
76
3.0
Mayo Clinic 
Model
-
M-protein ≥ 3 
g/dL
-
≥ 10% BM
plasma cells
-
FLC ratio <
0.125 or > 8
Total
51
NA
0
4
1
1
46
11.5
2
72
18
Spanish 
(PETHEMA)
Model
-
≥ 95% aPC
-
Immunoparesis
Total
46
NA
2.3
MGUS and SMM consistently precede multiple myeloma
Since the early description of monoclonal gammopathy of undermined significance it was known 
that some cases of MGUS progressed to symptomatic myeloma but it was not clear whether all 
cases of myeloma are preceded by MGUS. In a study of more than 77,000 individuals, 55 to 74 
years of age, from a cancer screening trial, Landgren et al found 71 patients who developed 
multiple myeloma35. They performed serum protein electrophoresis, immunofixation and kappa- 
lambda free light chain assay on prediagnostic samples in these patients. The study showed that 
patients who eventually developed multiple myeloma consistently had MGUS in the years 
preceding development of multiple myeloma. Interestingly, in half the patients, there was a steady 
increase in the M-protein before the development of symptomatic myeloma, while in the other half 
the M-protein stayed fairly stable. A second study by Weiss et al. found a monoclonal gammopathy 
in 27 of 30 patients (90%) in sera 2 or more years before the diagnosis of myeloma 36.
2.4
Molecular studies in MGUS and SMM
A recent study using SNP-based arrays compared MGUS, SMM and MM samples 37. They found 
copy number abnormalities in all stages. The incidence of genomic imbalance did increase from a 
median of 5/case for MGUS to 7.5/case for SMM and 12/case for MM. The study also noted certain 
genomic changes that were exclusive to MM including 11q and 21q gains and 16q and 22q 
deletions. Interestingly, the study found these abnormalities in a small subclone in MGUS patients 
indicating that most if not all of the chromosomal changes may be already present at the MGUS

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state. These findings also support a possible role of ‘clonal tides’ in the evolution from precursor 
state to symptomatic myeloma as explained below.
Two major pathways have been proposed as the early oncogenic events in the development of the 
myeloma cell based on chromosomal abnormalities noted in MGUS, SMM and MM- the non- 
hyperdiploid and the hyperdiploid pathway. The main cytogenetic changes that have been 
observed in MGUS and SMM are indicated in the table below.
Table 3: Cytogenetic abnormalities in MGUS, SMM and MM
Cytogenetic Abnormality
Involved Oncogene
MGUS%
SMM%
MM%
IgH Translocations
See below
40-50%
40-50%
50-70%
t(11;14)(q13;q32)
CCND1
(Cyclin D1)
10-25%
10-25%
15%
t(4;14)(p16;q32)
FGFR3 and MMSET
2-9%
3-13%
10-15%
t(14;16)(q32;q23)
C-MAF
2-5%
2-5%
2-5%
Other IgH Translocations
•
t(6;14)(p21;q32)
•
t(14;20)(q32;q11)
•
etc.
CCND3 (Cyclin D3), 
MAFB, etc.
6-10%
1-10%
10%
13q Deletion
Unknown
25-50%
35-50%
40-50%
Hyperdiploidy
Unknown
40-50%
40-50%
40-50%
Other molecular studies in MGUS and SMM included microRNA studies. MicroRNAs are single 
stranded RNA molecules that regulate gene expression post-transcriptionally and are being 
implicated in a large number of cancers 38. A study comparing miRNA profiles of normal PC, 
MGUS, SMM and MM found overexpression of mir-21, mir-106~25 and mir181a and mir181b in 
MGUS and MM compared to normal PCs 39. The study also found mir-32 and mir17~92 clusters 
to be upregulated only in MM and not in any other forms. Mir 17~92 and Mir 106~25 are known 
to have a role in B cell development as well as B cell lymphomas targeting PTEN, E2F1, Bcl2 and 
BIM 38,39. The mir17 cluster has been shown to upregulated by the transcription factor c-Myc, 
which is considered a late event in myeloma progression40-42.
With the advances in deep sequencing techniques, we are now able to study the whole genome of 
myeloma cells and compare that to the normal human genome. Several studies employing these 
techniques are beginning to shift our understanding of the pathogenesis of myeloma. These studies 
have revealed that the previously held dogma that cancer progression occurred through a linear 
cumulative acquisition of mutational changes may be too simplistic. A new model of clonal 
heterogeneity is beginning to emerge10. In fact, tumor evolution may indeed proceed like 
Darwinian evolution with tumor progression involving a branching process with coexistent clonal 
heterogeneity. In this model various subclones exist in a dynamic equilibrium, competing for 
limited resources and over time the subclonal populations ebb and flow under environmental 
evolutionary pressures with alternating dominance of various subclones at different time

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points11,12,43-45. Most of these studies were done on patients with symptomatic multiple myeloma 
and as similar studies involving MGUS and SMM emerge, our understanding of the pathogenesis 
of myeloma from these precursor states will continue to evolve. It is possible that the progression 
from myeloma precursor state to symptomatic disease also involves ‘clonal tides’ with expansion 
of a subclone leading to progression. Several previous studies have identified clonal heterogeneity 
in a subset of MGUS patients37,46,47.
2.5
Definition of SMM and MM
The diagnosis of smoldering (asymptomatic) multiple myeloma (SMM) is based on 48,49:
•
Serum monoclonal protein (IgG or IgA) ≥3 g/dL or urinary monoclonal protein ≥500 mg 
per 24 h and/or clonal bone marrow plasma cells (BPMC) 10–60%.
•
Absence of myeloma defining events or amyloidosis
•
No evidence of the following CRAB criteria* or other Myeloma defining events (MDE):
o
Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the 
upper limit of normal or >.275 mmol/dL) related to MM
o
Renal insufficiency (attributable to MM)
o
Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM
o
Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures)
New MDE criteria that indicates overt MM and not SMM 48,49
The following criteria are now incorporated with the CRAB criteria to indicate that patients meet 
criteria for therapy as symptomatic or overt MM:
•
Bone marrow plasma cells >60%
•
Serum involved/uninvolved FLC ratio ≥100, provided the absolute level of the involved 
free light chain is at least 100 mg/L and repeated twice (except for monoclonal light chain 
smoldering MM and for those with stable serum light chains for 6 months.)
•
MRI with >1 focal lesion that is at least 5 mm or greater in size
2.6
Daratumumab
Daratumumab is a human immunoglobulin G1 kappa (IgG1ĸ) monoclonal antibody (mAb) that 
binds with high affinity to a unique epitope on CD38, a transmembrane glycoprotein. It is a 
targeted immunotherapy directed towards tumor cells that express high levels of CD38, in a 
variety of hematological malignancies including MM, leukemia, and non-Hodgkin’s lymphoma 
(NHL).
Daratumumab induces lysis of CD38-expressing tumor cells, by a wide spectrum of mechanisms 
including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated 
cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), through activation 
of complement proteins, natural killer (NK) cells, and macrophages, respectively [de Weers 
2011, Overdijk 2013]1,19.JNJ-54767414 Daratumumab Clinical Protocol 54767414SMM2001 
Amendment 1 22 Approved, Date: 20 January 2015

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For the most comprehensive nonclinical and clinical information as well as Reference Safety 
Information regarding daratumumab, refer to the Daratumumab package insert [Daratumumab 
USPI].
2.6.1
Nonclinical Studies
Preliminary pharmacodynamic studies suggest that daratumumab utilizes multiple effector cell 
functions, resulting in immune mediated killing of CD38-expressing tumor cells. In ex vivo 
experiments utilizing human bone marrow stromal cells co-cultured with primary CD38- 
expressing MM cells, complement-dependent cytotoxicity (CDC) occurs rapidly and 
demonstrates maximal myeloma cell killing by daratumumab within 1 hour of antibody- 
mediated activation of the complement proteins 73. Daratumumab-induced antibody-dependent 
cell-mediated cytotoxicity (ADCC) is slower in its action, with maximal ADCC by daratumumab 
observed at 4 hours in vitro 73. Daratumumab has also been shown to induce antibody-dependent 
cellular phagocytosis (ADCP) in the presence of macrophages within 4 hours in vitro74. Further, 
in vitro studies indicated that daratumumab inhibited the cyclase activity of CD38 and stimulated 
the CD38 hydrolase activity (Study No. GMB 3003-013).
Studies on proliferation of and release of cytokines in human blood cells have indicated that 
daratumumab does not exert target-specific agonistic activity. The cytokine release observed is 
mainly caused by the Fc-portion of IgG1 and comparable to that of approved therapeutic 
antibodies already in clinical use. Specific binding of daratumumab was detected in multiple 
tissues of both human and chimpanzee origin.
2.6.2
Toxicology
Toxicology data have been derived from studies with daratumumab in chimpanzees and with a 
surrogate anti-CD38 antibody in cynomolgus monkeys. The primary toxicities identified in 
chimpanzees were infusion-related reactions during the first, but not subsequent, daratumumab 
infusions and thrombocytopenia. Anemia was observed in cynomolgus monkeys. The binding 
affinity of daratumumab is significantly higher for chimpanzee platelets than for human platelets, 
suggesting that thrombocytopenia may be less pronounced in humans. The effect on platelets and 
red blood cells (RBCs) was reversible.
Depletion of specific lymphocyte phenotypic cell populations, as expected, based on the intended 
pharmacological effect of daratumumab, was observed in both chimpanzees and cynomolgus 
monkeys. No genotoxicity, chronic toxicity, carcinogenicity, or reproductive toxicity testing has 
been conducted.
2.6.3
Clinical Studies
Preliminary data as of 31 July 2014 from 5 ongoing clinical studies are summarized. For further 
details and the most up-to-date information, please refer to the Daratumumab IB.
As of June 30, 2016, about 3,147 patients have been enrolled in studies using daratumumab via 
intravenous infusions. 717 patients received daratumumab alone and approximately 1310 
received daratumumab in combination with other drugs used to treat multiple myeloma

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(lenalidomide, bortezomib, pomalidomide, carfilzomib, dexamethasone, melphalan, prednisone, 
thalidomide)
2.6.4
Clinical Pharmacokinetics
Pharmacokinetic (PK) data are available from Study GEN501 Part 1. The doses ranged from
0.005 to 24 mg/kg. The PK profile was consistent with target mediated disposition (TMD) with 
rapid target-related clearance at low doses and slower clearance at higher doses. Following long- 
term treatment, clearance may decrease as the tumor burden decreases. The preliminary PK data 
in Studies GEN501 Part 2 and MMY2002 are consistent with the PK profile obtained in 
GEN501 Part 1. Preliminary PK data from Study GEN503 show that following both the first 
dose and multiple repeated doses, the PK profile of daratumumab in combination with 
lenalidomide and dexamethasone is similar to what was observed in Study GEN501 following 
the same dose and schedule. The data suggest that lenalidomide and dexamethasone do not affect 
the PK profile of daratumumab.
2.6.5
Preliminary Efficacy
Preliminary efficacy data for Study GEN501 Parts 1 and 2 were presented at the 2013 and 2014 
American Society of Clinical Oncology (ASCO) Annual Meetings, respectively. As the study is 
still ongoing, and data reconciliation activities are underway, the data should be considered 
preliminary. Among 12 subjects treated with daratumumab in Part 1 at doses ≥ 4mg/kg, 5 partial 
responses (PRs) and 3 minimal responses (MRs) were observed. Seven (7) of these subjects had 
a 50 to 100% concomitant reduction in bone marrow plasma cells. Among 29 subjects treated 
with 8 mg/kg daratumumab in Part 2, 3 subjects (10%) had a PR; the response rate was 10%.
Among 20 subjects treated with 16 mg/kg, 2 subjects (10%) had a CR, 1 subject (5%) had a very 
good partial response (VGPR), and 4 subjects (20%) had a PR; the response rate was 35%.
2.6.6
Safety and Tolerability
In general, daratumumab is tolerated well. Maximum tolerated dose (MTD) has not been reached 
following intravenous (IV) infusions up to 24 mg/kg monotherapy and 16 mg/kg in combination 
studies. The most frequently reported adverse events (AEs) across the daratumumab program 
have been infusion-related reactions (IRRs) following single agent therapy. Among all subjects 
treated in ongoing studies (monotherapy and combination therapy), IRRs have been reported in 
49% of subjects; among 151 subjects treated with 16 mg/kg daratumumab monotherapy in 
Studies GEN501 and MMY2002, the percentage of subjects with a reported IRR was identical 
(49%) to what was observed across all treated subjects. The most frequently reported adverse 
reactions (incidence ≥20%) were: infusion reactions, neutropenia, thrombocytopenia, fatigue, 
nausea, diarrhea, muscle spasms, back pain, pyrexia, cough, dyspnea, peripheral edema, 
peripheral sensory neuropathy and upper respiratory tract infection. Among subjects treated with 
16 mg/kg daratumumab monotherapy, the most commonly reported IRRs were nasal congestion 
(8%), cough (7%), and rhinitis allergic and throat irritation (5% each). Grade 3 or higher IRRs 
were reported in 5% of subjects treated with 16 mg/kg daratumumab as monotherapy, with 
bronchospasm and hypertension being the most frequently reported Grade 3 or higher IRRs (1% 
each).

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Across all ongoing studies, bronchospasm was reported in 10 subjects. Early in daratumumab 
development, in Study GEN501, 2 cases of bronchospasm were reported 24-48 hours following 
the second full-dose infusion of daratumumab. With the exception of those 2 cases, which had a 
delayed onset, all other reported bronchospasm events occurred following the first dose. All of 
the events occurring during the infusion period resolved quickly after standard treatments were 
administered. The daratumumab infusion was restarted, and no new onset of bronchospasm 
occurred. Most of the subjects who experienced bronchospasm had underlying respiratory 
diseases (asthma, chronic obstructive pulmonary disease [COPD], and others).
Among the 151 subjects treated with 16 mg/kg daratumumab as monotherapy in Studies 
GEN501 and MMY2002, the most frequently reported AEs (reported in >10% of subjects) were 
fatigue (29%); anemia (23%); nausea (19%); back pain (18%); cough (17%); thrombocytopenia 
(16%); decreased appetite (13%); pyrexia, dyspnea, upper respiratory tract infection (12% each); 
nasal congestion and neutropenia (11% each). Grade 3 and higher AEs were reported in 48% of 
subjects treated with 16 mg/kg monotherapy daratumumab. The most frequently reported Grade 
3 or higher AEs were anemia (13%) and thrombocytopenia (9%). All other Grade 3 and higher 
AEs were reported in <5% of subjects. No deaths due to daratumumab-related AEs have been 
reported in any ongoing study.
In a single center safety study of accelerated daratumumab in patients receiving standard of care 
daratumumab therapy, twenty-eight patients were treated with daratumumab utilizing the 
accelerated rate, 8 of which received the accelerated infusion with their third dose of 
daratumumab76. The premedication regimen varied patient-to-patient and did not impact 
tolerability of the accelerated infusion. There were 5 patients who did not receive any steroid 
premedication and 3 who received reduced doses (< 12 mg) of dexamethasone. Of the 28 
patients treated, there was only 1 adverse reaction - a grade 2 hypertension during which the 
infusion was paused for a patient that had received 10 prior infusions at standard rates. The 
patient received a diuretic, the infusion was resumed and subsequently increased to the 
accelerated rate without further incidence of hypertension. There were no grade 3 or higher 
IRRs. At the 4-week follow-up, all patients remaining on daratumumab treatment continued at 
the accelerated infusion rate. Please refer to Appendix F for further details regarding the rapid 
infusion guidelines.
2.7
Trial Rationale
Daratumumab is a targeted immunotherapy that binds to tumor cells that overexpress CD38, a 
transmembrane glycoprotein. Plasma cells in patients with SMM express high levels of CD38, 
similar to plasma cells in symptomatic MM 51. Daratumumab, as a single agent, has shown 
clinical activity at 16 mg/kg in patients with relapsed/refractory MM who have already failed a 
number of prior therapies and whose myeloma clones have become resistant to many therapies. 
Daratumumab has also demonstrated an acceptable and manageable safety profile.
Patients with MGUS and SMM are asymptomatic and relatively immunocompetent. In current 
practice, the standard of care for subjects with MGUS and SMM is watchful waiting. For high- 
risk patients, treatment under clinical trials has been recommended52.

