Clinical trial NCT03490344
Conditions: Multiple Myeloma
Keywords: bony plasmacytoma extramedullary plasmacytoma Daratumumab lenalidomide Memorial Sloan Kettering Cancer Center 18-048
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2018-05-03; Completion date: 2023-03-23
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the safety of short course Daratumumab in combination with lenalidomide and to find out what effects, if any, short course Daratumumab in combination with lenalidomide has on people and their risk of multiple myeloma. The study is also designed to test the amount of remaining myeloma cells in your body after treatment with daratumumab which is known as minimal residual disease (MRD).

Detailed description:

Arms: arm 1: Participants with MM with very good partial response (VGPR) or better after induction therapy with/without consolidative HDT/ASCT and MRD positive by bone marrow flow cytometry and MM participants who were previously MRD negative after induction and consolidation and recently (within last 3 months) turned MRD positive by bone marrow flow cytometry will be enrolled.
Interventions: intervention 1: Daratumumab intervention 2: Lenalidomide
Intervention descriptions: intervention 1: * Cycles 1 and 2: Daratumumab 16mg/kg weekly per cycle (28 days) as intravenous infusion (total duration: 8 weeks)
* Cycles 3-6: Daratumumab 16mg/kg once every 2 weeks per cycle (28 days) as intravenous infusion (total duration: 16 weeks) intervention 2: Lenalidomide maintenance therapy to be administered as standard treatment to all participants. This is administered as 5-15 mg daily 21-28/28 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-048 A(10) 
Approval date: 02-Feb-2023 
 
 
 
 
 
MSK PROTOCOL COVER SHEET 
 
Short Course Daratumumab in Minimal Residual Disease (MRD) Positive Myeloma Patients After 
Induction Therapy With/Without Consolidative High Dose Chemotherapy/Autologous Stem Cell 
Support 
 
Principal Investigator/Department: Sham Mailankody, MBBS/Multiple Myeloma/Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 11 
4.1 
Design .......................................................................................................................... 11 
4.2 
Intervention ........................................................................................................................ 11 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................. 12 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 12 
6.1 
Subject Inclusion Criteria ................................................................................................... 13 
6.2 
Subject Exclusion Criteria .................................................................................................. 15 
7.0 
RECRUITMENT PLAN .......................................................................................................... 16 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 15 
9.0 
TREATMENT/INTERVENTION PLAN ...................................................................................... 18 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 21 
11.0 TOXICITIES/SIDE EFFECTS .................................................................................................... 26 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 27 
13.0 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 29 
14.0 BIOSTATISTICS ................................................................................................................... 31 
15.0  RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
332 
15.1 Research Participant Registration ..................................................................................... 32 
15.2 Randomization ................................................................................................................... 32 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 32 
16.1 Quality Assurance .............................................................................................................. 33 
16.2 Data and Safety Monitoring ............................................................................................... 36 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 34 
17.1 Privacy ............................................................................................................................... 34 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 36 
17.2.1...................................................................................................................................... 38 
18.0 INFORMED CONSENT PROCEDURES............................................................................... 44 
19.0 REFERENCES ...................................................................................................................... 44 
20.0 APPENDICES ....................................................................................................................... 48 


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1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Primary Objective This is a phase II study to assess the efficacy of short course 
daratumumab in multiple myeloma patients with minimal residual disease (MRD) positivity 
after induction therapy with/without consolidative autologous stem cell transplant (ASCT). 
Primary objective of the study will be to determine the rate of MRD negativity by the 
completion of 6 months of daratumumab therapy. 
 
Secondary Objectives: 
 
1. To assess the rate of sustained MRD negativity in the bone marrow. 
2. To determine duration of MRD negativity 
3. To compare MRD techniques of multi-parametric flow cytometry with next-generation 
sequencing and mass spectrometry. 
4. To determine progression-free and overall survival 
 
 
Exploratory Studies: 
 
1. The gene panel MyType (or comparable next generation sequencing panel) will 
explore whether any mutations appear to be associated with response to therapy or 
toxicity associated with therapy. 
 