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As an immunotherapy, daratumumab’s immediate and effective cell-mediated (and potentially 
direct) cytotoxic effects against MM cells may be an ideal mechanism for providing disease 
interception and early intervention at the MGUS and SMM stage. Furthermore, the low risk of 
serious side effects increases the appeal of daratumumab as a treatment option to prevent and/or 
delay transition to symptomatic MM.
Therefore, this study is designed to examine the depth of response (primary objective) and 
by defining the number of patients in MRD negative disease during follow up every 6 months 
for up to 5 years (secondary objective) using a long therapeutic intervention with 
Daratumumab at the stage of high-risk MGUS and low-risk smoldering myeloma. This may 
lead to a complete eradication of the tumor clone and potential cure in a subset of these 
patients.
2.8
Correlative Studies Background
2.8.1
DNA and RNA sequencing of tumor cells
The "clonal evolution" model of cancer emerged amid ongoing advances in technology, especially 
in recent years during which next generation sequencing has provided ever higher resolution 
pictures of the genetic changes in cancer cells and heterogeneity in tumors where tumor 
progression proceeds in a branching rather than in a linear manner, leading to substantial clonal 
diversity and coexistence of wide genetic heterogeneity6,7. The genomic complexity in MM was 
recently corroborated by massive parallel-sequencing studies displaying the lack of a universal 
driving mutation10. Recent studies have shown intraclonal heterogeneity that occurs at different 
stages of progression in MM11,12. Most recently, exome sequencing confirmed that the 
heterogeneity observed in the transformation from MGUS/SMM to MM is likely to be an essential 
feature of clonal evolution and disease progression8,9. Point mutations such as N-RAS, K-RAS, 
MYC up-regulation53, and gain or loss of chromosome 1q or 1p seem to correlate with disease 
progression from MGUS and SMM42. A progressive increase in the incidence of copy number 
abnormalities from MGUS to SMM and to MM has been recently observed54.
We plan to perform exome sequencing and RNA sequencing studies on tumor cells obtained at the 
time of screening as well as from subsequent bone marrow biopsy samples to examine clonal 
heterogeneity, resistant clones at best response and at time of end of study or tumor progression. 
The hypothesis is that clonal evolution and the progression/response of different clones in response 
to immunotherapy would be critical to better understand clonal evolution in MM and help in the 
development of future therapeutic options for patients with MM.
The tumor research samples will be collected at the time of scheduled bone marrow biopsies. From 
these samples, high quality DNA (for tumor cells) and RNA for both exome sequencing and RNA 
sequencing will be obtained. In brief, BM aspirates will be obtained after informed consent. The 
tumor cells will be collected using CD138+ bead selection (over 90% purity based on prior 
publications)10,12. For samples that have a small fraction of plasma cells, we will use flow sorting 
for CD138/CD38/CD56 and CD19-ve to obtain a pure malignant plasma cell population based on

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prior published markers of malignant plasma cells55. Germline DNA will also be obtained from a 
buccal swab from all patients. De-identified specimens or genetic data may be placed into one or 
more publicly-accessible scientific databases such as the National Institutes of Health's Database 
for Genotypes and Phenotypes (dbGaP).
2.8.2
Exome sequencing of tumor cells
Whole-exome capture libraries will be constructed from 100ng of tumor and normal DNA 
followed by shearing, end repair, phosphorylation and ligation to barcoded sequencing adapters. 
The DNA will be size-selected to exonic hybrid capture using SureSelect v2 Exome bait (Agilent, 
CA). Samples will be multiplexed and sequenced on Illumina HiSeq flowcells with the goal of an 
average depth of coverage of 100x. The resulting data will be analyzed with the current Illumina 
pipeline, which generates data files (BAM files). The details of the current analysis pipeline are 
published elsewhere10,56. Briefly, somatic single nucleotide variants are determined using the 
MuTect algorithm57. Indels and translocations are determined by the algorithms IndelLocator and 
dRanger, respectively. The MutSig algorithm identifies genes in which the observed mutations are 
inconsistent with what would be expected at random58. To accurately assess the significance of 
mutations, MutSig takes into account several covariates, which influence the background mutation 
model. These include the expression level of genes (for which published gene expression data of 
MM samples can be used), and other gene characteristics observed empirically to co-vary with 
mutation rate: local relative replication time59, and open vs. closed chromatin status60. Focal, as 
well as arm-level, copy number variations will be determined based on whole exome sequencing 
and subsequent application of the GISTIC algorithm61.
2.8.3
RNA sequencing of tumor cells
For RNA Sequencing, poly-A selection and cDNA synthesis will be performed, followed by 
library preparation, sequencing (76bp or 101bp paired reads), and sample identification with 
quality control. Details of experimental design are described in62,63-65. We will perform library 
construction using a non-strand specific Illumina TruSeq Protocol and sequence coverage to 100M 
total reads. Analysis will be performed as described in the preliminary data and in previous 
studies63-65.
2.8.4
Immune cell characterization in peripheral blood and bone marrow
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic 
assessments to assess the impact of therapy on general measures of cellular immunity. We will 
determine the number of immune cells (T-regs, CD4 effector T cells, CD8 T-regs, CD8 effector T 
cells, NK, NKT, B cells, MSCs, M1 and M2 macrophages, Dendritic cells and MDSCs at screening 
and during therapy. These cells will be quantified using CyTOF. Each cell type will be defined by 
unique combinations of antibodies based on previous publications66,67. Regulatory T cells will be 
defined as CD4/CD25/FOXP3+ cells. Levels of naïve, effector and central memory cells will be 
quantified as CD45RA, CD45RO/CD62L-/CD27- and CD45RO/CD62L+/CD27+ cells, 
respectively. NK cells will be quantified by expression of CD56+ subsets. MDSCs will be 
quantified by CD33+/lineage-/DR- and CD11b/lineage-/DR- cells. We will also examine the 
percent expression of checkpoint regulators and how they are modulated with therapy. These 
checkpoint regulators include PD-1, Lag-3, Tim-3 and CTLA-4.

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2.8.5
T cell specific responses
Previous daratumumab clinical studies in myeloma have demonstrated robust T cell changes in the 
daratumumab treated patients, with significant CD8+ T cell expansion that was higher in 
responding patients compared to non-responders. In addition, naïve CD8+ T cells decreased, and 
central memory CD8+ T cells increased. T cell clonality was monitored by TCR sequencing 
(ImmunoseqTM) and significantly increased with daratumumab treatment. Responders had 
significantly higher changes in clonality compared to non-responders. In addition, CD38+ 
immune suppressive cells (regulatory T cells, MDSC) were noted to decrease with daratumumab 
treatment. This data suggests that daratumumab may increase the adaptive immune response 
against malignant disease, and in patients with pre-malignancy who are treatment naïve, this 
immune response could be even more robust. Therefore, we will examine the T cell response to 
daratumumab treatment in this study through in depth immunophenotyping (flow or CyTOF), 
functional studies examining T cell response pre- and post-daratumumab treatment.
2.8.6
RNA sequencing of immune cells during therapy
We will dissect molecular alterations that occur in these cells during progression in MM and the 
role of therapy on these cells. We will obtain the T-regs, NK cells and MDSCs from the peripheral 
blood and bone marrow at the same time points described in Appendix B. The cells will be isolated 
by flow sorting using single cell sequencing and submitted for RNA sequencing as described 
above. Single cell sequencing of immune cells has recently shown significant advances in 
understanding immune regulation of the tumor microenvironment.
3. PARTICIPANT SELECTION
3.1
Eligibility Criteria
3.1.1
Age ≥ 18 years
3.1.2
Must meet criteria for high-risk MGUS or low-risk smoldering myeloma as described 
below:
High-Risk MGUS
Must have <10% plasma cells and <3.0g/dL M-spike and at least 2 
of the following 3 criteria:
1. Abnormal free light-chain (FLC) ratio (<0.26 or >1.65)
2. M-protein concentration (≥1.5 g/dL)
3. Non-IgG M protein (including IgA)
Low-Risk Smoldering Multiple Myeloma
Must only present with 1 of the following criterion:

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1. Monoclonal Protein ≥ 3 g/dL
2. ≥ 10% Bone Marrow Plasma Cells
3. FLC ratio < 0.125 or > 8
3.1.3
No evidence of CRAB criteria† or new criteria of active MM which including the 
following:
•
Increased calcium levels (corrected serum calcium >0.25 mmol/dL above 
the upper limit of normal or >0.275 mmol/dL)
•
Renal insufficiency (attributable to myeloma)
•
Anemia (Hb 2 g/dL below the lower limit of normal or <10 g/dL)
•
Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures)
•
No evidence of the following new criteria for active MM including the 
following: Bone marrow plasma cells >60%, Serum involved/uninvolved 
FLC ratio ≥100, and MRI with more than one focal lesion
† Participants with CRAB criteria that are attributable to conditions other than the disease 
under study may be eligible
3.1.4
ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)
3.1.5
The following laboratory values obtained ≤ 42 days prior to registration:
•
ANC ≥ 1000/μL
•
PLT ≥ 50,000/μL
•
Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal 
patient is eligible.)
•
AST ≤ 3 x institutional upper limit of normal (ULN)
•
ALT ≤ 3 x institutional upper limit of normal (ULN)
•
Creatinine ≤ 2 mg/dL or Creatinine Clearance ≥ 40 mL/min
3.1.6
Ability to understand and the willingness to sign an informed consent before performance 
of any study-related procedure not part of normal medical care, with the understanding 
that consent may be withdrawn by the subject at any time without prejudice to future 
medical care.
3.1.7
Female patients who are postmenopausal for at least 1 year before the screening visit or 
are surgically sterile are eligible. Females of childbearing potential (as defined below) 
may also be eligible but must have a negative serum or urine pregnancy test with a 
sensitivity of at least 25 mIU/mL within 42 days of registration.
•
A female of childbearing potential is a sexually mature female who:

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o
Has not undergone a hysterectomy (the surgical removal of the 
uterus) or bilateral oophorectomy (the surgical removal of both 
ovaries)
OR
o
Has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 
24 consecutive months (i.e., has had menses at any time during the 
preceding 24 consecutive months)
3.2
Exclusion Criteria
3.2.1
Any prior therapy for symptomatic Multiple Myeloma or smoldering Multiple Myeloma 
should also be excluded, including prior use of IMIDs, proteasome inhibitors, or CD138 
inhibitors. Prior therapy for smoldering Multiple Myeloma with agents that are not 
therapeutically active against MM is not an exclusion criterion. Other prior treatment 
may be allowed after discussion and approval by the overall PI.
3.2.2
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy 
considered investigational. Prior therapy with bisphosphonates is allowed. Prior radiation 
therapy to a solitary plasmacytoma is allowed.
3.2.3
Concurrent exposure to any commercially available agents known to be active against 
SMM and MM.
3.2.4
Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study.
3.2.5
Diagnosed or treated for another malignancy within 2 years of enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
3.2.6
Subject has known chronic obstructive pulmonary disease (COPD) or severe, persistent 
asthma with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal.
•
Note that FEV1 testing is required at screening for patients suspected of 
having COPD or severe, persistent asthma and subjects must be excluded 
if FEV1 <50% of predicted normal.

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3.2.7
Subject has known moderate or severe persistent asthma within the past 2 years or 
currently has uncontrolled asthma of any classification.
•
Subjects who currently have controlled intermittent asthma or controlled 
mild persistent asthma are allowed in the study
3.2.8
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, uncontrollable cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements.
3.2.9
Pregnant or nursing women will be excluded from the study.
3.2.10 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Daratumumab.
3.2.11 Seropositive for or has active viral infection with human immunodeficiency virus (HIV), 
hepatitis B virus (HBV) as defined by a positive test for hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV).
•
Subjects with resolved infection (ie, subjects who are HBsAg negative 
but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or 
antibodies to hepatitis B surface antigen [anti-HBs]) must be screened 
using real-time polymerase chain reaction (PCR) measurement of 
hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be 
excluded. EXCEPTION: Subjects with serologic findings suggestive of 
HBV vaccination (anti-HBs positivity as the only serologic marker) AND 
a known history of prior HBV vaccination, do not need to be tested for 
HBV DNA by PCR.
•
Those who are seropositive for hepatitis C (except in the setting of a 
sustained virologic response [SVR], defined as aviremia at least 12 weeks 
after completion of antiviral therapy).
3.2.12 Major surgery within 4 weeks before enrollment.
3.2.13 Subject is known or suspected of not being able to comply with the study protocol (eg, 
because of alcoholism, drug dependency, or psychological disorder). 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 the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments.
3.2.14 Vaccination with live attenuated vaccines within 4 weeks of first study agent 
administration
3.2.15 Subject has clinically significant cardiac disease, including significant ischemic

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coronary disease, congestive heart failure (New York Heart Association 
[NYHA] Class III or IV), unstable arrhythmias, myocardial infarction or 
unstable angina within 6 months before randomization, a history of additional 
risk factors for torsades de pointes (eg, electrolyte abnormalities, family history 
of Long QT Syndrome), or a family history of sudden cardiac death before age 
40.
3.2.16 Participation in other therapeutic clinical trials, including those with other investigational 
agents not included in this trial, within 30 days of the start of this trial and throughout the 
duration of this trial.
3.3
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. For 
restrictions related to concomitant medications, please refer to Section 8.2.
3.3.1
Blood type and Indirect Antiglobulin Test (IAT) results
CD38 is expressed at very low levels on erythrocytes. Preliminary data indicate that 
daratumumab interferes with IAT (also known as indirect Coombs test) testing and will 
make complete blood typing difficult while subjects are receiving treatment. In case of 
an urgent need for a blood transfusion, a blood sample should be obtained before the 
first infusion of daratumumab and the subject’s blood type (ABO, Rh, and IAT) 
determined. Subjects should be provided a blood type card, which they will carry with 
them throughout the treatment period.
If the participating site’s institution does not have a participant blood type card that 
they provide, please refer to Appendix G for a template to be printed and completed by 
the study staff, and given to the participant. Documentation of this process should be 
included in the source document.
3.4
Inclusion of Women and Minorities
3.4.1
Both men and women of all races and ethnic groups are eligible for this trial.
4. REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS)

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OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible.
4.2
Registration Process for DF/HCC and DF/PCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at DFCI by the Research Project Manager. 
All sites should call the Lead Site Research Project Manager, by phone with any questions.
Following registration, participants should begin protocol therapy as soon as feasible. Issues that 
would cause treatment delays should be discussed with the Overall PI. If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. The Research Project Manager should be notified of cancellations as soon as possible.
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the research nurse or 
data manager and e-mailed to the Lead Site Research Project Manager:
•
Copy of labs and clinical information that satisfy inclusion criteria
•
Signed participant consent form
•
HIPAA authorization form
•
Registration Form
The research nurse or data manager at the participating site will then e-mail the Lead Site Research 
Project Manager, to verify eligibility. To complete the registration process, the Coordinator will 
follow DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) and register the participant on the protocol. The 
coordinator will e-mail the participant study number, and if applicable the dose treatment level, to 
the participating site. The coordinator will also call the research nurse or data manager at the 
participating site and verbally confirm registration.

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Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered.
NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 
PM Eastern Time Monday through Friday.
Same day treatment registrations will only be accepted with prior notice and discussion with the 
Coordinating Center.
5. TREATMENT PLAN
5.1
Treatment Regimen
Daratumumab is to be administered as described in the table below per local standard of care. 
Reasons for early discontinuation of treatment are listed in Section 8.3.
Table 4: Daratumumab Treatment Regimen
Agent
Pre-medications/ 
Precautions
Dose
Route
Schedule
Cycle 
Length
Q1 Week 
Cycles 1-2
Q2 Weeks 
Cycles 3-6
Daratumumab
Please see section
5.2.1.3 for a list of 
pre-medications and
post-medications
16 mg/kg
Intravenous
Q4 Weeks 
Cycles 7-20
4 Weeks
There is no maintenance therapy. Assessment of myeloma and progression will be performed at 
the beginning of each cycle, EOT, and every 3 months thereafter.
5.2
Agent Administration
5.2.1
Daratumumab
5.2.1.1
Daratumumab Preparation
The infusion solution will be prepared on the day of the planned infusion. Please see section 11.1 
for detailed instructions for preparation of daratumumab.
5.2.1.2
Daratumumab Administration
Daratumumab (16 mg/kg) will be administered by IV infusion to subjects:

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•
Weekly during cycles 1 and 2
•
Every other week during cycles 3 through 6
•
Monthly during cycles 7 through 20
Each subject’s dose will be calculated per local institutional standards. There is no cap on the 
absolute dose allowed, as long as the dose does not exceed 16 mg/kg. Subjects will receive pre- 
infusion medications and post-infusion medications as outlined in Section 5.2.1.3. Every effort 
should be made to keep subjects on the planned dosing schedule.
Please see Section 11.1 and site SOPs for administration of commercial daratumumab for full 
detailed instructions for administration of daratumumab.
5.2.1.3
Guidelines for Prevention of Infusion Reactions
Pre-Infusion Medication
Pre-infusion medications for subjects receiving daratumumab should be administered as 
described in Table 5 at the minimum, however sites may follow local guidelines for pre-infusion 
medications if more robust. On daratumumab infusion days, subjects should receive the 
following medications prior to infusion:
•
Paracetamol (acetaminophen) 650-1000 mg IV or orally (PO) approximately 1 hour prior 
to daratumumab infusion.
•
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent) approximately 1 
hour prior to daratumumab infusion.
•
Approximately 1 hour prior to daratumumab infusion, methylprednisolone IV 100 mg for 
the first 2 infusions, 60 mg for all subsequent infusions (in the absence of infusion related 
AEs in the first 2 infusions). An equivalent intermediate-acting or a long-acting 
corticosteroid may substitute. IV administration is required prior to the first 2 infusions, 
but oral steroids may be substituted with subsequent infusions.
Post-Infusion Medication
For the prevention of delayed infusion-related reactions, all subjects are recommended to receive 
corticosteroid orally (20 mg methylprednisolone or equivalent in accordance with local 
standards) 24 hours and 48 hours following daratumumab infusions for the first cycle of therapy, 
after which it is at the treating physician’s discretion. Sites should follow the above and below 
outlined post-infusion medications at the minimum, however sites may follow local guidelines 
for post-infusion medications if more robust.
For subjects with higher risk of respiratory complications (ie, subjects who have a FEV1 <80% 
or subjects with asthma), the following post-infusion medications are recommended:
•
Antihistamine (diphenhydramine or equivalent) 24 hours and 48 hours following all 
daratumumab infusions

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•
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 COPD)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their FEV1 should be measured before discharge. If 
these subjects are not hospitalized, then a follow up telephone call should be made to monitor 
their condition within 48 hours after all infusions. If the subject has not experienced a significant 
medical event but is hospitalized overnight (under 24 hours) only for observation, then the 
hospitalization should not be reported as a serious adverse event (SAE). Investigators may 
prescribe bronchodilators, antihistamines, and corticosteroids that are deemed necessary to 
provide adequate supportive care in the event a bronchospasm occurs after subjects are released 
from the hospital/clinic. If, after 4 full doses, an at-risk subject experiences no major infusion- 
related reactions, then post-infusion medications may be stopped at the investigator’s discretion.

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Table 5: Time and Events Schedule for Pre- and Post-Infusion Medication
Cycle (each cycle is 4 weeks in length)
Cycle 1
Cycle 2
Cycle 3 - 6
Cycle 7 - 20
Day During Cycle
D1
D8
D15
D22
D1
D8
D15
D22
D1
D15
D1
Study Drug Administration
Refer to Section 11.1 for recommendations on daratumumab infusion rate.
Daratumumab Administration
X
X
X
X
X
X
X
X
X
X
X
Pre-Infusion Medications
Methylprednisolone 
(IV)
Methylprednisolone 100 mg for 
first 2 infusions, 60 mg for all 
subsequent infusions. Substitutions 
allowed.
approximately 1 hr prior to every infusion of daratumumab
Antihistamine 
(IV or PO)
Diphenhydramine 25-50 mg or 
equivalent
approximately 1 hr prior to every infusion of daratumumab
Paracetamol 
(IV or PO)
Paracetamol or acetaminophen 650- 
1000 mg
approximately 1 hr prior to every infusion of daratumumab
Post-Infusion Medications
Methylprednisolone 
(PO)
Methylprednisolone 20 mg/day orally 
or equivalent
24 hours and 48 hours days following daratumumab infusions in cycle 1 (beginning the day after the infusion). Treatment 
with methylprednisolone 24 hours and 48 hours following infusion after the first cycle is at the discretion of the treating 
physician.
Antihistamine 
(PO)
Antihistamine (diphenhydramine or 
equivalent) 24 and 48 hours following all 
daratumumab infusions
β2 adrenergic 
receptor
(INH)
Short-acting β2 adrenergic receptor 
agonist such as salbutamol aerosol
Control Medications 
for lung disease
(INH)
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 
COPD)
For subjects with higher risk of respiratory complications (ie, subjects who have a FEV1 <80% or subjects with asthma), the 
following post-infusion medications are recommended. If, after 4 full doses, an at-risk subject experiences no major infusion- 
related reactions, then post-infusion medications may be stopped at the investigator’s discretion.
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5.2.1.4
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 any infusion reactions occurring, and resources necessary for resuscitation (eg, 
agents such as epinephrine and aerosolized bronchodilator, also medical equipment such as oxygen tanks and a 
defibrillator) should be available at the bedside. Attention to staffing should be considered when multiple 
subjects will be dosed at the same time.
If an infusion-related reaction develops, then the infusion should be temporarily interrupted or slowed down. 
Subjects who experience AEs during the infusion should be treated according to the investigator’s judgment and 
best clinical practice. The following guidelines may apply:
•
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. Intravenous saline may 
be indicated. For bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen, 
corticosteroids, or bronchodilators. For hypotension, subjects may require vasopressors.
•
In the event of a life-threatening infusion-related reaction (which may include pulmonary or cardiac 
events), or anaphylactic reaction, daratumumab should be discontinued and no additional daratumumab 
should be administered to the subject. Aggressive symptomatic treatment should be applied.
If an infusion is paused or the infusion rate is decreased, then a longer-than-anticipated infusion time may 
occur. Overnight stays at the hospital because of slow infusion times should not be reported as an SAE. 
However, if the underlying cause of the delayed infusion time is an AE or SAE, then that should be reported as 
such.
Infusion-Related Events of Grade 1 or Grade 2
If the site investigator assesses an AE to be related to the daratumumab infusion, then the infusion should be 
paused. When the subject’s condition is stable, the infusion may be restarted at the site investigator’s discretion. 
Upon restart, the infusion rate should be half of that used before the interruption. Subsequently, the infusion rate 
may be increased at the site investigator’s discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher event of 
bronchospasm that does not respond to systemic therapy and does not resolve within 6 hours from the onset, 
then the subject should be withdrawn from treatment after discussion with the overall principal investigator.
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related AEs that are Grade 3 or higher, the daratumumab infusion should be stopped, and the 
subject should be observed carefully until the resolution of the AE or until the intensity of the event decreases to 
Grade 1. The subject must be withdrawn from treatment after discussion with the overall principal investigator.

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5.2.1.5 Hepatitis B Virus Serology Testing, and Management
HBV Serology
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (Anti- 
HBs), and hepatitis B core antibody (Anti-HBc) at Screening. Additionally, subjects who are currently in the 
treatment phase of the study who are within 6 months of starting study treatment when Protocol Amendment 11 
is implemented will be required to have HBV serology performed locally upon signing the updated ICF.
HBV serology is not required at Screening or for subjects ongoing in the Treatment Phase who are within 6 
months of starting study treatment if this was performed as part of standard of care within 3 months prior to first 
dose.
HBV DNA Tests:
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by PCR. Subjects 
with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) and a 
known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. During and following 
study treatment, subjects who have history of HBV infection will be closely monitored for clinical and 
laboratory signs of reactivation of HBV as specified in the Study Calendar (Section 10). Where required by 
local law, the results of HBV testing may be reported to the local health authorities.
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA testing by PCR 
is mandatory for subjects at risk for HBV reactivation see Section 10.
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment should be interrupted 
until the infection is adequately controlled. If the benefits outweigh the risks, study treatment may be resumed 
with concomitant antiviral prophylaxis as per local standard of care. Consult a liver disease specialist as clinically 
indicated.
Table 6: Testing and Monitoring
Screening 
Phase
Treatment Phase
Follow-up Phase
Notes
Within 42 days 
of registration
Day 1 of each cycle 
(28-day cycles)
EOT within 30 
days of last 
dose
Up to 6 
months
After 6 months: 
Testing per 
standard of care
Laboratory Assessments
Hepatitis B 
(HBV)
serology
X
Local testing for 
hepatitis B surface 
antigen (HBsAg), 
hepatitis B surface 
antibody (Anti-HBs), 
and hepatitis B core 
antibody (Anti-HBc). 
Refer to Section 5.2.1.5

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Q12W during treatment, at the End of Treatment Visit, and Q12W for up
For subjects with
to 6 months after the last dose of study treatment
serologic evidence of
resolved HBV infection
HBV DNA
X
(i.e., positive Anti-HBs
testing
or positive Anti-HBc)
at Screening, HBV
DNA testing by PCR
must be performed
locally.
Refer to Section 5.2.1.5
6. DOSE DELAYS
Dose modification of daratumumab is not permitted, but dose delay is the primary method for managing 
daratumumab-related toxicities.
6.1
Daratumumab Toxicity Management
Refer to Section 5.2.1.4 for details on management of infusion-related reactions. If any of the following criteria 
are met, then the daratumumab infusion should be held (delayed not omitted) to allow for recovery from toxicity.
Hematologic Toxicities: For adverse hematologic events that are considered possibly, probably or definitely 
related to Daratumumab, the following criteria for retreatment and dose modification should be followed.
Treatment may be delayed for a maximum of 14 days. Holds other than described below may occur at the 
investigator’s discretion, after discussion with the overall principal investigator.
Table 7 Daratumumab Hematologic Toxicities
CTCAE 4.0 Category
CTCAE Grade
Daratumumab Dose Modification
≤ Grade 2
Hold dose until resolved to ≤ Grade 1
Thrombocytopenia
(with bleeding)
≥ Grade 3
Discontinue study medication
≤ Grade 2
Hold dose until resolved to < Grade 1
Febrile Neutropenia
≥ Grade 3
Discontinue study medication
≤ Grade 2
Hold dose until resolved to < Grade 1
Neutropenia with 
Infection
≥ Grade 3
Discontinue study medication
All other related 
toxicities not listed
≤ Grade 2
Hold dose until resolved to ≤ Grade 1

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previously in this table
≥ Grade 3
Discontinue study medication
Non Hematologic Toxicity: For adverse non hematologic events that are considered to be possibly, probably or 
definitely related to daratumumab, the following criteria for retreatment and dose modification should be 
followed. The treating investigator should determine the clinical significance of laboratory values or 
radiographic findings and attribution to study medications before a treatment decision is made. Treatment may 
be delayed for a maximum of 14 days. Holds other than described below may occur at the investigator’s 
discretion, after discussion with the overall principal investigator.
Table 8 Daratumumab Non-Hematologic Toxicities
CTCAE 4.0 Category
CTCAE Grade
Daratumumab Dose Modification
≤ Grade 2
Hold dose until resolved to ≤ Grade 1
All non-hematologic 
toxicities:
≥ Grade 3
Discontinue study medication
6.2
Daratumumab Delays
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 1 or below, with the 
exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully recovered. If more than 2 
consecutive planned doses of daratumumab are delayed due to AEs, treatment should be permanently 
discontinued after discussion with the overall principal investigator.
If 2 consecutive doses of daratumumab are delayed for any reason other than AEs, this should be brought to the 
attention of the Principal Investigator at the earliest possible time and study treatment should be discontinued, 
unless, upon consultation with the overall Principal Investigator and the review of safety and efficacy, 
continuation is agreed upon. Documentation of this discussion should be placed in the research chart or medical 
record. Delays for vacations or non-AE related events may be held for a maximum of 7 days. If held for longer, 
a discussion with the overall PI must occur to discuss whether the participant may remain on study.
7. TREATMENT COMPLIANCE
Study drug (daratumumab) will be administered by qualified site staff and the details of each administration will 
be recorded in the electronic case report form (eCRF).

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8. CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments deemed necessary 
to provide adequate supportive care except for those listed in Section 8.2. The overall principal investigator must 
be notified in advance (or as soon as possible thereafter) of any instances in which prohibited therapies are 
administered.
Routine systemic use of all concomitant medications should be collected and recorded in the source documents 
beginning at registration to 30 days after the last dose of the last study treatment or until the start of subsequent 
anticancer treatment. AEs and SAEs will be recorded as per Section 9.5.
Antiviral prophylaxis is permitted if that is the participating institution’s’ standard procedure.
8.1
Permitted Therapies
Supportive management for infections is strongly recommended, including vaccination with pneumococcal 
vaccine before beginning treatment with daratumumab. Concurrent use of bisphosphonates is allowed. 
Management of infusion related reactions is also recommended, as discussed in Section 5.2.1.3. Other symptoms 
may be managed according to institutional guidelines however; medications that could potentially prolong the 
QT interval should be discussed with the overall principal investigator prior to administration.
8.2
Prohibited Therapies
Use of the prohibited treatments listed below during the study will result in discontinuation of study drug for 
subjects:
•
Administration of commercially available agents or agents under investigation for SMM or MM such as 
bortezomib, thalidomide, or lenalidomide, etc.
•
Other agents that target CD38.
8.3
Criteria for Taking a Participant Off Protocol Therapy
Patients will be informed that they have the right to withdraw from the study at any time for any reason, without 
prejudice to their medical care.
In the absence of treatment delays due to adverse event(s), treatment may continue for 20 cycles or until one of 
the following criteria applies:
•
Progression to overt Multiple Myeloma as described in Section 2.1 Table 1
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event(s)

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•
Participant decides to withdraw from the protocol therapy
•
Participant demonstrates protocol non-compliance that, in the eyes of the investigator, jeopardizes patient 
safety or the endpoints of the trial.
•
General or specific changes in the participant's condition render the participant unacceptable for further 
treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal 
from protocol therapy, and the date the participant was removed, must be documented in the case report form 
(CRF). Alternative care options will be discussed with the participant.
The reason for taking a participant off treatment, and the date the participant discontinued study treatment, must 
be documented in the case report form (CRF) and conveyed immediately to the Lead Site Research Project 
Manager.
In the event of unusual or life-threatening complications, treating investigators must immediately notify the 
Overall PI, Irene Ghobrial at telephone # 
8.4
Duration of Follow Up
Participants will be followed every 3 or 6 months (+/-28 days) for up to 5 years after end of treatment. We plan 
to capture progression free survival, second progression free survival as well as time to biochemical progression, 
and time to progression to active symptomatic MM and any subsequent therapies for MGUS, SMM or MM. . If 
travel to the main site is financially burdensome for the participant during maintenance, an alternate schedule may 
be approved after discussion with the Overall PI.
Participants unable to participate in follow up every 3 months may follow up every 6 months at PI discretion in 
accordance with standard of care follow-up frequency and COVID precautions. Physical exams and correlative 
blood draws that are not done due to virtual visits will not be considered violations. Local myeloma labs must be 
provided to the participating site for data entry purposes. Bone marrow biopsy and scans are strongly 
recommended yearly after EOT, but not require however, scans and bone marrow biopsy and research samples 
are required at time of suspected disease progression
The following is required during the Active Follow Up period (for up to 5 years):
1. Physical exams are voluntary during this period
a.
Virtual visits/telehealth visits are acceptable
2. SPEP and Immunofixation
3. Serum Free Light Chains (SFLC)
4. UPEP and Immunofixation only for those where disease is tracked by the urine
5. Serum Immunoglobulin test
6. PET/CT assessments are strongly recommended yearly and is required at the time of suspected 
progression
a.
The same assessment modality should be used consistently across the duration of the trial

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7. Bone marrow biopsies are and strongly recommended yearly after EOT and is required at the 
time of suspected progression
8. Research bone marrow samples will be collected at the time of any bone marrow biopsy/aspirate 
procedure
9. Research blood will be collected whenever an in person visit to the site occurs. Research blood 
samples that are not collected at time points in the collection calendar due to COVID precautions 
or q6 month follow up will not be considered violations unless it is missed at the time of 
suspected progression.
10. Response
11. CRAB/MDE Assessment
12. Bone marrow biopsy/aspirate results and cytogenetics/FISH if ordered
13. Scan results and modality
Participants who come off active follow up when they pursue other MGUS, SMM or MM directed therapy will 
be followed for survival indefinitely which will capture survival stats, and subsequent therapy information.
8.5
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:
•
Lost to follow-up
•
Completion of 5 years follow up
•
Withdrawal of consent for data submission
•
Participant non-compliance, or loss to follow up
•
Death
The reason for taking a participant off study, and the date the participant was removed, must be documented in 
the case report form (CRF) and conveyed immediately to the Lead Site Research Project Manager.
9. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
9.1
Definitions
9.1.1
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product 
whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous 
condition that has increased in severity or frequency since the administration of study drug. CTCAE version
4.0 will be used for this study.

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9.1.2
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it were more severe)
•
Requires inpatient hospitalization or prolongation of an existing hospitalization (see clarification in 
the paragraph below on planned hospitalizations)
•
Results in persistent or significant disability or incapacity. (Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions)
•
Is a congenital anomaly/birth defect
•
Is a suspected transmission of any infectious agent via a medicinal product
•
Is a medically important event. This refers to an AE that may not result in death, be immediately life 
threatening, or require hospitalization, but may be considered serious when, based on appropriate medical 
judgment, may jeopardize the patient, require medical or surgical intervention to prevent one of the 
outcomes listed above, or involves suspected transmission via a medicinal product of an infectious agent. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse; any organism, virus, or infectious particle (eg, 
prion protein transmitting Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT.
Hospitalization
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization that is the 
serious event for which details must be provided.
Any event requiring hospitalization or prolongation of hospitalization that occurs during the study must be 
reported as a serious adverse event, except hospitalizations for the following:
•
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons such as 
pending placement in long-term care facility)
•
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were planned 
before the start of data collection 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

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results in a prolongation of the originally planned hospitalization is to be reported as a new serious 
adverse event.]
•
[For convenience the investigator may choose to hospitalize the subject for the duration of the 
treatment period.]
Life-Threatening Conditions
Disease progression should not be recorded as an adverse event or serious adverse event term; instead, signs 
and symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be reported if they 
fulfill the serious adverse event definition.
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 
3 or 4), because the terms serious and severe are NOT synonymous. The general term severe is often used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as the serious, which is based on patient/event 
outcome or action, criteria described above, and is usually associated with events that pose a threat to a patient’s 
life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be 
considered serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of reported 
and/or potential AEs (Section 9.2) and the characteristics of an observed AE (Section 9.3) will determine whether 
the event requires expedited reporting in addition to routine reporting.
9.2
Expected Toxicities
9.2.1
Adverse Events List(s)
9.2.1.1
Adverse Event List of Daratumumab
In general, daratumumab is tolerated well. The most frequently reported adverse events (AEs) across the 
daratumumab program have been infusion-related reactions (IRRs) following single agent therapy. Among all 
subjects treated in ongoing studies (monotherapy and combination therapy), IRRs have been reported in 49% of 
subjects; among 156 subjects treated with 16 mg/kg daratumumab monotherapy in Studies GEN501 and 
MMY2002, the percentage of subjects with a reported IRR was identical (48%) to what was observed across all 
treated subjects. Ninety-five percent (95%) of those patients, who had an IRR, had it during the first infusion; 
11% of patients had a reaction at more than one daratumumab infusion. Most of the reactions were mild or 
moderate, and ended by temporarily stopping the infusion and giving medicines to treat the side effect. The most 
frequently reported AEs (reported in ≥5% of subjects) reported as IRRs were rhinitis allergic (8%), cough (7%), 
and nasal congestion (6%). Among subjects treated with 16 mg/kg daratumumab monotherapy, the most 
commonly reported IRRs were nasal congestion (8%), cough (7%), and rhinitis allergic and throat irritation (5% 
each). Grade 3 or higher IRRs were reported in 5% of subjects treated with 16 mg/kg daratumumab as 
monotherapy, with bronchospasm and hypertension being the most frequently reported Grade 3 or higher IRRs

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(1% each). Across all ongoing studies, bronchospasm was reported in 10 subjects. Early in daratumumab 
development, in Study GEN501, 2 cases of bronchospasm were reported 24-48 hours following the second full- 
dose infusion of daratumumab. With the exception of those 2 cases, which had a delayed onset, all other reported 
bronchospasm events occurred following the first dose. All of the events occurring during the infusion period 
resolved quickly after standard treatments were administered. The daratumumab infusion was restarted, and no 
new onset of bronchospasm occurred. Most of the subjects who experienced bronchospasm had underlying 
respiratory diseases (asthma, chronic obstructive pulmonary disease [COPD], and others).
Among the 156 subjects treated with 16 mg/kg daratumumab as monotherapy in Studies GEN501 and MMY2002, 
the most frequently reported AEs (reported in >10% of subjects) were fatigue (39%); anemia (27%); nausea 
(27%); back pain (23%); neutropenia (22%); cough (21%); pyrexia (21%); thrombocytopenia (20%); decreased 
appetite (15%); infection of the nose, sinuses, or throat (20% each). Grade 3 and higher AEs were reported in 
33% of subjects treated with 16 mg/kg monotherapy daratumumab. The most frequently reported Grade 3 or 
higher AEs were lung infection (6%); decline in general physical health (3%); pyrexia (3%); and hypercalcemia 
(3%). All other Grade 3 and higher AEs were reported in <3% of subjects. No deaths due to daratumumab-related 
AEs have been reported in any ongoing study.
9.3
Adverse Event Characteristics
•
CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.03. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP web site:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
•
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
9.4
Expedited Adverse Event Reporting
9.4.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the initial 
dose of study treatment, during treatment, or within 30 days of the last dose of treatment on the local 
institutional SAE form.
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the DF/HCC. 
This applies to any medical event equivalent to an unexpected grade 2 or 3 with a possible, probable or 
definite attribution, all unexpected grade 4 toxicities, and grade 5 (death) regardless of study phase or 
attribution from the time of consent through 30 days after the last dose of the investigational agent.