2. MyType(or comparable next generation sequencing panel)  will also be evaluated 
using samples at the time of progression of disease and  will be compared to the pre- 
treatment baseline samples to explore whether pathways leading to emergence of 
resistance to the drug regimen can be identified. 
 
Patient Population   
 
The proposed study will enroll newly diagnosed multiple myeloma patients achieving a 
very good partial response (VGPR) or better with MRD positivity by flow cytometry after 
induction therapy with/without ASCT as well patients previously MRD negative for at least 
3 months (after induction and consolidation therapy) and have turned MRD positive by 
flow cytometry with no evidence of progressive disease. All patients must be on standard 
of care lenalidomide maintenance for at least 6 months at the time of enrollment. 
 
Study Design 
 
• 
Single arm phase II trial of daratumumab for MRD positive multiple myeloma 
patients currently receiving standard of care lenalidomide maintenance therapy. 
• 
Daratumumab is administered weekly for cycles 1 and 2 and bi-weekly for the 
remaining 4 cycles.. 
• 
Bone marrow biopsy will be obtained at baseline for confirmation of diagnosis and 
correlative studies. A follow-up bone marrow biopsy will be performed at the 
completion of treatment or at disease progression. 


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• 
Patients will also undergo evaluation for response at monthly intervals using 
traditional IMW uniform response criteria (Kumar. et al.  Lancet Oncology 2016) 
with serum and urine protein electrophoresis, immunofixation, and serum free light 
chains (FLC). 
• 
Patients will continue standard of care lenalidomide maintenance during the 
protocol and after completing daratumumab as recommended by the treating 
physician. 
 
Statistics 
 
The primary objective of this trial is to determine whether treatment with daratumumab is 
associated with a substantial fraction of patients with MRD positive multiple myeloma 
converting to a MRD negative state as assessed by multicolor flow cytometry. Previously 
studies have reported that approximately 10% of patients will achieve deeper responses 
including MRD negativity after maintenance therapy with lenalidomide alone29. The current 
study will be considered positive if the rate of MRD negativity is 30% or higher with 
daratumumab. This study will implement a Simon’s two-stage minimax design to 
distinguish between an unpromising rate of 10% and a promising rate of 30%. The study is 
designed to have a type I error and a type II error of 0.10. The maximum sample size is 25 
patients 
 
 
 
 
Treatment Plan (see schema below) 
 
• 
Cycles 1 and 2: Daratumumab 16mg/kg weekly as intravenous infusion 
(total duration: 8 weeks) 
• 
Cycles 3-6: Daratumumab 16mg/kg once every 2 weeks as intravenous 
infusion (total duration: 16 weeks) 
• 
Lenalidomide maintenance therapy to be administered as standard treatment to 
all patients. This is administered as 5-15 mg daily 21-28/28 day cycle. 


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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daratumumab 16mg/kg weekly for 8 weeks, followed by every 2 weeks for 16 weeks  along with standard of care lenalidomide 
maintenance 
MM patients who were previously MRD 
negative after induction and consolidation 
and recently (within last 3 months) turned 
MRD positive by bone marrow flow 
cytometry. 
MM patients with very good partial 
response (VGPR) or better after induction 
therapy with/without consolidative 
HDT/ASCT and MRD positive by bone 
marrow flow cytometry. 


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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: 
 
This is a phase II study to assess the efficacy of short course daratumumab in multiple 
myeloma patients with minimal residual disease (MRD) positivity after induction therapy 
with/without consolidative autologous stem cell transplant (ASCT). Primary objective of the 
study will be to determine the rate of MRD negativity by the completion of 6 months of 
daratumumab therapy. 
 
Secondary Objectives: 
 
1. To assess the rate of sustained MRD negativity in the bone marrow). 
2. To determine duration of MRD negativity 
3. To compare MRD techniques of multi-parametric flow cytometry with next-generation 
sequencing and mass spectrometry. 
4. To determine progression-free and overall survival 
 
 
Exploratory Studies: 
 
1. The gene panel MyType(or comparable  next generation sequencing panel) will 
explore whether any mutations appear to be associated with response to therapy or 
toxicity associated with therapy. 
 