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9.5
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for Human Research 
Studies (OHRS) per the DFCI IRB reporting policy.
The lead site (sponsor) study team will submit SAEs to the DFCI IRB on behalf of the site. Participating sites 
must report the event to the lead site study team within the time specified in order to comply with the reporting 
window.
Other investigative sites will also report SAEs to their respective IRB according to the local IRB’s policies and 
procedures in reporting adverse events. A copy of the submitted institutional SAE form should be forwarded to 
the Overall PI within the timeframes detailed in the table below.
Table 9- DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE
Unexpected
Gr. 4 AE
Unexpected
Gr. 5 AE
Expected or 
Unexpected
Unrelated 
Unlikely
Not required
Not required
5 calendar days
24 hours*
Possible 
Probable 
Definite
Not required
5 calendar days
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported except through routine reporting mechanisms ( entry in the EDC)
* For participants enrolled and actively participating in the study or for AEs occurring within 30 
days of the last intervention, the AE should be reported within 1 business day of learning of the 
event.
**** Events that are expected (event term), but were experienced at a more severe grade, or 
longer duration should also be reported, as this is considered unexpected
The Sponsor/Lead site study team will submit SAE reports from outside institutions to the DFCI OHRS per DFCI 
IRB policies and procedures in reporting adverse events.
If, following initiation of the investigational product, it is subsequently discovered that a study subject is pregnant 
or may have been pregnant at the time of investigational product exposure, including during at least 6 half lives 
after product administration, the investigational product will be permanently discontinued in an appropriate 
manner (e.g., dose tapering if necessary for subject safety).
Protocol-required procedures for study discontinuation and follow-up must be performed on the subject unless 
contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up procedures should be 
considered if indicated. The coordinating center must forward an SAE Form to Janssen within 24 hours and in 
accordance with the reporting procedures described in section 9.7.

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•
age at AE onset
•
reporter ID
•
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action taken, outcome, 
(if available)
•
Janssen protocol ID
9.8
Adverse Events of Special Interest
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is actively monitoring as a 
result of a previously identified signal (even if non-serious). These adverse events are:
•
Infusion reactions: ≥ grade 3
•
Infections: ≥ grade 4
•
Cytopenias: ≥ grade 4
•
HBV Reactivation
•
Other malignancies
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be recorded on a 
Serious Adverse Event Report Form and be reported to the COMPANY within 24 hours of knowledge of 
the event.
9.9
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety reports or 
sentinel events that require reporting according to institutional policy.
9.10
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case report 
forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be reported in 
routine study data submissions.
9.11
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 a medicinal product(s) with a marketing authorization, the expectedness of an 
adverse event will be determined by whether or not it is listed in the applicable product information.
http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf
For DARZALEX® (daratumumab), the expectedness of an adverse event will be determined by whether or not 
it is listed in the Investigator's Brochure
9.12
Special Reporting Situations

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Safety events of interest for a Janssen medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to:
•
Drug exposure during pregnancy (maternal and paternal)
•
Overdose of a Janssen medicinal product
•
Exposure to a Janssen medicinal product from breastfeeding
•
Suspected abuse/misuse of a Janssen medicinal product
•
Inadvertent or accidental exposure to a Janssen medicinal product
•
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen medicinal product
•
Medication error involving a Janssen medicinal product (with or without patient exposure to the 
Janssen medicinal product, e.g., name confusion)
•
Suspected transmission of any infectious agent via administration of a medicinal product
•
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product
These safety events may not meet the definition of an adverse event; however, from a Janssen Scientific 
Affairs, LLC perspective, they are treated in the same manner as adverse events. Special situations 
should be recorded on the Adverse Event page of the CRF.
Any special situation that meets the criteria of a serious adverse event should be recorded on a Serious 
Adverse Event Report Form and be reported to Janssen Scientific Affairs, LLC within 24 hours of 
becoming aware of the event.
9.13
SAEs, Adverse Events of Special Interest and Special Reporting Situations
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)
The coordinating center will transmit all SAEs, Adverse Events of Special Interest and special situations 
following exposure to a Janssen product under study in a form provided by Janssen Scientific Affairs, LLC in 
accordance with Section 9.7, Expedited Reporting to Janssen, in English within 24-hours of becoming aware 
of the event(s).
In the event the study is blinded, the coordinating center will submit an unblinded SAE or pregnancy exposure 
report to Janssen Scientific Affairs, LLC.
All follow-up information for serious adverse events that are not resolved at the end of the study or by the time 
of patient withdrawal must be reported directly by the coordinating center, within 24 hours becoming aware, 
to Janssen Scientific Affairs, LLC using the Janssen Scientific Affairs, LLC Serious Adverse Event Report

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All available clinical information relevant to the evaluation of a related SAE, Adverse Events of Special 
Interest, serious ADR or special situation is required.
•
The coordinating center is responsible for ensuring that these cases are complete and if not are 
promptly followed-up. A safety report is not considered complete until all clinical details needed to 
interpret the case are received. Reporting of follow-up information should follow the same timeline as 
initial reports.
•
Copies of any and all relevant correspondences with regulatory authorities and ethics committees 
regarding any and all serious adverse events, irrespective of association with the Janssen Product under 
study, are to be provided to Janssen Scientific Affairs, LLC using a transmission method in Section
9.7 within 24 hours of such report or correspondence being sent to applicable health authorities.
9.14
Non-Serious AEs
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according to the timeframe 
outlined in the Research Funding Agreement section entitled Reporting of Data.
9.15
Product Quality Complaint (PQC)
A product quality complaint is defined as any suspicion of a product defect related to a potential quality issue 
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage or distribution 
of the product, or delivery system. Not all PQCs involve a subject. Lot and batch numbers are of high significance 
and need to be collected whenever available.
Examples of PQC include but not limited to:
•
Functional Problem: e.g., altered delivery rate in a controlled release product
•
Physical Defect: e.g. abnormal odor, broken or crushed tablets/capsules
•
Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle detaching from 
syringe
•
Suspected Contamination
•
Suspected Counterfeit
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 patients, investigators, and Janssen 
Scientific Affairs, LLC, and are mandated by regulatory agencies worldwide. Janssen Scientific Affairs, LLC has 
established procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of 
PQC information. Lot and/or Batch #s shall be collected for any reports of failure of expected pharmacological 
action (i.e., lack of effect). The product should be quarantined immediately and if possible, take a picture.
All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen Scientific Affairs, 
LLC by the coordinating center within 24 hours after being made aware of the event. The Janssen contact will 
provide additional information/form to be completed.

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If the defect for a Janssen medicinal product under study is combined with either a serious adverse event or non- 
serious adverse event, the coordinating center must report the PQC to Janssen Scientific Affairs, LLC according 
to the serious adverse event reporting timelines. A sample of the suspected product should be maintained for 
further investigation if requested by Janssen Scientific Affairs, LLC.
9.16
Pregnancy
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC by the Overall Principal 
Investigator within 24 hours of becoming aware of the event using the Serious Adverse Event Form. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, 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.
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in partners of male subjects 
exposed to a Janssen medicinal product will be reported by the Overall Principal Investigator within 24 hours of 
their knowledge of the event using the Serious Adverse Event Form. Depending on local legislation this may 
require prior consent of the partner.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required.
10. STUDY CALENDAR
Screening evaluations are to be conducted within 42 days prior to registration. Baseline assessments are to be 
conducted on C1D1 of initial therapy and should be considered separate from screening evaluations. If screening 
assessments are performed within 7 days of C1D1, disease assessments do not need to be repeated. All assessments 
must be performed prior to administration of any study medication. See below for detailed scheduled of 
assessments. Study medications will be administered according to the schedule and guidelines outlined in Section 
5.
Pre-registration
During Treatment1, 3
Follow Up18
Tests and procedures
≤ 42 days prior to 
registration
Cycle 1-20
Day 1
Cycle 1-20 
Intracycle on 
Days of Dosing
Clinically 
Indicated 
or to 
confirm 
CR9
End of 
Treatment13
Every 3-6 
Months22
History and exam, height, weight, vital 
signs. Performance Status
X
X
X
X
Toxicity Notation
X
X
X
Hematology group (WBC w/ diff, PLT, 
Hgb, ANC)1,10
X
X
X
X
X
Chemistry4, 10
X
X
X
X
X
Direct & total bilirubin2, 10
X
X
X
X
Blood Type and IAT Testing14
X

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HIV, HBV, HCV Testing 19,20
X
X20
X20
X20
Free light chain assay10
X
X
X
X
Serum and Urine Immunofixation 
(SPEP and UPEP) with quantitative 
immunoglobulins10, 11
X
X8
X
X
Response Assessment17
X
X
X
β2M, CRP, LDH10
X
X
X
X
X
Metastatic Bone Survey and MRI of the 
Full Spine
OR
PET/CT16
X
X
X
EKG
X
X
PFT 21
X
Serum or urine pregnancy test
X
Unilateral bone marrow aspirate and 
biopsy5
X
X
X
X12
Research bone marrow aspirate6
X5
X6
X6
X12
Research Blood7
X7
X7
X7
X7
X
Research Buccal Swab15
X
1- Cycle 1, Day 1 hematologic laboratory values need to meet eligibility criteria to begin treatment 
2- Direct bilirubin to be obtained if total bilirubin is abnormal.
3- Scheduling allows for -2/ +7 days.
4- Chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, glucose, albumin, 
ALT (SGPT), total protein, AST (SGOT), total bilirubin, uric acid, alkaline phosphatase, magnesium, and phosphorus.
5- These procedures should also be done at any time during the course of the study to confirm CR, or as clinically indicated 
6- Research bone marrow aspirate and biopsy at same time of clinically indicated bone marrow biopsy and to confirm response.
7- Peripheral blood samples for correlative studies.
8- SPEP with immunofixation and quantitative immunoglobulins should be performed at screening, cycles 1-20 day 1, EOT, 
and at each follow-up visit.
9- If confirmation of response BM biopsy/aspirate was performed within 12 weeks of subsequent time point listed; the aspirate 
need only be repeated.
10- For Cycle 1 Day 1, no need to repeat tests if they have been performed within the past 7 days. Testing may be performed 
up to 2 days before other infusion days. Results of hematology tests must be evaluated before each study drug administration. 
Perform at additional timepoints, as clinically indicated. To be done by local lab. Patients need only meet hematologic inclusion 
criteria to begin treatment on C1D1.
11- If the participant’s disease response is not followed primarily via a UPEP and Urine immunofixation, these tests may be 
done only at screening, as clinically indicated during treatment, end of treatment, and as clinically indicated during follow-up. 
12- Strongly recommended to be performed yearly after EOT during follow-up and is required when there is suspected clinical 
progression
13- End of Treatment Assessments should be performed 4 weeks (+/- 1 week) after the last dose of daratumumab
14- Participants should receive blood typing card per section 3.3.1, prior to first dose of therapy- If the participating institution 
does not have a card that it provides its patients, refer to Appendix G for a template for completion by the study team and 
given to each participant
15-Buccal swab(s) may be collected at any time during the study
16- If PET/CT results are concerning for myeloma involvement, a follow up MRI must be conducted to confirm eligibility 
(baseline) or progression (on study and in follow up) PET CT strongly recommended yearly after EOT during follow up and 
are required at time of suspected disease progression.
17- A response assessment is required starting on C2D1, and at cycle thereafter based on Day 1 values, at EOT, and at each 
follow up Day 1 until off study.
18- If travel to the main site is financially burdensome on the participant, an alternate follow up schedule may be approved 
after discussion with the Overall PI- Window for follow up visits is +/- 4 weeks ( 28 days)
19- Subjects who are currently in the treatment phase of the study who are within 6 months of starting study treatment when 
DFCI Protocol Amendment 11 is implemented will be required to have HBV serology performed locally upon signing the 
updated ICF- HBV serology and DNA testing is not required at screening or for subjects ongoing in the Treatment Phase who 
are within 6 months of starting study treatment if this was performed as part of standard of care within 3 months prior to first 
dose of daratumumab.
20- HBV testing for those with serologic evidence of resolved HBV infection (i.e., positive Anti-HBs or positive Anti-HBc)

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at Screening, HBV DNA testing by PCR must be performed locally every 12 weeks during treatment, at the End of Treatment 
Visit, and every 12 weeks for up to 6 months (24 weeks) after the last dose of study treatment- Refer to 5.2.1.5
21- Only those who are known to have COPD (chronic obstructive pulmonary disease) or severe, persistent asthma, or thought 
to have compromised lung function must have a PFT to confirm eligible (must have a FEV1 <50% of predicted normal. )
22- Participants unable to participate in follow up every 3 months may follow up every 6 months at PI discretion in accordance 
with standard of care follow-up frequency and COVID precautions. Physical exams and correlative blood draws that are not 
done due to virtual visits will not be considered violations. Local myeloma labs must be provided to the participating site for 
data entry purposes. Bone marrow biopsy and scans are strongly recommended yearly after EOT but are required when there 
is suspicion of clinical progression. These assessments can be waived due to extenuating circumstances or for insurance 
coverage reasons. Scans and bone marrow biopsy and research samples are required at time of suspected disease progression 
if one is performed
11. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with Daratumumab can be found in Section 9.2.1.
11.1
Daratumumab
11.1.1 Physical Description of Study Drug
Daratumumab is supplied as a colorless to pale yellow preservative-free solution for intravenous infusion in 
single-dose vials. Daratumumab drug product is formulated as a concentrate of 20 mg/mL ± 2 mg/mL in an 
isotonic buffer consisting of sodium acetate, sodium chloride, mannitol and polysorbate 20 at pH 5.5. It will be 
manufactured and provided under the responsibility of Janssen. Study drug labels will contain information to 
meet the applicable regulatory requirements.
11.1.2 Storage and Stability
All study drug vials must be stored in the original carton in a refrigerator ranging from 2°C to 8°C and must 
not be utilized after the expiry date printed on the label. The 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.
11.1.3 Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a 
self-contained and protective environment.
11.1.4 Availability and Ordering
Daratumumab will be provided free of charge by Janssen Scientific Affairs, LLC as 400mg/20ml vials. 
Biologics, Inc. will provide drug distribution services for the study. In the event that 400mg/20mL vials are not 
available, Janssen Scientific Affairs, LLC will provide an equivalent formulation of daratumumab in 100mg 
vials as a substitute.
The Janssen Scientific Affairs internal study number is 
.

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comprehensively characterize the MM genome and immune cells function and define molecular events driving 
development and progression of MM.
We will attempt to obtain samples on all patients at the following time points: before therapy, day 1 of each cycle, 
end of treatment, every three months during follow up, at the time of response determination (CR) and at disease 
relapse, and at the time of completion of the study. It is anticipated that approximately 90% of samples collected 
will be adequate for sequencing studies proposed. Samples will be kept until exhausted.
The tumor cells will be collected as described below. From these samples, high quality DNA (for tumor cells) 
and RNA (for tumor cells and immune cells) for both exome sequencing and RNA sequencing will be obtained. 
Germline DNA will be also obtained from a buccal swab from all patients at any time point of the study.
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic assessments to assess 
the impact of therapy on general measures of cellular immunity, MM reactive T cells, and antigen specific 
immunity. The percentage of circulating and bone marrow derived regulatory immune cells will be determined.
12.1
Minimal residual disease assessment (MRD)
Bone marrow samples will be collected per the collection time described in the table of sample collection 
(appendix b). Samples for MRD testing will be collected on all patients who achieve a VGPR or better in treatment 
or during follow-up at the specified timepoints laid out in Appendix B.
MRD will be assessed using Adaptive’s LymphoSIGHT platform as part of normal clinical care for Dana- 
Farber Cancer Institute patients only in patients that experience a Very Good Partial Response or better.
Bone marrow samples will be collected per the collection time described in the sample collection table. The 
samples will be prepared in the Ghobrial lab and sent for testing in bulk by Adaptive at an undetermined time 
during the study for analysis.
Using Adaptive’s LymphoSIGHT platform, rearranged immunoreceptor loci from genomic DNA will be 
extracted, amplified, and sequenced using V and J segment primers for each immunoreceptor gene. Tumor- 
specific clonotypes will be identified for each patient based on their high prevalence in bone marrow.
Sequences will be analyzed using standardized algorithms for clonotype determination. Adaptive MRD levels 
will be quantified using spiked-in reference sequences. Adaptive Inc. will hold samples for up to 6 months after 
they have been analyzed, and then will subsequently destroy the samples after exhaustion of the DNA.
12.2
Correlative Studies
Correlative studies will be performed to determine:
1. Clonal evolution during therapy and at time of progression (using whole exome sequencing)
2. Immune cell activity and numbers before therapy and during therapy

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12.2.1 Exome sequencing of tumor cells
Whole-exome capture libraries will be constructed from 100ng of tumor and normal DNA followed by shearing, 
end repair, phosphorylation and ligation to barcoded sequencing adapters. The DNA will be size-selected to 
exonic hybrid capture using SureSelect v2 Exome bait (Agilent, CA). Samples will be multiplexed and sequenced 
on Illumina HiSeq flowcells with the goal of an average depth of coverage of 100x. The resulting data will be 
analyzed with the current Illumina pipeline, which generates data files (BAM files). The details of the current 
analysis pipeline are published elsewhere10,56. Briefly, somatic single nucleotide variants are determined using 
the MuTect algorithm57. Indels and translocations are determined by the algorithms IndelLocator and dRanger, 
respectively. The MutSig algorithm identifies genes in which the observed mutations are inconsistent with what 
would be expected at random58. To accurately assess the significance of mutations, MutSig takes into account 
several covariates, which influence the background mutation model. These include the expression level of genes 
(for which published gene expression data of MM samples can be used), and other gene characteristics observed 
empirically to co-vary with mutation rate: local relative replication time59, and open vs. closed chromatin status60. 
Focal as well as arm-level copy number variations will be determined based on whole exome sequencing and 
subsequent application of the GISTIC algorithm61.
The DNA library will be prepared at the Ghobrial Lab, and then sequencing will be done at the following external 
lab:
Broad Institute Genomics Services 
Sequencing data will then be provided back to Ghobrial lab in the form of BAM file. The samples that are sent 
for analysis are exhausted during the process, and thus not able to be returned.
12.2.2 RNA sequencing of tumor cells
For RNA Sequencing, poly-A selection and cDNA synthesis will be performed, followed by library preparation, 
sequencing (76bp or 101bp paired reads), and sample identification with quality control. Details of experimental 
design are described in62,63-65. We will perform library construction using a non-strand specific Illumina TruSeq 
Protocol and sequence coverage to 100M total reads. Analysis will be performed as described in the preliminary 
data and in previous studies63-65.
The DNA library will be prepared at the Ghobrial Lab, and then sequencing will be done at the following external 
lab:
Broad Institute Genomics Services 

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Sequencing data will then be provided back to Ghobrial lab in the form of BAM file. The samples that are sent 
for analysis are exhausted during the process, and thus not able to be returned.
12.2.3 Immune cell characterization in peripheral blood and bone marrow
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic assessments to assess 
the impact of therapy on general measures of cellular immunity. We will determine the number of immune cells 
(T-regs, CD4 effector T cells, CD8 T-regs, CD8 effector T cells, NK, NKT, B cells, MSCs, M1 and M2 
macrophages, Dendritic cells and MDSCs at screening and during therapy. These cells will be quantified using 
CyTOF at DFCI. Each cell type will be defined by unique combinations of antibodies based on previous 
publications66,67. Regulatory T cells will be defined as CD4/CD25/FOXP3+ cells. Levels of naïve, effector and 
central memory cells will be quantified as CD45RA, CD45RO/CD62L-/CD27- and CD45RO/CD62L+/CD27+ 
cells, respectively. NK cells will be quantified by expression of CD56+ subsets. MDSCs will be quantified by 
CD33+/lineage-/DR- and CD11b/lineage-/DR- cells. CD38 expression in these immune cell subpopulations will 
be examined, and the CD38+ groups will be evaluated for response to daratumumab. We will also examine the 
percent expression of checkpoint regulators and how they are modulated with therapy. These checkpoint 
regulators include PD-1, Lag-3, Tim-3 and CTLA-4.
12.2.4 T cell specific responses
Previous daratumumab clinical studies in myeloma have demonstrated robust T cell changes in the daratumumab 
treated patients, with significant CD8+ T cell expansion that was higher in responding patients compared to non- 
responders. In addition, naïve CD8+ T cells decreased, and central memory CD8+ T cells increased. T cell 
clonality was monitored by TCR sequencing (ImmunoseqTM) and significantly increased with daratumumab 
treatment. Responders had significantly higher changes in clonality compared to non-responders. In addition, 
CD38+ immune suppressive cells (regulatory T cells, MDSC) were noted to decrease with daratumumab 
treatment. This data suggests that daratumumab may increase the adaptive immune response against malignant 
disease, and in patients with pre-malignancy who are treatment naïve, this immune response could be even more 
robust. Therefore, we will examine the T cell response to daratumumab treatment in this study through in depth 
immunophenotyping (flow or CyTOF), functional studies examining T cell response pre- and post-daratumumab 
treatment.
12.2.5 RNA sequencing of immune cells during therapy
We will dissect molecular alterations that occur in these cells during progression in MM and the role of therapy 
on these cells. We will obtain the T-regs, NK cells and MDSCs from the peripheral blood and bone marrow at 
the same time points described above. Similar samples will be obtained from the comparative untreated cohort. 
The cells will be isolated by flow sorting and submitted for RNA sequencing as described above.
The RNA library will be prepared at the Ghobrial Lab, and then sequencing will be done at the following external 
lab:
Broad Institute Genomics Services 

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Sequencing data will then be provided back to Ghobrial lab in the form of BAM file. The samples that are sent 
for analysis are exhausted during the process, and thus not able to be returned.
12.3
Bone Marrow Aspirate Samples
Collection of bone marrow aspirate specimens for exploratory analysis is voluntary for this study and will be 
obtained at the times of bone marrow collections. Specimens will be shipped (via traceable carrier) to and 
subsequently processed, analyzed, and stored at Dana-Farber Cancer Institute.
12.3.1 Specimens Required
•
2 Purple Top Tubes (EDTA), 10mL each. At certain timepoints, an additional 3ml Purple Top Tube 
(EDTA) is requested. Specimens should be collected on Mondays to Thursdays for same-day shipment.
12.3.2 Processing Information
•
Package tubes at room temperature and wrap in a liberal amount of paper towel around the tubes to ensure 
adequate insulation of the specimen(s) and absorption in the event of a breakage. Place wrapped specimen 
in a biohazard labeled Ziploc bag with a fridge pack and zip close. Wrap bubble wrap around the bag and 
place in a cardboard box. If space remains in the box, stuff with extra paper towel to reduce shifting of 
samples. Complete the shipping requisition form using the address listed below. Prepare the package for 
shipping, applying packing tape as needed. Ship the package using FedEx or UPS next day or overnight 
delivery the same day the sample was collected. Please only ship Monday-Thursday.
12.3.3 Shipping Information
•
Label all specimens with the following: Subject Initials, Subject study number (will include protocol 
number), Visit at which sample was drawn (screening, response or relapse/progression), Date sample 
drawn (mm/dd/yyyy), Time sample drawn (24 hour clock)
12.3.4 Shipping Instructions:
Shipments must be sent on the day of collection and cannot be batched.
1. An inventory sheet including a complete list of samples shipped (patient number, timepoint, study #) must 
accompany each shipment. Please sign and date the form.
2. An electronic copy (Word or Excel) of the sample list must also be sent via email. The listing must also 
include a contact name, address and phone number of the person who is responsible for the shipment.
3. Please email the Lead Site Research Project Manager to notify of an incoming shipment.

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For measurement of response:
The disease response will be assessed using criteria based on the International Working Group Uniform Response 
Criteria in Section 14.2.2.1. If the only measurable parameter is serum immunoglobulins free light chain (FLC), 
the participant will be followed by IMWG Response Criteria provided in Section 13.2.2.2
Disease response by the Modified EBMT Response Criteria in Section 13.2.2.3 will also be collected on 
participants as a secondary measure.
The same method of assessment and technique should be used for disease measurement at baseline and 
during follow-up. Disease response should be confirmed by two consecutive assessments.
13.2
Antitumor Effect
13.2.1 Methods for Evaluation of Disease
All baseline evaluations should be performed on Cycle 1, Day 1 (Week 1) of initial therapy.  Response will be 
assessed at at each cycle, at the end of treatment visit, and every 3 months (follow up) thereafter. Response 
will be assessed by M-protein quantification, protein electrophoresis and immunofixation from serum and a
24-hour urine collection (unless participants are not measured for response in their urine), A serum sample for 
free light chain ratio testing will be obtained. In addition, bone marrow aspiration and biopsy, as well as 
skeletal survey/PET-CT/MRI will be performed to determine overall response or confirm response.
Evaluations should be performed as determined by the Study Calendar, Section 10.
Daratumumab, as an immunoglobulin, may interfere with clinical SPE/IFE assessments. In cases 
where daratumumab interference is suspected, a reflex assay (DIRA: Daratumumab- specific 
Interference Reflex Assay) confirming the presence of daratumumab will be performed. In cases where 
CR or sCR is suspected and DIRA confirms that daratumumab is present on SPE/IFE, additional 
clinical assessments will be triggered to confirm the CR/sCR. A patient who meets all other clinical 
criteria for CR/sCR, and who has daratumumab interference confirmed by the reflex assay, will be 
considered a CR/sCR.
13.2.2 Response Criteria
A confirmation measurement for disease response assessments is required in this protocol.
13.2.2.1
International Myeloma Working Group Response Criteria
Response criteria for all categories and subcategories of response except CR are applicable only to patients 
who have ‘measurable’ disease, as defined in Section 11.1.1 All response categories require two 
consecutive assessments made at any time before the institution of any new therapy; all categories also 
require no known evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements.

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Response
Criteria for Response
Stringent CR 
(sCR)
CR as defined below plus normal free light chain ratio and absence of 
clonal cells in bone marrow* by immunohistochemistry or 
immunofluorescence.**
*Confirmation with repeat bone marrow biopsy is not needed.
**Presence/absence of clonal cells is based upon the k/λ ratio. An 
abnormal k/l ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is k/λ of > 4:1 or < 1:2.
Complete 
Response (CR)
Negative immunofixation on the serum and urine and disappearance of 
any soft tissue plasmacytomas and <5% plasma cells in bone marrow.
*Confirmation with repeat bone marrow biopsy is not needed.
Very Good Partial 
Response (VGPR)
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 90% or greater reduction in serum M-protein plus 
urine M-protein level <100 mg per 24 hours.
Partial Response 
(PR)
> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by
> 90% or to < 200 mg per 24 hours. If the serum and urine M-protein are 
unmeasurable, a > 50% decrease in the difference between involved and 
uninvolved free light chain levels is required in place of the M-protein criteria 
(definition of measurable disease in Section 10.2.3). If serum and urine M- 
protein are unmeasurable, and serum free light assay is also unmeasurable, > 
50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30%. In addition to the 
above listed criteria, if present at baseline, a > 50% reduction in the size of soft 
tissue plasmacytomas is also required.
Stable Disease 
(SD)
Not meeting criteria for CR, VGPR, PR or progressive disease. 
This is not recommended as an indicator of response; stability of 
disease is best described by providing the time to progression 
estimates.
Progressive 
Disease (PD)
> 25% increase of serum M-protein (which must also be an absolute increase of >
0.5 g/dL) and/or urine M-protein (which must also be an absolute increase of > 
200 mg/24hr). If serum and urine M-protein are unmeasurable, there must be an 
absolute increase of > 10 mg/dL between involved and uninvolved FLC levels. 
PD is also measured by an absolute increase in bone marrow plasma cells > 10%. 
In addition to the above listed criteria, progression may also be measured by a 
definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas 
or development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder.

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*Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria 
listed above. VGPR in such patients requires a > 90% decrease in the difference between involved and uninvolved 
FLC levels.
†Clarifications for coding PD: Bone marrow criteria for PD are to be used only in patients without measurable 
disease by M protein and by FLC levels. The “25% increase” refers to M protein, FLC, and bone marrow results, 
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response
value” does not need to be a confirmed value.
13.2.2.2
Modified EBMT Disease Response Criteria
Response
Criteria for Responsea
Complete Response 
(CR)
Requires all of the following:
Disappearance of the original monoclonal protein from the blood and urine on 
at least two determinations for a minimum of six weeks by immunofixation 
studies.
<5% plasma cells in the bone marrow on at least two determinations for 
a minimum of six weeks. b
No increase in the size or number of lytic bone lesions (development of 
a compression fracture does not exclude response).c
Disappearance of soft tissue plasmacytomas for at least six weeks.
Near Complete Response 
(nCR)
Requires the following:
Same as CR, but immunofixation studies continue to show presence of 
the monoclonal protein
Very Good Partial Response 
(VGPR)
Requires the following:
> 90% reduction in serum M-protein plus urine M-protein level <100mg per 
24 hours on at least two determinations for a minimum of six weeks.

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Partial response (PR)
PR includes participants in whom some, but not all, criteria for CR are 
fulfilled providing the remaining criteria satisfy the requirements for PR. 
Required all of the following:
≥50% reduction in the level of serum monoclonal protein for at least 
two determinations six weeks apart.
If present, reduction in 24-hour urinary light chain excretion by either ≥90% or 
to < 200 mg for at least two determinations six weeks apart.
≥50% reduction in the size of soft tissue plasmacytomas (by clinical 
or radiographic examination) for at least six weeks.
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).c
Minimal response (MR)
MR included participants in whom some, but not all, criteria for PR were 
fulfilled, providing the remaining criteria satisfied the requirements for 
MR. Required all of the following:
≥25% to 49% reduction in the level of serum monoclonal protein for at least 
two determinations six weeks apart.
If present, a ≥50 to 89% reduction in 24-hour light chain excretion, which 
still exceeds 200 mg/24 h, for at least two determinations six weeks apart.
≥25-49% reduction in the size of plasmacytomas (by clinical or 
radiographic examination) for at least six weeks.
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).c
No change (NC)
Not meeting the criteria for MR or PD.

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Response
Criteria for Responsea
Progressive disease 
(PD)
(for participants not 
in CR)
Requires one or more of the following:
>25% increased in the level of serum monoclonal paraprotein, which must also be 
an absolute increase of at least 5 g/L and confirmed on a repeat investigation.
>25% increased in 24-hour urinary light chain excretion, which must also be an 
absolute increase of at least 200 mg/24 h and confirmed on a repeat investigation.
>25% increased in plasma cells in a bone marrow aspirate or on trephine biopsy, 
which must also be an absolute increase of at least 10%.
Definite increase in the size of existing lytic bone lesions or soft tissue 
plasmacytomas.
Development of new bone lesions or soft tissue plasmacytomas (not including 
compression fracture).
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 
mmol/L not attributable to any other cause).
Relapse from CR
Required at least one of the following:
Reappearance of serum or urinary paraprotein on immunofixation or routine 
electrophoresis confirmed by at least one follow-up and excluding oligoclonal 
immune reconstitution.
≥5% plasma cells in the bone marrow aspirate or biopsy.
Development of new lytic bone lesions or soft tissue plasmacytomas or definite 
increase in the size of residual bone lesions (not including compression fracture).
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 
mmol/L not attributable to any other cause)e.
a Based on the criteria reported by Blade et al., 1998.
b Per Blade et al., 1998, if absence of the monoclonal protein is sustained for 6 weeks it is not necessary to repeat the bone marrow except in participants with nonsecretory myeloma where the 
marrow examination must be repeated after an interval of at least 6 weeks to confirm CR.
c Per Blade et al., 1998, skeletal X-Rays are not required for the definition of response, but if performed there must be no evidence of progression of bone disease (no increase in size or number of 
lytic bone lesions).

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d It is suggested that the reference point for calculating any increase should be the lowest value of the preceding confirmed response (MR, PR or CR) or the baseline value if there is no previous 
confirmed response.
e Other clinical data may be requested by the IRC, as necessary, to assess the cause of the hypercalcemia.
13.2.3 Criteria for Molecular CR and Minimal Residual Disease (MRD) measurement
We will measure MRD via Adaptive’s LymphoSIGHT platform in Dana-Farber Cancer Institute patients 
who achieve VGPR or better to determine the number of patients who are MRD negative vs MRD positive.
13.2.3.1
MRD Analysis
MRD will be performed via LymphoSIGHT, flow cytometry, or both.
MRD will be carried out according to the LymphoSIGHTTM method (Adaptive Inc,) using clinical bone marrow 
aspirate samples66. Prior studies have compared this technique to the traditional MRD immunofluorescence 
technique, as previously reported 67 and showed that MRD by LymphoSight is a sensitive method that can be 
used in future clinical practice.
For MM diagnostic samples, genomic DNA will be amplified using locus-specific primer sets for the 
immunoglobulin heavy-chain locus (IGH) complete (IGH-VDJH), IGH incomplete (IGH-DJH), and 
immunoglobulin κ locus (IGK). The amplified product will be subjected to sequencing, and the sequences and 
frequencies of the different clonotypes in the sample will be obtained. Myeloma gene rearrangements will be 
identified. Patients in whom a high-frequency myeloma clone (>5%) is not identified will be excluded from the 
MRD analysis. MRD will be assessed in patients with a high-frequency myeloma clone using the IGH-VDJH and 
IGK or IGH-VDJH, IGH-DJH, and IGK assays. Once the absolute amount of total cancer-derived molecules 
present in a sample will be determined, a final MRD measurement will be calculated, providing the number of 
cancer-derived molecules per 1 million cell equivalents. In cases in which 2 or more tumor clones existed, the 
clone with the highest MRD value will be reported. Molecular CR will be defined according to the International 
Myeloma Working Group (IMWG) consensus recommendations
13.2.4 Duration of Response and Endpoint Definitions
Duration of overall response: The duration of overall response is measured as the time from initiation of 
first response to first documentation of disease progression or death. Patients who have not progressed or died 
are censored at the date last known progression-free.
Duration of overall complete response: The duration of overall CR is progression or death. Patients 
who have not progressed or died are censored at the date last known progression-free.
Time to progression: Time to progression is defined as the time of randomization until progression. Patients 
who have died without evidence of progression are censored in the TTP analysis at the time of death and patients 
who are alive without progression are censored at the last disease assessment.
13.2.5 Progression-Free Survival
Progression-Free Survival (PFS): PFS is defined as the time from first-dose to the disease progression or death from

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any cause. Patients who have not progressed or died are censored at the date last known progression-free.
13.2.6 Response Review
Central review of disease response assessments is not planned.
14. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements).
14.1
Data Reporting
14.1.1 Method
The Office of Data Quality will collect, manage, and perform quality checks on the data for this study.
14.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the Office 
of Data Quality according to the schedule set by ODQ. Data should be entered within 14 business days of the 
corresponding visit and within 14 business days of the end of a cycle for any forms to be completed per 
cycle.
14.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data 
from this study. The committee is composed of clinical specialists with experience in oncology and who have no 
direct relationship with the study. Information that raises any questions about participant safety will be addressed 
with the Overall PI and study team.
The DSMC will review each protocol up to four times a year or more often if required to review toxicity and 
accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene therapy 
protocols, summary of all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.
15. STATISTICAL CONSIDERATIONS
The primary objective of this study is to determine the proportion of patients who are in VGPR or better after 
therapy with Daratumumab. Secondary objectives include safety, duration of response and MRD negative rate.