2. MyType will (or comparable next generation sequencing panel)  also be evaluated 
using samples at the time of progression of disease and  will be compared to the pre- 
treatment baseline samples to explore whether pathways leading to emergence of 
resistance to the drug regimen can be identified. 


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3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Introduction 
 
 
Multiple Myeloma and daratumumab 
 
Multiple myeloma is characterized by clonal proliferation of malignant plasma cells in the 
bone marrow, affecting an estimated 22,000 people in the US annually 1; about 75,000 
people are living with, or in remission from, multiple myeloma. Disease hallmarks include 
presence of monoclonal protein in serum or urine and features of end organ damage, 
including hypercalcemia, renal insufficiency, anemia, and bone lytic lesions 2.  Multiple 
myeloma remains incurable with an estimated median survival of 3-4 years with 
conventional therapies and longer with newer agents 3,4. 
CD38 is a 45-kD, type II transmembrane glycoprotein that associates with cell-surface 
receptors in lipid rafts, regulates cytoplasmic Ca2+ flux, and mediates signal transduction in 
lymphoid and myeloid cells5,6. CD38 is highly and uniformly expressed on myeloma cells7,8 
and is expressed at relatively low levels on normal lymphoid and myeloid cells and in some 
tissues of nonhematopoietic origin, which makes it a potential target in the treatment 
of myeloma6. Daratumumab (HuMax-CD38, Genmab), a human IgG1κ monoclonal 
antibody, binds to a unique CD38 epitope9. Preclinical studies showed that daratumumab 
induced target-cell killing of CD38-expressing tumor cells by means of multiple 
mechanisms, including complement-mediated and antibody-dependent cell-mediated 
cytotoxic effects, antibody-dependent cellular phagocytosis, apoptosis9,10, and to a lesser 
extent, inhibition of the enzymatic activity of CD38. 
 
Early phase clinical trials have established the single agent activity and efficacy of this 
drug in patients with relapsed and/or refractory myeloma patients11. Furthermore, the drug 
is fairly well tolerated with infusion related reactions being the most common adverse 
events11. Daratumumab was approved by the FDA as monotherapy for patients with 
relapsed/refractory multiple myeloma in November 2015. This approval was based on a 
single arm phase trial with 106 patients that demonstrated an objective response rate of 
29% with median duration of response of 7.4 months. 
 
Daratumumab in Combination with Lenalidomide and Dexamethasone 
 
More recently, Dimopoulos et al published the results of a Phase 3 study in patients with 
multiple myeloma with one or more prior lines of therapy randomized to receive 
lenalidomide (Revlimid®) and dexamethasone either alone or in combination with 
daratumumab12. The estimated 12 month progression-free survival was 83.2% of patients 
receiving the three drug combination compared to 60.1% amongst patients receiving 
lenalidomide and dexamethasone only12. Daratumumab was approved by the FDA in 
combination with lenalidomide and dexamethasone for patients with relapsed/refractory 
multiple myeloma in November 2016. However, daratumumab is not currently approved by 
the FDA for the indication under the current study i.e. patients with MRD positivity after 
induction therapy with/without consolidative HDT/ASCT. 


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Minimal Residual Disease Testing in Myeloma 
 
In the past decade, multiple myeloma patients have reached deeper response rates with 
use of effective anti-myeloma therapeutics, immunomodulatory agents and proteasome 
inhibitors, approximating up to 75% patients achieving near-complete response (>90% 
decrease in monoclonal protein) or complete response (100% decrease in monoclonal 
protein). In general, improved therapeutics and deeper response rates have resulted in 
improved overall survival of multiple myeloma patients across most age groups. As a 
result, there has been an increasing interest for the development of sensitive assays to 
detect minimal residual disease (MRD) in treated MM patients13.  In MM patients, MRD- 
negative status using multi-parametric flow cytometry (MFC) is associated with improved 
progression free survival and overall survival14,15.  Similar studies using next generation 
sequencing methods for MRD have also been shown to be associated with improved 
outcomes in MM MRD-negative patients. 
 