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Correlative objectives include correlative immune cell regulation and clonal evolution.
15.1
Study Design/Endpoints
The primary endpoint of this study is to determine the proportion of patients with high-risk MGUS and low-risk 
smoldering multiple myeloma (SMM) patients who have a deep response (defined as VGPR or better) to 
daratumumab. Secondary endpoints include toxicity rates, MRD negative rate, and duration of response.
Correlative objectives are to a) evaluate clonal heterogeneity using deep sequencing at the DNA and RNA level 
and determine association of genomic aberrations with response/progression to daratumumab and progression to 
SMM/MM, b) evaluate T cell response (flow cytometry, TCR sequencing, functional T cell status) in this 
patient population, c) assess changes in the immune microenvironment in high-risk MGUS patients over the 
course of the study; to assess these immune changes and association with progression to SMM or MM, d) 
examine the immunoglobulin sequence in MGUS and SMM patients to determine if common clonal sequences 
are noted among high-risk MGUS and low-risk SMM, and to evaluate whether common Ig sequences are 
associated with progression and e) assess the rate of secondary hematologic malignancies.
Fifty patients will be entered on study. The criteria used to determine the treatment is promising that the lower 
limit of the two-sided 90% binomial confidence interval for the deep response rate is at least 50%. Given that 
this group of patients is usually not treated, the design is such that the true deep response rate is at least 50%. If 
an observed deep response (VGPR or better) rate is 64% (≥ 32/50 patients) the treatment will be considered 
promising. The power to detect a treatment effect was computed assuming a response rate of 70% or 75%. In 
these two scenarios, the power is equal to 86% and 97% (with type I errors of 0.03).
15.1.1 Analysis of Primary Endpoint
The primary endpoint is the proportion of patients in deep response (VGPR or better). The estimate and the two- 
sided 90% binomial confidence interval will be provided in the analysis.
15.1.2 Analysis of Secondary Endpoints
The objective response rate (partial response or better according to the modified IMWG criteria) and the 
proportion of patients that are MRD negative, CR, PR or MR will be reported with 90% exact binominal 
confidence interval (CI).
To estimate the duration of response (time from objective response to disease progression or death, or date last 
known progression-free and alive for those who have not progressed or died) the Kaplan-Meier method will be 
used.
Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study 
treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed 
using CTCAE version 4 as appropriate.
15.2
Sample Size, Accrual Rate and Study Duration

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A total of 50 eligible patients will be enrolled. We expect 2 years of active accrual (approximately 2 patients per 
month) and 5 years of follow-up of patients.
15.3
Stratification Factors
There are no stratification factors.
15.4
Interim Monitoring Plan
The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The DSMC will meet at 
least four times a year and more often if needed (e.g., for safety review). For each meeting, the study will be 
reviewed for safety and progress toward completion. Copies of the toxicity reports prepared by the DSMC 
meetings will be distributed to the Principal Investigator. The Principal Investigator will then distribute to sub 
investigators. Any DSMC recommendations for changes to the study will be distributed to the Principal 
Investigator and then circulated to sub- investigators by the Principal Investigator. No interim analysis of the 
outcome data is planned.
15.5
Stopping Rule for Safety
All participants will be evaluable for treatment-related toxicity from the time of therapy initiation. The severe 
adverse event (SAE) is defined as any grade 3 adverse events that affect organ function (cardiac, hepatic, 
thromboembolic) or grade 4/5 non-hematologic AEs. We anticipate that the rate of SAE is low in this study 
population and there is no pre-defined stopping rule for safety.
16. PUBLICATION PLAN
The results should be made public within 12 months of reaching the end of the study. The end of the study is the 
time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for 
analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of 
the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no 
later than two (2) years after the end of the study. Data sets from other relevant studies such as 14-338, 16-313, 
or data from other collaborators may be used and/or analyzed for the purposes of the publication.

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aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple 
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47. Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J 
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48. Kyle RA, Larson DR, Therneau TM, et al: Clinical course of light-chain smouldering multiple myeloma 
(idiopathic Bence Jones proteinuria): a retrospective cohort study. Lancet Haematol 1:e28-e36, 2014
49. Rajkumar SV, Dimopoulos MA, Palumbo A, et al: International Myeloma Working Group updated 
criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538-48, 2014
50. Rajkumar SV, Landgren O, Mateos MV: Smoldering multiple myeloma. Blood, 2015
51. Tiedemann RE, Gonzalez-Paz N, Kyle RA, et al: Genetic aberrations and survival in plasma cell 
leukemia. Leukemia 22:1044-52, 2008
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53. Chng WJ, Huang GF, Chung TH, et al: Clinical and biological implications of MYC activation: a common 
difference between MGUS and newly diagnosed multiple myeloma. Leukemia 25:1026-35, 2011
54. Lopez-Corral L, Sarasquete ME, Bea S, et al: SNP-based mapping arrays reveal high genomic complexity 
in monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26:2521-9, 2012
55. Paiva B, Gutierrez NC, Rosinol L, et al: High-risk cytogenetics and persistent minimal residual disease by 
multiparameter flow cytometry predict unsustained complete response after autologous stem cell 
transplantation in multiple myeloma. Blood 119:687-91, 2012
56. Lohr JG, Stojanov P, Lawrence MS, et al: Discovery and prioritization of somatic mutations in diffuse 
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58. Hammerman PS, Hayes DN, Wilkerson MD, et al: Comprehensive genomic characterization of squamous 
cell lung cancers. Nature 489:519-25, 2012
59. Chen CL, Rappailles A, Duquenne L, et al: Impact of replication timing on non-CpG and CpG substitution 
rates in mammalian genomes. Genome research 20:447-57, 2010
60. Lieberman-Aiden E, van Berkum NL, Williams L, et al: Comprehensive mapping of long-range 
interactions reveals folding principles of the human genome. Science 326:289-93, 2009
61. Beroukhim R, Getz G, Nghiemphu L, et al: Assessing the significance of chromosomal aberrations in 
cancer: methodology and application to glioma. Proceedings of the National Academy of Sciences of the 
United States of America 104:20007-12, 2007
62. Eswaran J, Horvath A, Godbole S, et al: RNA sequencing of cancer reveals novel splicing alterations. Sci 
Rep 3:1689, 2013
63. Kothari V, Wei I, Shankar S, et al: Outlier kinase expression by RNA sequencing as targets for precision 
therapy. Cancer Discov 3:280-93, 2013
64. Yu M, Ting DT, Stott SL, et al: RNA sequencing of pancreatic circulating tumour cells implicates WNT 
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65. Griffith M, Griffith OL, Mwenifumbo J, et al: Alternative expression analysis by RNA sequencing. Nat 
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66. Rosenblatt J, Glotzbecker B, Mills H, et al: PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex 
vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 34:409-18, 2011
67. Azzi J, Moore RF, Elyaman W, et al: The novel therapeutic effect of phosphoinositide 3-kinase-gamma 
inhibitor AS605240 in autoimmune diabetes. Diabetes 61:1509-18, 2012
68. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al: Prognostic value of deep sequencing method for minimal 
residual disease detection in multiple myeloma. Blood 123:3073-9, 2014
69. Paiva B, Gutierrez NC, Rosinol L, et al: High-risk cytogenetics and persistent minimal residual disease by 
multiparameter flow cytometry predict unsustained complete response after autologous stem cell 
transplantation in multiple myeloma. Blood 119:687-91, 2012
70. Rajkumar SV, Harousseau JL, Durie B, et al: Consensus recommendations for the uniform reporting of 
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117:4691-5, 2011
71. Korde, Neha, Kristinsson, Sigurdur Y., Landgren, Ola et al: Monoclonal gammopathy of undetermined 
significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and 
development of early treatment strategies. Blood. 2011; 117:5573-5581
72. Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal

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gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow 
cytometry analysis of bone marrow plasma cells. Blood. 2007;110(7):2586-2592.
73. 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.
74. Overdijk MB, Verploegen S, Bogels M, et al. Phagocytosis is a potent mechanism of action for the 
therapeutic human monoclonal antibody daratumumab in lymphoma and multiple myeloma. Submitted to 
Blood. 13 May 2013.
75. Barr H, Dempsey J, Waller A, et al. Ninety-Minute Daratumumab Infusion Is Safe in Multiple Myeloma. 
Blood 2017 130: 1889
76. Barr H, Demspey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. 
Leukemia. 31 March 2018; 1476-5551

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APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his/her needs.
2
In 
bed 
<50% 
of 
the 
time. 
Ambulatory and capable of all self- 
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely
disabled,
hospitalization 
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% 
bedridden. 
Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair.
10
Moribund,
fatal
processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B: SPECIMEN COLLECTION SCHEDULE
Sample Time Point3
Recipient
Sample Type
Shipping Method
Container1
Peripheral Blood
3x 10mL Purple Top 
1x6ml Red Top
Bone Marrow Aspirate
Fridge pack same day
2x10mL Purple Top 
1x3ml Purple Top
Baseline
DFCI
Buccal Swab2
Ambient same day
2x Buccal Swab
Cycle 1 – 20
Day 1 
(Pre- Dose)
DFCI
Peripheral Blood
Fridge pack same day
2x10mL Purple Top 
1x6ml Red Top3
Bone Marrow Aspirate
2x10mL Purple Top 
1x3ml Purple Top
Annually
(Yearly from EOT +/-28 
days)
DFCI
Peripheral Blood
Fridge pack same day
3 x 10mL Purple Top 
1 x 6ml Red Top
Peripheral Blood
3x 10mL Purple Top 
1x6ml Red Top
Confirm Response4
DFCI
Bone Marrow Aspirate
Fridge pack same day
2x10mL Purple Top 
1x3ml Purple Top
Peripheral Blood
3 x 10mL Purple Top 
1 x 6ml Red Top
End of Treatment 
and/or Disease 
Progression
DFCI
Bone Marrow Aspirate
Fridge pack same day
2 x10mL Purple Top 
1 x 3mL Purple Top
Peripheral Blood
3 x 10mL Purple Top 
1 x 6ml Red Top
Follow-up5 
(Blood samples will be 
collected every 3 or 6
months +/- 28 days)
DFCI
Bone Marrow Aspirate5
Fridge pack same day 
Same day
2 x10mL Purple Top 
1 x 3mL Purple Top
Bone Marrow Aspirate
2x10mL Purple Top 
1 x 3mL Purple Top
Clinically Indicated 
and/or Yearly Bone 
Marrow 
Biopsy/Aspirate
DFCI
Peripheral Blood
Fridge pack same day
3 x 10mL Purple Top 
1 x 6ml Red Top
1 Purple Top= K2EDTA Tube; Red Top= No Additive
2 Buccal swabs can be collected at any point while on the study- Two swabs may be taken to ensure collection of cells
3 Samples at all time points are voluntary, and do not exclude patients from treatment
4 For this study, VGPR or CR- For definition of Response, please refer to section 13.2.2.
5 During follow up, bone marrow aspirate procedures are requested yearly from the time of EOT

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APPENDIX D: DANA-FARBER/ HARVARD CANCER CENTER MULTI-CENTER OVERSIGHT 
PLAN AND DATA SAFETY MONITORING PLAN
Version 2 7.28.2017
DFCI IRB Protocol #:17-212

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TABLE OF CONTENTS
1.
INTRODUCTION ........................................................................................................................74
1.1
Purpose .......................................................................................................................................74
1.2
Multi-Center Data and Safety Monitoring Plan Definitions ......................................................75
2.
GENERAL ROLES AND RESPONSIBILITIES......................................................................75
2.1
DF/HCC Sponsor........................................................................................................................75
2.2
Coordinating Center ...................................................................................................................75
2.3
Participating Institution ..............................................................................................................76
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ...................................77
3.1
Protocol Distribution ..................................................................................................................77
3.2
Protocol Revisions and Closures................................................................................................77
3.3
Informed Consent Requirements................................................................................................77
3.4
IRB Documentation....................................................................................................................78
3.5
IRB Re-Approval .......................................................................................................................78
3.6
Participant Confidentiality and Authorization Statement...........................................................78
3.7
DF/HCC Multi-Center Protocol Registration Policy .................................................................79
3.8
DF/HCC Protocol Case Number ................................................................................................80
3.9
Safety Assessments and Toxicity Monitoring............................................................................81
3.10
Data Management ......................................................................................................................81
4.
REQUISITIONING INVESTIGATIONAL DRUG..................................................................87
5.
MONITORING: QUALITY CONTROL...................................................................................82
5.1
Ongoing Monitoring of Protocol Compliance............................................................................82
5.2
Monitoring Reports ....................................................................................................................83
5.3
Accrual Monitoring ....................................................................................................................83
6.
AUDITING: QUALITY ASSURANCE......................................................................................84
6.1
DF/HCC Internal Audits.............................................................................................................84
6.2
Audit Notifications.....................................................................................................................84
6.3
Audit Reports..............................................................................................................................84
6.4
Participating Institution Performance.........................................................................................84

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1.
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) 
outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP 
serves as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical trial.
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol 
will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) 
requirements and applicable DF/HCC Standard Operating Procedures.
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol: A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. 
DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates.
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-Farber 
Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center 
(BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital (BWH) responsible for the 
coordination, development, submission, and approval of a protocol as well as its subsequent amendments 
per the DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), 
Office of Biotechnology Activities (OBA) etc.). The Lead Institution is typically the home of the DF/HCC 
Sponsor. The Lead Institution also typically serves as the Coordinating Center for the DF/HCC Multi- 
Center Protocol.
DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol who takes responsibility 
for initiation, management and conduct of the protocol at all research locations. In applicable protocols, 
the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (i.e. FDA). The DF/HCC 
Sponsor has ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC 
and all Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Overall Principal Investigator; however, both roles can be filled by two different people.
Participating Institution: An institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator. The Participating 
Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the 
overall conduct of the study.
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization 
(CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill 
the responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory

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guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center 
for the DF/HCC Multi-Center Protocol.
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-quality 
standards are used for data collection and the ongoing management of clinical trials, auditing, and data and 
safety monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research.
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC responsible 
for providing a comprehensive data management platform for managing clinical trial data.
2.
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating 
Institutions are expected to adhere to the following general responsibilities:
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, Irene M. Ghobrial, MD will accept responsibility for all aspects of conducting a 
DF/HCC Multi-Center protocol which includes but is not limited to:
•
Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.
•
Ensure that the investigators, study team members, and Participating Institutions are qualified and 
appropriately resourced to conduct the protocol. A current CV will be collected at study initiation.
•
Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.
•
Ensure all Participating Institutions are using the correct version of the protocol, as well as current 
Investigator Brochure or product information.
•
Ensure that each participating investigator and study team member receives adequate protocol 
training (and/or a Site Initiation Visit prior to enrolling participants) and throughout trial’s conduct 
as needed. All site Principal Investigators will sign protocol signature pages at study initiation and 
each protocol version change.
•
Ensure the protocol will be provided to each participating site in a language understandable to all 
applicable site personnel when English is not the primary language.
•
Monitor progress and overall conduct of the study at all Participating Institutions.
•
Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. FDA) 
reporting requirements are met.
•
Review data and maintain timely submission of data for study analysis.
•
Act as the single liaison with FDA (investigator-held IND trials), as applicable. All tasks delegated 
by the Sponsor-Investigator to the CRO will be detailed to the appropriate regulatory authority, as 
applicable.
•
Ensure compliance with all requirements as set forth in the Code of Federal Regulations, applicable 
DF/HCC requirements, HIPAA requirements, and the approved protocol.
•
Commit to the provision that the protocol will not be rewritten or modified by anyone other than 
the DF/HCC Sponsor.
•
Identify and qualify Participating Institutions and obtain accrual commitments prior to extending 
the protocol to that site.

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•
Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.
2.2
Coordinating Center
The general responsibilities of the Coordinating Center may include but are not limited to:
•
Assist in protocol development.
•
Maintain FDA correspondence, as applicable.
•
Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS).
•
Distribute protocol and informed consent document updates to Participating Institutions as needed.
•
Oversee the data collection process from Participating Institutions.
•
Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation 
submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely review and 
submission to the DFCI IRB, as necessary.
•
Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting Policy to all Participating Institutions.
•
Provide Participating Institutions with information regarding DF/HCC requirements that they will 
be expected to comply with.
•
Carry out plan to monitor Participating Institutions either by on-site or remote monitoring. Source 
data will be maintained and Case Report Forms (CRFs) will be verified with source data, as 
applicable.
•
Maintain Regulatory documents of all Participating Institutions which includes but is not limited 
to the following: local IRB approvals/notifications from all Participating Institutions, 
confirmation of Federalwide Assurances (FWAs) for all sites, all SAE submissions, Screening 
Logs for all sites, IRB approved consents for all sites
•
Conduct regular communications with all Participating Institutions (conference calls, emails, etc) 
and maintain documentation all relevant communications.
2.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC 
requirements, the protocol and HIPAA requirements.
The general responsibilities for each Participating Institution may include but are not limited to:
•
Document the delegation of research specific activities to study personnel.
•
Commit to the accrual of participants to the protocol.
•
Submit protocol and/or amendments to their local IRB.
•
Maintain regulatory files as per sponsor requirements.
•
Provide the Coordinating Center with regulatory documents or source documents as requested.
•
Participate in protocol training prior to enrolling participants and throughout the trial as required 
(i.e. teleconferences).
•
Update Coordinating Center with research staff changes on a timely basis.
•
Register participants through the Coordinating Center prior to beginning research related activities.

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•
Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements and to the 
Coordinating Center, in accordance with DF/HCC requirements.
•
Submit protocol deviations and violations to local IRB per institutional requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements.
•
Order, store and dispense investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements as listed in the IP Management Plan.
•
Have office space, office equipment, and internet access that meet HIPAA standards.
•
Participate in any quality assurance activities and meet with monitors or auditors at the conclusion 
of a visit to review findings.
•
Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings.
3.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for participating 
in a DF/HCC Multi-Center protocol.
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center. It is the individual Participating Institution’s responsibility to notify its IRB of these 
revisions.
•
Non life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Coordinating Center. Non-life- 
threatening protocol revisions must be IRB approved and implemented within 90 days from receipt 
of the notification.
•
Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect lives 
with follow-up by fax, mail, e-mail, etc. Life-threatening protocol revisions will be implemented 
immediately followed by IRB request for approval.
•
Protocol closures and temporary holds: Participating Institutions will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds will be 
effective immediately. In addition, the Coordinating Center, will update the Participating 
Institutions on an ongoing basis about protocol accrual data so that they will be aware of imminent 
protocol closures.

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3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed consent for 
Participating Institutions. The Participating Institution consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on 
Model Consent Language for PI-Initiated Multi-Center Protocols. This document will be provided 
separately to each Participating Institution upon request.
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the Coordinating 
Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
Participating institutions must follow the DF/HCC requirement that only attending physicians obtain 
informed consent and re-consent for all interventional drug, biologic, or device research. The informed 
consent will be explained to each subject and signed and dated by the subject prior to participation in the 
study. The consent will be retained on file by the investigator.
3.4
IRB Documentation
The following must be on file with the Coordinating Center:
•
Initial approval letter of the Participating Institution's IRB.
•
Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.
•
Participating Institution’s IRB approval for all amendments.
•
Annual approval letters by the Participating Institution's IRB.
3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to continue research 
activities. There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from the 
Participating Institution on or before the anniversary of the previous approval date.
3.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known as the 
Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the physical or 
mental health of an individual is called Protected Health Information (PHI). HIPAA outlines how and under 
what circumstances PHI can be used or disclosed.

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In order for covered entities to use or disclose protected health information during the course of a study, 
the study participant must sign an authorization statement. This authorization statement may or may not 
be separate from the informed consent document. The Coordinating Center, with the approval from the 
DFCI IRB, will provide a consent template, with information regarding authorization for the disclosure of 
protected health information.
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be collected. 
DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than limited data 
sets with data use agreements.
3.6.1 DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly confidential. 
Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, 
Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended 
that the assigned protocol case number (as described below) be used for all participant specific documents. 
Participant initials may be included or retained for cross verification of identification.
3.7
DF/HCC Multi-Center Protocol Registration Policy
3.7.1 Participant Registration and Randomization
To register a participant, the following documents should be completed by the Participating Institution 
and e-mailed to the Lead Site Research Project Manager at the Coordinating Center
•
Copy of labs and clinical information that satisfy inclusion criteria
•
Signed participant consent form
•
HIPAA authorization form
•
Registration Form
The Coordinating Center will review the submitted documents in order to verify eligibility and consent. 
To complete the registration process, the Coordinating Center will:
•
Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS).
•
Upon receiving confirmation of registration, the Coordinating Center will inform the Participating 
Institution and provide the study specific participant case number, and, if applicable, assigned 
treatment and/or dose level.
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered.
Enrollment can only occur during normal business hours, Monday through Friday from 8:00 AM to 5:00 
PM Eastern Standard Time.
3.7.2 Initiation of Therapy

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Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other protocol- 
specific interventions. Treatment and other protocol-specific interventions may not be initiated until the 
Participating Institution receives confirmation of the participant’s registration from the Coordinating 
Center. The DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy.
3.7.3 Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. 
All Participating Institutions are required to fully comply with this requirement. The process for requesting 
an eligibility exception is defined below.
3.8
DF/HCC Protocol Case Number
At the time of registration, the following identifiers are required for all subjects: initials, date of birth, 
gender, race and ethnicity. Once eligibility has been established and the participant successfully registered, 
the participant is assigned a unique protocol case number. Participating Institutions should submit all de- 
identified subsequent communication and documents to the Coordinating Center, using this case number 
to identify the subject.
3.8.1 Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure that 
researchers do not initiate changes in approved research without IRB review and approval, except when 
necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all departures 
from the defined procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, 
who in turn is responsible for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to describe 
departures from a protocol. All Participating Institutions must adhere to these requirements for reporting 
to the DF/HCC Sponsor and will follow their institutional policy for reporting to their local IRB.
3.8.2 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved protocol 
which is prospectively approved prior to its implementation.
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior to its 
initiation or implementation.
3.8.3 Reporting Procedures

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DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record 
and/or regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC 
Sponsor will also be responsible for ensuring that all protocol violations/deviations are promptly reported 
per DFCI IRB guidelines.
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The 
Participating Institution must submit the deviation request to the Coordinating Center who will then submit 
the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the 
Participating Institution IRB, per institutional policy. A copy of the Participating Institution’s IRB report 
and determination will be forwarded to the Coordinating Center within 10 business days after the original 
submission. The deviation may not be implemented without all required approvals.
All protocol violations must be sent to the Coordinating Center in a timely manner. The Coordinating 
Center will provide training for the requirements for the reporting of violations.
Coordinating Center: Upon receipt of the violation/deviation report from the Participating Institution, the 
Coordinating Center will submit the report to the DF/HCC Sponsor for review. Subsequently, the 
Participating Institution’s IRB violation/deviation report will be submitted to the DFCI IRB for review per 
DFCI IRB reporting guidelines. DF/HCC will forward all violation reports to CTEP via an internal 
DF/HCC process, as applicable.
3.9
Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights and well- 
being of study participants. Recording and reporting of adverse events that occur during the course of a 
study help ensure the continuing safety of study participants.
All participants receiving investigational agents and/or other protocol mandated therapy will be evaluated 
for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical 
examination findings, and spontaneous reports of adverse events reported by participants. All toxicities 
encountered during the study will be evaluated according to the NCI criteria specified in the protocol.
Life-threatening toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
3.9.1 Guidelines for Reporting Serious Adverse Events
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in protocol 
section 9.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating Center 
following the DFCI IRB Adverse Event Reporting Policy.

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The Coordinating Center will maintain documentation of all Participating Institution Adverse Event reports 
and be responsible for communicating to all participating investigators, any observations reportable under 
the DFCI IRB Reporting Requirements. Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures
3.9.2 Guidelines for Processing IND Safety Reports
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports are 
distributed to the Participating Institutions. Participating Institutions will review/submit to their IRB 
according to their institutional policies and procedures.
3.10
Data Management
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol. These forms are 
designed to collect data for each study. DF/HCC CTRIO provides a web based training for all eCRF users.
3.10.1 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study forms are received 
with missing or questionable data, the submitting institution will receive a written or electronic query from 
the DF/HCC Office of Data Quality, Coordinating Center, or designee.
Responses to all queries should be completed and submitted within 14 calendar days.
Responses may be returned on the written query or on an amended paper case report form, or in the case 
of electronic queries, within the electronic data capture (eDC) system. In the case of a written query for 
data submitted on a paper case report form, the query must be attached to the specific data being re- 
submitted in response.
If study forms are not submitted on schedule, the Participating Institution will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms.
4. REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in the protocol section 11.
Participating Institutions should order their own agent regardless of the supplier. (i.e., NCI or a 
pharmaceutical company.) Janssen Scientific Affairs, LLC will supply the investigational agent. A drug 
distribution vendor will be engaged for ordering and re-supply at each individual site.
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent according 
to state and federal requirements. The local IRB should be kept informed of who will supply the agent (i.e., 
NCI or a pharmaceutical company) so that any regulatory responsibilities can be met in a timely fashion.

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5. MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol.
5.1
Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the Coordinating 
Center for monitoring. Participating Institution may also be subject to on-site monitoring conducted by the 
Coordinating Center.
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring practices may include but are not limited to source data verification, and review and analysis 
of eligibility requirements, informed consent procedures, adverse events and all associated documentation, 
review of study drug administration/treatment, regulatory files, protocol departures reporting, pharmacy 
records, response assessments, and data management.
Additionally, regular and ongoing communication with Participating Institutions will be accomplished by 
holding all site teleconferences at quarterly until enrollment is completed and the last participant in has 
been on study for at least 6 months. After this there will be teleconferences every 6 months until all 
participants are off treatment. Additional teleconferences will take place as needed for significant events 
(i.e. change in accrual, event involving participant, etc.) The Lead Institution will keep in close touch 
with the Participating Institutions via email and phone. Source documents from Participating Institutions, 
will be collected at specific data points that support the primary and or secondary endpoints.
Remote Monitoring
Participating Institutions will be required to forward de-identified copies of participants’ medical record 
and source documents to the Coordinating Center to aid in source data verification. Each participant’s 
initial consent and eligibility will be reviewed within 30 days of enrollment. Study visits and corresponding 
CRFs will be reviewed every 6 months for protocol compliance, AEs, SAEs, study drug administration, 
dose modifications, and follow-up of action items. Pharmacy records will be remotely reviewed every 6 
months.
On-Site Monitoring
Participating Institutions will have annual on-site visits to for a Pharmacy site review, Regulatory binder 
review, and to meet with the site PI (if available).
Closeout Monitoring
Closeout monitoring will be done remotely at the end of the study.

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5.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable to comply with 
the protocol, DF/HCC Sponsor requirements or federal and local regulations. Monitoring logs will be 
maintained to ensure monitoring activities are adequately documented.
5.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements 
for each participating institution. Accrual will be monitored for each participating institution by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to 
termination. Due to the small patient population, the accrual minimum requirement is at least 1 patient 
every two years.
6. AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance and involves the systematic and independent examination of all 
trial related activities and documents. Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per the 
protocol, applicable Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR).
6.1
DF/HCC Internal Audits
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2 day period. If violations which impact 
participant safety or the integrity of the study are found, more participant records may be audited.
6.2
Audit Notifications
It is the Participating Institution’s responsibility to notify the Coordinating Center of all scheduled audit 
dates (internal or NCI) and re-audit dates (if applicable), which involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the 
Coordinating Center, within 12 weeks after the audit date.
6.3
Audit Reports
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. The 
Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for review by the 
DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the 
final audit report and corrective action plan to the DFCI IRB as applicable.

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6.4
Participating Institution Performance
The DF/HCC Sponsor and the DFCI IRB, is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol.
Participating Institutions that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal regulations, may 
be recommended for a six-month probation period. Such institutions must respond with a corrective action 
plan and must demonstrate during the probation period that deficiencies have been corrected, as evidenced 
by the improved performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC 
Sponsor and/or the DFCI IRB may terminate a site’s participation if it is determined that a site is not 
fulfilling its responsibilities as described above.

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APPENDIX E: INVESTIGATIONAL PRODUCT MANAGEMENT PLAN
A Phase II Study of the CD38 Antibody Daratumumab in Patients 
with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma
Overall Principal Investigator: Irene M. Ghobrial, MD 
Coordinating Center: Dana-Farber Cancer Institute
Version 3.4
Version Date September 10tht, 2019

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1. IP Forecasts
1.1 IP projections for the duration of the IIS
Patients will be treated with daratumumab at a dose level of 16mg/kg on the following schedule:
Cycle
Dosing Schedule
Cycle 1-2
Days 1, 8, 15, 22
Cycle 3-6
Days 1, 15
Cycle 7-20
Day 1
Dosing will be an IV infusion following the guidance for commercial daratumumab administration outlined in 
the United States Package Insert as well as according to site policy. Each cycle will be 28 days.
With an expected accrual of 50 patients, all of whom will receive daratumumab as detailed above, the projected 
product requirement for this study is as follows:
•
Assuming 4 vials per dose and a patient weight of 100kg: 400mg vials
•
Daratumumab: 4 vials of 400mg x 30 doses x 50 patients = 6,000 vials
Drug
Vials/ 
Dose
Total 
Doses
# of 
Patients
Vials/ 
Patient
Total Vials
10%
Overage
20%
Overage
Daratumumab
4
30
50
120
6000
6600
720
•
Assuming 16 vials per dose and a patient weight of 100kg: 100mg vials
•
Daratumumab: 16 vials of 100mg x 30 doses x 50 patients = 24,000 vials
Drug
Vials/ 
Dose
Total 
Doses
# of 
Patients
Vials/ 
Patient
Total Vials
10%
Overage
20%
Overage
Daratumumab
16
30
50
480
24,000
26,400
28,800

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1.2 Overall plan per Quarter for IP requirements (inclusive of each participating site, over-all 
subject enrollment rate, current inventory and expiring IP at each site)
The study team anticipates an accrual of 2 patients/ month (approximately 6 patients per quarter) to complete 
accrual of 50 patients in 25 months. Each patient will be dispensed study drug at the timepoints described in 
section 1.1 of this IP Management Plan. Each subsite will be allowed to maintain IP dispensation and 
accountability records per their individual site SOPs. Dana-Farber Cancer Institute, as the coordinating center 
will review each sites SOPs to ensure they comply with GCP and ICH guidelines. Each subsite will maintain 
drug destruction records per their sites individual SOPs. Dana-Farber Cancer Institute, as the coordinating 
center, will collect all pharmacy records at the completion of the study.
1.3 Process to re-evaluate IP requirements (inclusive of all participating sites)
DFCI will submit monthly enrollment information to Janssen Scientific Affairs, LLC. The study team will 
inform the pharmacy when a new patient is enrolled. Biologics, Inc., the drug distribution center, will provide 
monthly dispensing and accountability reports to Janssen Scientific Affairs, LLC and Dana-Farber Cancer 
Institute.
2. Inventory Control
2.1 Record of receipt and disposition of IP
Biologics, Inc.,the drug distribution center, will receive and check all incoming shipments with proper 
documentation, enter into a 21CFR Part 11 compliant system, and place in proper and monitored storage. Upon 
destruction, or return of study drug, all documents are completed, accountability logs are signed off on and 
closed, and drug is disposed of or returned properly.
Biologics, Inc. will ship the study drug to each participating site. All study drug will be shipped in original 
manufacturer’s packaging with a protocol-specific label adhered to the outer packaging. Study Drug is shipped 
in a Biologics branded package with appropriate materials to maintain temperature stability. All drug orders are 
shipped via FedEx for Priority Overnight delivery for shipments to US sites.
Each shipment includes a label on the Ziploc bags with the following information:
o
The Study Number
o
IND caution statement and/or local regulatory statements
o
Drug identification
o
Lot Number
o
Expiration date
o
Dosing instructions (i.e., “Administer as Directed per Protocol”)
o
Storage instructions (i.e., “Store at controlled refrigerated temperature, 2-8°C”)
o
Emergency contact instructions