Minimal Residual Disease Platforms 
 
A recent survey including 30 major institutions in the US found major heterogeneity in 
MRD testing of multiple myeloma by flow cytometry16. In brief, there was considerable 
variation in the number of bone marrow cells analyzed (events) and number of abnormal 
plasma cells needed to define the presence of MRD, which affects maximum possible 
sensitivity. The maximum detection sensitivity ranged from 0.0005% to 0.02%, a 100-fold 
difference in sensitivity. Also, the variation in antibodies studied and definition of an 
abnormal plasma cell by flow cytometry affected the ability to differentiate normal from 
neoplastic plasma cells. 
 
In 2015, the Department of Laboratory Medicine developed, validated and implemented 
the 10-color flow cytometry platform in collaboration with the Myeloma Service and 
the International Myeloma Foundation. The MSK single tube 10-color flow cytometry 
platform demonstrates similar results to Euroflow and is already in use under clinical 
practice17 .  Because there is currently no data available to compare the sensitivity of the 
MSK model and molecular MRD assays, as a secondary endpoint, we will compare our 
10-color flow cytometry platform against next generation sequencing and mass 
spectrometry. These studies will help us to better understand and further develop details 
of various MRD methods. 
 
3.2 
Proposed Study Investigation with Correlative Studies 
 
MRD negativity after induction (with/without consolidative ASCT) is an increasingly important 
outcome for patients with multiple myeloma. The management of low burden disease (VGPR or 
better) after initial induction and during maintenance therapy is unclear at this time. In the current 
study, we propose short course daratumumab for newly diagnosed MM patients with very good 
partial response (VGPR) or better after induction therapy with/without consolidative HDT/ASCT 
and MRD positive by bone marrow flow cytometry and for patients who were previously MRD 
negative after induction and consolidation and recently (within last 3 months) turned MRD positive 
(with no evidence of clinical progression) by bone marrow flow cytometry. All patients must be on 
standard of care lenalidomide maintenance for at least 6 months at the time of enrollment 


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All patients will receive a total of 24 weeks of daratumumab therapy (16 mg/kg intravenous 
infusion weekly for 8 weeks followed by every 2 weeks for 16 weeks) and continue standard of 
care lenalidomide maintenance therapy. Baseline studies will include bone marrow biopsy and 
aspirates with the first pulled bone marrow sample sent for multi-parametric flow cytometry as a 
priority sample to determine MRD status and determine eligibility. Upon completion of protocol 
therapy or when patients achieve sCR, patients will undergo a repeat bone marrow biopsy and 
aspirate for MRD assessment and correlative studies. 
 
The study is powered to assess efficacy (as determined by rate of MRD negativity) of 
daratumumab in combination with standard of care lenalidomide maintenance amongst patients 
with low burden disease (i.e. MRD positivity). Our study is novel since no prior myeloma study 
has been designed to target MRD positive disease with the primary endpoint of achieving status 
MRD negativity.  Secondary endpoints include evaluation of sustain MRD negativity, 
progression-free survival, overall-survival, and comparison of MRD platforms.  Based on the 
rapidly evolving field with new powerful drugs, the anticipation is that MRD will become a new 
endpoint for future myeloma trials. MSK myeloma service is a global leader in this context. 
 
3.3 
Federal Regulations: The Privacy Rule 
 
In the case of research repositories of tissue and biological specimens, the collection of such 
samples is treated as research under the Privacy Standards (67 Fed Reg 53231; HIPAA Privacy 
Rule and Public Health: Guidance from CGC and HHS).  Under HIPAA, all subjects must agree to 
sign research authorizations that describe the uses and disclosures of their protected health 
information, as well as informed consents that describe the risks and benefits of participating in 
the study. It is not acceptable to sign one or the other.  Both documents must be signed by the 
subject to be considered a valid study participant (45 CFR 164.508(b)(3)). 
 