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For all shipments from Biologics:
o
A complete accountability record including date of dispense, site name, quantity dispensed, and 
balance forward will be recorded.   Study accountability records are documented in electronic 21 
CFR format and are kept in a secured area for duration of the study.
o
Provide a Pharmacist review; a licensed pharmacist checks off package for accuracy of contents, 
authorizing order via 21 CFR compliant trial accountability log.
o
Enclose a packing slip that includes the quantity of drug provided with a section to be completed 
once received by the site coordinator. This section includes confirmation of drug receipt, 
verification of package contents, and instruction to fax the completed packing slip to Biologics.
o
Process and ship authorized and completed orders “same day” of receipt if received before 2:00
p.m. ET Monday through Thursday. Authorized and completed orders received after 2:00 pm ET 
Monday through Thursday will be processed and shipped the next business morning.
o
Packages are tracked until confirmed delivered and delivery exceptions are managed with the 
highest level of urgency to ensure therapy start date adherence. Packing slips with the shipment 
tracking number included will be faxed to the designated site coordinator for all shipments.
DFCI will receive and check all incoming shipments with proper documentation. DFCI keeps the shipping 
receipt and records the disposition of the drug. DFCI will place all received shipments in proper and monitored 
storage. Upon destruction of study drug, all documents are completed, accountability logs are signed off on and 
closed, and drug is disposed of properly.
Each participating sub-site will maintain records of drug accountability and destruction according to their local 
SOPs, which will be reviewed by the coordinating center for compliance with GCP and ICH guidelines.
2.2 Periodic review and documentation of current supply of all IP
Biologics will effectively manage inventory to reduce waste due to expiration issues through strict adherence to 
FIFO inventory procedures, just in time inventory management, and end of day and monthly audits.
Each day Biologics will perform an end of day audit for all trial specific drugs that were dispensed on that 
particular day. The end of day audit reconciles the physical shelf inventory to accountability records. During 
the monthly inventory report Biologics personnel will compare shelf inventory against the balance as stated on 
the drug accountability report. Perpetual inventory audits are documented via 21 CFR Part 11 compliant 
accountability records throughout the duration of the study and with oversight by the Director of Clinical Trial 
Services.
The DFCI pharmacy routinely reviews the amount of IP on site and re-orders as needed based on current 
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2.3 Plan for resupply of IP based upon overall IIS use and/or expiration of IP
Biologics, Inc. will request resupply as needed based on inventory level and expiry dates from Janssen 
Scientific Affairs. The coordinating center will liaise with the drug distribution center as needed based on drug 
supply levels via telephone or email to review currently supply and expiry dates
Each individual sub-site will measure drug supply levels and forecast needed drug supply based on local 
practice.
2.4 System to quarantine and control expired or recalled IP
All study product that requires quarantine will immediately be recorded in the accountability record, moved 
from general storage, placed into a secure quarantined area separate from other study drug. Janssen Scientific 
Affairs, LLC will be notified and the supply will be handled as required.
3. Storage
3.1 IP storage conditions
All participating sites are required to maintain adequate accountability and storage of investigational agents as 
specified in the study protocol and the study data safety monitoring plan. Each individual sub-site may store IP 
per their local SOP for storage procedures for investigational drug supply.
Biologics, Inc. will store the study drug in secure temperature and humidity controlled storage for the duration 
of the study. Drug and the accountability log is reviewed and signed off by the qualified personnel as outlined 
in Biologics operating procedures. This quality check is documented via Clinical Trial Material 
Accountability/Quality Assurance Log (Receipt) and the document is then stored in the trial files for the 
duration of the study. All study drugs will be stored at controlled temperatures until shipment with access 
limited to essential personnel only.
Daratumumab will be stored at controlled refrigerated temperatures of 2-8°C. Biologics will assume receipt of 
one study drug supply on at least a quarterly basis. Temperature and humidity monitoring that is 21 CRF Part 
11 compliant is provided 24/7/365 throughout the duration of the study. During non-operational hours, 
electronic surveillance alerts Biologics after-hour’s response personnel to out of range fluctuations in 
temperature and humidity. Biologics will provide temperature monitoring reports upon request. Temperature 
excursions will be communicated to the manufacturer & Coordinating Center to provide an assessment of 
affected drug supplies.
Biologics will maintain separate inventories for protocol-specific drug supplies.
Inventory Maintenance includes:
•
Separate physical locations with shelf labeling
•
Study, Drug, Strength, Expiration shelf labeling
•
Inventory management within Biologics information system
•
Inventory reports on agreed fields submitted on agreed schedule

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DFCI will store the study drug in secure temperature and humidity controlled storage for the duration of the 
study. All study drugs will be stored at controlled temperatures until shipment with access limited to essential 
personnel only.
3.2 Plan for maintaining documentation of proper storage conditions according to the package 
insert/IP guidelines
Biologics, Inc. will include proper storage and drug usage information on packing slips and auxiliary documents 
in all shipments sent to the study sites.
Proper storage and drug usage information is contained in section 8 of the protocol. All participating sites are 
required to maintain adequate accountability and storage of investigational agents as specified in the study 
protocol and the study data safety and monitoring plan.
Each individual sub-site may follow their local SOP for maintaining documentation of drug supply. Each site’s 
SOP will be reviewed by the coordinating center to ensure it complies with GCP and ICH guidelines.
3.3 IP storage separate from non-clinical material, in secure location and limited access
Prior to distribution, the IP will remain separate from other study drugs and will be stored in a secure facility at 
the drug distribution center, Biologics, Inc., as described in the drug distribution center’s SOPs.
All drug is received in dry dock and then sent to the DFCI Pharmacy. Once the packages are opened the 
packing slip is examined. Proper documentation of the Janssen specific protocol number is required on the 
packing slips. The pharmacy technicians identify the received drug as investigational and the drug is 
transferred to the investigational pharmacy for receipt and acknowledgement. Investigational drug is stored 
according to the DFCI protocol number in research refrigerators, separated from non-research material.
Each individual sub-site will be allowed to utilize their local SOP for investigational product once the SOP is 
reviewed by the coordinating center for compliance with GCP and ICH guidelines.
3.4 Temperature excursions
Biologics, Inc. should follow their standard of practice as well as the guidance from the protocol document 
regarding temperature excursions.
DFCI pharmacy refrigerators record temperatures continuously and are attached to an alarm for any excursion. 
If an excursion happens after hours a pharmacist is on call to answer the alarm. Investigational product is then 
quarantined according to the requirements per protocol.
Each individual sub-site should follow their local standard of practice as well as the guidance from the protocol

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document regarding temperature excursions. The coordinating center will review each SOP to ensure that it 
complies with GCP and ICH guidelines.
Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze or shake. Protect from light. This product 
contains no preservative. If the storage temperature falls outside of the range accepted in the institutional SOP, 
this is considered a temperature excursion. When a temperature excursion occurs, each individual sub-site must 
quarantine the product and inform the coordinating center as soon as possible. The coordinating center is 
responsible for liaising with Janssen Scientific Affairs, LLC for guidance on continued use of the product and 
will inform sites whether the product is suitable for continued use.
4. IP Accountability
4.1 IP use in accordance with this IIS
Biologics, Inc. will include pertinent information on all packing slips and include auxiliary documents to inform 
sites of instructions for use. In all communications with the sites prior to shipment, the drug distribution center 
can review this information with the receiver
Each supply of investigational product will come equipped with a packing slip from Janssen Scientific Affairs, 
LLC. This packing slip will have the Janssen Scientific Affairs, LLC study number. Each participating site 
will be informed during the site initiation visit that investigational product should only be used for the IIS.
4.2 Process for maintaining IP transaction logs
All participating sites are required to maintain adequate accountability and storage of investigational agents. As 
outlined in the study protocol and study data safety monitoring plan.
5. IP Destruction
5.1 Confirmation of each site’s SOP to destroy IP at site
Because of their participation in studies using DFCI-supplied investigational drug, all DFCI institutions have 
the capability of either destroying Study Product at their site or have an SOP for return of the Study Product to 
the distributor for destruction.
5.2 Confirmation that documentation of each site’s SOP for IP destruction will be retained
A copy of the sub-site drug destruction SOP will be filed in the Trial Master File.
5.3 Confirmation that each site will retain documentation of IP destruction
Drug destruction and/or pharmacy records will be kept current reviewed during routine monitoring visits and 
prior to study closeout at all participating sites, as outlined in the study protocol and study data safety 
monitoring plan.

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6. IP Distribution
6.1 Shipping information contacts at S-I site or at drug distribution supplier for sites participating in 
the IIS
Biologics, Inc. and the coordinating center will provide drug ordering instructions to all participating sites. 
Biologics, Inc. contact details for drug ordering:
Fax: 919-256-0794
Email: CRSOrders@biologicsinc.com
Throughout the course of the study, a clinical hotline support, staffed with clinical pharmacists, is made 
available 24/7/365 in the event an investigator or site coordinator has a question.
Hotline phone: 1-800-693-4906
During the approval and activation process, the coordinating center will inform Janssen Scientific Affairs, LLC 
and the drug distribution center of any new site prior to activation of said site and prior to any IP shipment to 
said site.
6.2 Confirmation that all necessary documents are in place prior to shipment to any participating 
site
Biologics, Inc. and DFCI will execute a contract prior to study launch. DFCI will execute any agreements 
required with the sub-sites prior to the activation of said site. DFCI has existing process in place for 
confirmation of local IRB review prior to patient registration. Each site will be unable to request shipment until 
IRB approval centrally at the coordinating center is received and all regulatory documents (e.g. CVs, MLs, 
DOA, etc.) have been filed in the Trial Master File.
6.3 Distribution/coordination plan for shipping IP to participating sites
In general, a minimum of a three-month forecasted supply of study drug will be shipped to each participating 
site to ensure that drug shipments do not occur more frequently than once a quarter to each site. Exceptions to 
this rule of thumb should be reviewed with DFCI.
6.4 Confirmation that S-I or IP distribution supplier will record and maintain shipping 
documentation of IP to participating sites
Biologics, Inc. will record a complete accountability record including date of dispense, site name, quantity 
dispensed, and balance forward will be recorded. Study accountability records are documented in electronic 
21CFR format and are kept in a secured area for the duration of the study.

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Each individual sub-site will maintain a record of shipment according to their local SOPs for maintaining 
documentation of IP shipment. This SOP will be reviewed by the coordinating center for compliance with GCP 
and ICH guidelines.
7. Packaging and Labeling
7.1 IP should be clearly identified to be used only for the specified IIS
Biologics, Inc. will include a disclaimer that IP is to be used only for the specified IIS on the packing slip, or on 
auxiliary documentation that is placed on the study product prior to dispense to the study site.
Janssen Scientific Affairs, LLC will include the Janssen protocol number clearly on the packing slip or auxiliary 
documentation in the shipment of study drug to Biologics Inc.
The coordinating center will ensure a yearly monitoring review of pharmacy drug accountability records. The 
drug accountability record and the drug destruction log will be collected at the end of the study per DFCI SOPs.
7.2 Any additional participating sites’ labeling requirements per institution’s policy/SOP and/or local 
and/or country regulations
Biologics, Inc. will create, submit, and agree upon the shipping label with DFCI prior to study launch and any 
requirements at specific study sites will need to be discussed during this process. Shipping and handling from 
the drug distribution vendor to each site will follow the drug distribution vendor’s standards of practice. The 
practices will meet all GCP and ICH guidelines as appropriate.

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APPENDIX F: RAPID DARATUMUMAB INFUSION GUIDELINE
Standard daratumumab infusion
Cycle 1, days 1 and 8:
The first infusion of daratumumab should be prepared in a total volume of 1000 mL. After the first infusion, if 
no infusion reactions were experienced during the first 3 hours, the medication may be prepared using a total 
volume of 500 mL going forward. The initial rate of administration is 50 mL/hr. If hypersensitivity or infusion- 
related events do not occur, escalate the infusion rate in 50 ml/hour increments every 60 minutes to a maximum 
of 200 mL/hr.
Subsequent infusions:
The initial rate of administration can be increased to 100 mL/hr if there were no grade 1 (mild) or greater 
infusion reactions during a final infusion rate of >100 mL/hr in the first two infusions. If hypersensitivity or 
infusion-related events do not occur, escalate the infusion rate in 50 mL/hour increments every 60 minutes to a 
maximum of 200 mL/hr.
Standard premedication regimen:
First and Second Infusions
Subsequent Infusions
Pre-infusion 
(~1 hour 
before start of 
infusion)
•
diphenhydramine 25- 50 mg IV /PO
•
acetaminophen 975 mg PO
•
methylprednisolone 100 mg IV
•
famotidine 20 mg IV*
•
montelukast 10 mg PO*
•
fexofenadine 60 mg PO*
•
diphenhydramine 25- 50 mg 
IV/PO
•
acetaminophen 975 mg PO
•
methylprednisolone 60mg mg IV
Peri-infusion 
(~2 hours after 
start of 
infusion)
•
diphenhydramine 25 mg IV*
•
famotidine 20mg IV*
•
methylprednisolone 40 mg IV*
Post infusion
•
oral steroid (methylprednisolone 20 
mg or equivalent) Days 2-3 after 
infusion (24 and 48 hours after the 
completion daratumumab).
•
oral steroid (methylprednisolone 
20 mg or equivalent) Days 2-3 
after infusion (24 and 48 hours 
after the completion 
daratumumab).
* If after completion of cycle 2 and no infusion reactions were experienced or if approved by the treating 
investigator, the 24-48 post infusion steroid may be waived if clinically appropriate
Cycle 2 and Subsequent Rapid Infusion:
For patients who tolerate Cycle 1 Day 22 without any grade (grade 1 or greater) hypersensitivity reaction, 
subsequent daratumumab infusions can be administered at an initial rate of 20% of the total dose over 30 
minutes, followed by the remaining 80% of the total dose over 60 minutes (90-minute total infusion time).
•
Rapid infusion will be given in a total volume of 500 mL

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Background: Daratumumab, an anti-CD38 monoclonal antibody, was first approved for the treatment of 
relapsed and refractory multiple myeloma (MM) in November of 2015. The approved initial infusion lasts at 
least 6.5 hours, second infusion for 4.5 hours and all subsequent infusions over 3.5 hours. The risk of infusion 
related reactions (IRRs) is very low after the second infusion, and the prolonged continued infusion time results 
in long days for patients. Because of our success infusing other monoclonal antibodies over shorter times, such 
as rituximab, we hypothesized that shortening the daratumumab infusion from 3.5 hours to 90 minutes 
beginning with the third infusion would not increase the incidence of IRRs.
Methods: This is a single-center safety study of an accelerated daratumumab infusion in patients receiving 
standard of care daratumumab therapy. Patients were eligible once they received at least 2 prior doses of
•
This allows for a rate of 200 mL/hr for the first 30 minutes and a rate of 400 mL/hr for the final 60 
minutes.
•
If a patient experiences any grade hypersensitivity reaction during standard infusion rate, the patient is 
not eligible for rapid infusion until they have received standard infusion daratumumab for two 
subsequent infusions without any grade hypersensitivity reaction.
•
If during a rapid infusion, the patient experiences an infusion reaction of any grade, the patient is not 
eligible to receive additional rapid infusions until they have received standard infusion daratumumab 
without any grade hypersensitivity reaction
•
Please see table below for hypersensitivity reaction grading criteria
Grading of Infusion Related Reactions NCI CTCAE v5.0
Grade
1
2
3
4
5
Infusion
Mild transient
Therapy or
Prolonged
Life-
Death
related
reaction;
infusion
(e.g., not
threatening
reaction
infusion
interruption
rapidly
consequences;
interruption
indicated but
responsive to
urgent
not indicated;
responds
symptomatic
intervention
intervention
promptly to
medication
indicated
not indicated
symptomatic
and/or brief
treatment (e.g.,
interruption of
antihistamines,
infusion);
NSAIDS,
recurrence of
narcotics, IV
symptoms
fluids);
following
prophylactic
initial
medications
improvement;
indicated for
hospitalization
</= 24 hours
indicated for
clinical
sequelae
Clinical Trial Experience: Barr H, Dempsey J, Waller A, et al. Ninety-Minute Daratumumab Infusion Is Safe 
in Multiple Myeloma. Blood 2017 130: 1889.

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daratumumab, administered per standard prescribing information. Previous IRR was not an exclusion criterion. 
The accelerated infusion was calculated to deliver 20% of the dose over the first 30 minutes, then the remaining 
80% over 60 minutes, resulting in an estimated 90-minute infusion. Patients who tolerated the infusion well 
were allowed to continue the accelerated rate. Premedication regimens were allowed to be altered based on 
previous tolerability. Simon's two-stage optimal design was utilized to design the study based on the incidence 
of grade 3 or above IRR. With 80% power the design allows 7 patients to be treated in the first stage, and if no 
patients experienced ≥ grade 3 IRR, an additional 21 patients would be treated. Out of all 28 patients, if 2 or 
more experienced ≥ grade 3 IRR, the regimen would be declared as too toxic. The protocol was approved by the 
cancer institutional review board.
Results: Twenty-eight patients were treated with daratumumab utilizing the accelerated rate, 8 of which 
received the accelerated infusion with their third dose of daratumumab. The premedication regimen varied 
patient-to-patient and did not impact tolerability of the accelerated infusion. There were 5 patients who did not 
receive any steroid premedication and 3 who received reduced doses (< 12 mg) of dexamethasone. Of the 28 
patients treated, there was only 1 adverse reaction - a grade 2 hypertension during which the infusion was 
paused for a patient that had received 10 prior infusions at standard rates. The patient received a diuretic, the 
infusion was resumed and subsequently increased to the accelerated rate without further incidence of 
hypertension. There were no grade 3 or higher IRRs. At the 4-week follow-up, all patients remaining on 
daratumumab treatment continued at the accelerated infusion rate.
Conclusion: An accelerated infusion rate of daratumumab delivering 20% of the dose over 30 minutes and 80% 
over 60 minutes is feasible and well-tolerated in patients who have received 2 prior doses of daratumumab at 
standard infusion rates. Starting with the third dose of daratumumab therapy, the 90-minute infusion is now 
standard practice at our institution.
References:
1.
Barr H, Demspey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. 
Leukemia. 31 March 2018; 1476-5551

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In case of emergency, or if you find this card, please contact the 
doctor listed below:
Study Doctor’s Name/Hospital:
24-Hour Emergency Telephone:
If you are unable to reach the study doctor in the event of an 
emergency, please contact the study supporter at:
24-Hour Emergency Telephone: 
1-866-447-2701
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Patient ID Card for Clinical Trial 
DFCI 17-212
Please always carry this card with you and share with all your 
healthcare providers
Site Number:   
         
Subject’s Number:   
I am participating in a clinical study being supported by Janssen 
Scientific Affairs, LLC. As part of this study, I am taking the 
following medication:
Daratumumab (marketed as DARZALEX), an Investigational 
Medicinal Product
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Patient ID card, v1.0, 19-Jul-2016
4 of 4
Before I started taking daratumumab 
my test results collected on
(insert date dd-mmm-yyyy)
were: 
Blood type:  □ A
□ B
□ AB
□ O
□ Rh+
□ Rh-
Indirect antiglobulin test (antibody screen) was:
□Negative
□Positive for the following antibodies:  
DARATUMUMAB PATIENTS: Provide this card to health 
care providers BEFORE blood transfusion
Indirect antiglobulin test (IAT) also known as an Indirect 
Coombs test (antibody screen and crossmatch) will show 
positive results in patients taking daratumumab.
This phenomenon and the methodology to correct a positive 
IAT is described in the publication in the journal Transfusion: 
http://onlinelibrary.wiley.com/doi/10.1111/trf.13069/epdf
You may also call the doctor listed on this card for more 
information.
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APPENDIX G: SUBJECT SAFETY CARD