The aim of informed consent is to educate potential research participants about the risks and 
benefits of the study, how confidentiality of records will be protected, and other elements outlined 
in 45 CFR 46 and 21 CFR 50 and 56. HIPAA requires an authorization that can be incorporated 
into an informed consent document if both the Privacy Rule and either the Common Rule or FDA 
regulation apply to the research study. If the health information is de-identified under the privacy 
standards (eliminating the 18 elements of PHI), then the Privacy Rule does not apply. 
 
 
3.4 
Office of Human Research Protections Guidance 
 
The Office of Human Research Protections (OHRP, 1997) provides clarification, guidance, and 
oversight for research subject to the Common Rule. Research use of banked tissue or biological 
material is specifically addressed by an OHRP policy guideline. IRB oversight is recommended for 
the process of specimen acquisition into the repository as well as for the process of distributing 
samples to subsequent researchers and their local IRBs. OHRP suggests informed consent 
“should be as specific as possible” and include a “clear description” of the following basic 
elements: a) the operation of the cell repository; b) the specific types of research to be conducted; 
c) the conditions under which data and specimens will be released to recipient-investigators; and 
d) procedures for protecting the privacy of subjects and maintaining the confidentiality of data. 


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3.5 
New York State Law 
Under HIPAA, in instances where a state law is more stringent than the Privacy Rule, the state 
law is to be followed. In New York State, genetic test results (those that contain genetic 
information on inherited risk of disease) are confidential and cannot be disclosed to anyone 
without the written informed consent of the individual to whom the genetic test result relates (New 
York State Civil Rights Law §79-1(3)(a)). Genetic testing is defined by this law as: 
 
any laboratory test of human DNA, chromosomes, genes, or gene products to 
diagnose the presence of a genetic variation linked to a predisposition to a genetic 
disease or disability in the individual or the individual’s offspring; such term shall 
also include DNA profile analysis… 
 
According to §79-1(4)(a), anonymous samples may be genetically tested for Institutional Review 
Board (IRB)-approved research in which the anonymity of the samples is assured. For research 
genetic testing using human tissue stored in repositories, a general waiver of informed consent 
may be obtained (§79-1(2)(c)) if the individuals who supplied the samples “have given prior 
written informed consent for the use of their sample for general research purposes and did not 
specify time limits or other factors that would restrict use of the sample” (§79-1(9)(a)). The 
samples must be either permanently de-identified or coded such that the researcher performing 
the genetic test is unable to re-identify the specimens. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single arm phase II study to investigate the efficacy of short course daratumuab for 
patients who are MRD positive. Patients with MM with very good partial response (VGPR) or 
better after induction therapy with/without consolidative HDT/ASCT and MRD positive by bone 
marrow flow cytometry and MM patients who were previously MRD negative after induction and 
consolidation and recently (within last 3 months) turned MRD positive by bone marrow flow 
cytometry will be enrolled. 
 
4.3 
Intervention 
 
• 
Cycles 1 and 2: Daratumumab 16mg/kg weekly per cycle (28 days) as 
intravenous infusion (total duration: 8 weeks) 
• 
Cycles 3-6: Daratumumab 16mg/kg once every 2 weeks per cycle (28 
days) as intravenous infusion (total duration: 16 weeks) 
• 
Lenalidomide maintenance therapy to be administered as standard treatment to 
all patients. This is administered as 5-15 mg daily 21-28/28day cycle. 
• 
Premedications: 
o Dexamethasone 20mg/dose IV on Days 1, 8, 15, 22 for Cycles 1 and 2 
and Day 1 and Day 15 for Cycles 3-6. 
o 
Montelukast 10mg PO for the first 4 weeks 
o Tylenol 650 mg PO prior to each dose of daratumumab 
o Benadryl 25 mg PO prior to each dose of daratumumab 


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5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 
Daratumumab 
 
DARZALEX™ (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, respectively9,10. For the 
most comprehensive nonclinical and clinical information as well as Reference Safety 
Information regarding daratumumab, refer to the latest version of the Investigator's Brochure 
[Daratumumab IB]. 
 
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 proteins9  . Daratumumab-induced antibody- dependent cell- 
mediated cytotoxicity (ADCC) is slower in its action, with maximal ADCC by 
daratumumab observed at 4 hours in vitro (de Weers 2011)2 . Daratumumab has also been 
 
shown to  induce antibody-dependent cellular phagocytosis (ADCP) in the presence of 
macrophages within 4 hours in vitro (Overdijk 2013)10. Further, in vitro studies indicated that 
daratumumab inhibited the cyclase activity of CD38 and stimulated the CD38 hydrolase activity 
(Study No. GMB 3003-013). Daratumumab induces the elimination of CD38+ populations of 
Tregs, Bregs and MDSCs and is hypothesized to support the clonal expansion of effector T 
cells. 
 
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. 
 
 
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 


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of subjects with  a  reported  IRR  was  identical  (49%)  to  what  was  observed  across  all 
treated  subjects.  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 (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 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. 
 
Among the 283 patients who received daratumumab in combination with lenalidomide and 
dexamethasone in the POLLUX trial12, please see Table 7 and Table 8 (DRd (N=283) %) for the 
most frequently reported AEs (reported in >10% of subjects) and the most frequently reported 
Grade 3 or higher AEs. All other Grade 3 and higher AEs were reported in <5% of subjects. 


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6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the patient/subject population. 
 
6.2 
Subject Inclusion Criteria 
 
 
 
1. Patients with a diagnosis of Multiple Myeloma who have achieved a VGPR or better (based 
on best response) after induction with or without consolidation therapy/ HDT ASCT 
 
2. MRD positive at screening by flow cytometry 
 
3. Additionally, patients who were previously MRD negative after induction therapy with/without 
consolidative HDT/ASCT and have turned MRD positive (by flow cytometry) based on bone 
marrow done at screening and do not have any evidence of progressive disease are eligible. 
 
4. Patients must be on standard of care lenalidomide maintenance therapy for at least 6 months 
at the time of study enrollment. 


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5. Patient can be receiving bisphosphonate therapy per the treating oncologist’s discretion. 
 
6. Creatinine clearance ≥45 ml/min using the Cockcroft-Gault method, MDRD, or CKD-EPI 
formula.  If the calculated CrCl based on Cockcroft-Gault method, MDRD, or CKD-EPI is <45 
mL/min, patient will have a 24 hr urine collection to measure CrCl. 
 
7. Age >18 years. 
 
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 
 
9. Male or female patient who accepts and is able to use recognized effective contraception (oral 
contraceptives, IUCD, barrier method of contraception in conjunction with spermicidal jelly) 
throughout the study when relevant. 
10. Absolute neutrophil count (ANC) ≥1.0 x 109 /L, hemoglobin ≥8 g/dL, and platelet count ≥75 x 
109/L. No transfusion or growth factor support for one week prior to labs. 
11. Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 2.5 x ULN 
 
 
 
6.3 
Subject Exclusion Criteria 
 
Patients will not be eligible for the study if they fulfil one or more of the following exclusion criteria: 
 
1. Patients with a diagnosis of MM not achieving a VGPR or better to the most recent therapy. 
 
2. Patients with a diagnosis of MM who are MRD Negative by flow cytometry 
 
3. Patients must not have measurable disease at the time of enrollment. Measurable disease is 
defined as follows- 
• 
Serum monoclonal protein > 0.5gm/dL 
• 
Urine monoclonal protein >200 mg/24 hours 
• 
Involved serum free light chain > 10 mg/dL 
 
4. Pregnant or lactating females. 
 
5. Uncontrolled hypertension or diabetes. 
 
 
6. Has significant cardiovascular disease with NYHA Class III or IV symptoms, or hypertrophic 
cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to 
enrollment, or unstable angina, or unstable arrhythmia. 
 
7. Uncontrolled intercurrent illness including but not limited to active infection or psychiatric 
illness/social situations that would compromise compliance of study requirements. 
 
8. Active infection requiring treatment within two weeks prior to first dose. 
 
9. Contraindication to any concomitant medication, including antivirals, anticoagulation 
prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy. 


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10. Major surgery within 1 month prior to enrolment. 
 
11. Previous therapy with daratumumab or other anti-CD38 monoclonal antibodies. 
 
12. History of other malignancy (apart from basal cell carcinoma of the skin, or in situ cervix 
carcinoma) except if the patient has been free of symptoms and without active therapy during  at 
least 5 years. 
 
13. Active hepatitis B or C infection. 
 
14. Subject is: 
• 
seropositive for human immunodeficiency virus (HIV) 
• 
seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen 
[HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative 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. 
• 
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). 


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7.0 
RECRUITMENT PLAN 
 
This study will be conducted at MSKCC. Efforts will be made to ensure that women and 
minority groups are adequately represented in this trial.  Internally, an effort will be made 
to position this protocol for patients that demonstrate high-risk prognostic features, so as 
not to conflict with other ongoing newly-diagnosed multiple myeloma studies.  All patients 
will be seen by MSKCC myeloma physicians and associated MSKCC co-investigators, 
enrolled and registered at MSKCC. All co-investigators agree to follow the treatment in the 
protocol and to conduct the proposed investigation according to recognized principles of 
good clinical practice. Participation is voluntary. Each patient must be informed about the 
neoplastic nature of his/her disease and willingly consent to participation in this study. 
Every patient will be informed of the procedures to be followed, the potential benefits, side 
effects, risks, and discomforts of the trial and of potential therapeutic alternatives. All 
participants will be required to sign statements of informed consent and research 
authorization that conform to FDA, IRB and HIPAA guidelines. Informed consent will be 
documented by the use of a written consent form that has been approved by the MSKCC 
IRB. 
 
 
 
8.1 
PRETREATMENT EVALUATION 
 
• 
A complete history and physical examination with documentation of measurable 
disease and assessment of performance status using the ECOG scale must be 
performed within 4 weeks prior to study entry 
 
The following laboratory tests will be completed within 4 weeks prior to study entry 
• 
CBC with differential and reticulocyte count 
• 
Chem 14, Magnesium, and Phosphate and eGFR determination 
• 
Uric acid, LDH, and Beta-2 Microglobulin 
• 
PT, PTT 
• 
Serum protein electrophoresis (SPEP) and immunofixation to assess for presence and 
quantity of monoclonal protein (M-protein) 
• 
24 hour urine sample for protein electrophoresis (UPEP) and immunofixation to assess 
for monoclonal protein in the urine (Bence-Jones proteinuria) at baseline. 
• 
Serum free light-chain studies, determined using the FreeliteTM assay system 


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• 
Quantitative immunoglobulins 
• 
Review of bone marrow core biopsy and aspirate. 
• 
Serum or urine pregnancy test in women of child-bearing potential. 
• 
12-lead EKG 
• 
Optional Echocardiogram – 2D Echo or strain echo (Please refer to Section 10.0) 
• 
Viral serologies 
o Hepatitis B surface antigen (HBsAg) 
o Hepatitis B surface antibody (Anti-HBs) 
o Hepatitis B core antibody (Anti-HBc) 
o Anti-Hepatitis C (HCV) antibody. If positive, will follow with HCV RNA PCR 
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 as indicated 
above. 
• 
Additionally, subjects ongoing in the Treatment Phase who are within 6 months of starting 
study treatment when Protocol Amendment 03 is implemented will be required to have HBV 
serology performed locally upon signing the updated ICF. 
o 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 Evaluation during Treatment/Intervention (Section 
10.0). Where required by local law, the results of HBV testing may be reported to the local 
health authorities. 
 
 
Research and clinical laboratory tests to be performed within 4 weeks of study entry and prior to 
starting therapy 
• 
Bone Marrow 
o Histopathological evaluation on bone marrow aspirate and biopsy 
o Immunophenotyping of aberrant clonal plasma cells by multiparametric flow 
cytometry. 
o Immunoglobulin heavy and/or light chain rearrangement. 
o Interphase FISH/cytogenetics 
o Index clone identification for NGS MRD evaluation. 
 
 
• 
Peripheral Blood/Urine 
o Peripheral blood and urine samples for storage and establishing a biobank. 


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o Immune cells – including, but not limited to T cells (CD4 and CD8), LGL, and 
NK cells. 
 
Imaging (FDG/PET/CT scan) within 4 weeks of study entry and prior to starting therapy 
Prior to 18F-FDG PET/CT imaging, the subject will be fasted and have not received any sugar 
containing substance (i.e. glucose, sucrose, dextrose) for 4-6 hours.  Subjects will be encouraged 
to drink water during this period to reduce radiation dose to the kidneys and will be asked to void 
prior to 18F-FDG injection. Women of childbearing potential will have a documented report of 
negative pregnancy test before the scan. 
 
18F-FDG, [18F]-fludeoxyglucose is an FDA approved radiopharmaceutical. Immediately prior to 
injection, the subject’s blood glucose level will be evaluated via fingerstick. Non-diabetic subjects 
with fasting blood glucose levels above 200 mg/dl may be rescheduled at the discretion of the PI. 
Subjects will be asked to refrain from excessive physical exertion for the 24 hours prior to 
injection. 
 
PET-CT performed within the 4 weeks at an outside institution can be acceptable as baseline 
study as long as the images are uploaded in PACS and reviewed at MSKCC. 
 
 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Patients who have signed the consent form and are deemed eligible for this clinical trial will start 
therapy with daratumumab with the following schedule: 
 
• 
Cycles 1 and 2: Daratumumab 16mg/kg weekly for 4 weeks as intravenous 
infusion 
• 
Cycles 3-6: Daratumumab 16mg/kg once every 2 weeks for 4 weeks as 
intravenous infusion 
• 
Lenalidomide maintenance therapy to be administered as standard treatment to 
all patients. 
• 
Premedications: 
o Dexamethasone 20mg/dose IV on Days 1, 8, 15, 22 for Cycles 1 and 2 and 
Day 1 and 15 for Cycles 3-6. Montelukast 10mg PO for the first 4 weeks 
o Tylenol 650 mg PO prior to each dose of daratumumab 
o Benadryl 25 mg PO prior to each dose of daratumumab 
Recommended Concomitant Medications: 
• 
Post-infusion Medications: 
o Administer post-infusion medication to reduce the risk of delayed infusion 
reactions to all patients as follows: 
▪ 
Oral dexamethasone 4 mg (e.g. methylprednisolone 20 mg or 
equivalent) daily for two days starting the day after infusion. 


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• 
Prophylaxis for Herpes Zoster Reactivation 
o Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 
week of starting DARZALEX and continue for 3 months following treatment 
 
• 
Management of Hepatitis B Virus Reactivation 
o 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 10.0 
o 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. 
 
Infusion Related Reaction (IRR) Management - Daratumumab 
Severe infusion reactions associated with Daratumumab include bronchospasm, hypoxia, 
dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may 
include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as 
chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, 
pyrexia, chest discomfort, pruritus, and hypotension. Patients will be pre-medicated with 
antihistamines, antipyretics and corticosteroids and frequently monitored during entire 
infusion. Infusions will be interrupted for interactions of any severity and medical 
management will be managed. Daratumumab will be permanently discontinued for life- 
threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, the infusion 
rate will be reduced when re-starting the infusion. To reduce the risk of delayed infusion 
reactions, corticosteroids will be given to all patients.)]. Patients with a history of chronic 
obstructive pulmonary disease may require additional post-infusion medications to manage 
respiratory complications. In these instances post-infusion short and long-acting 
bronchodilators, and inhaled corticosteroids medications maybe prescribed. If the patient 
experiences no major infusion reactions, following the first four infusions, these additional 
inhaled post-infusion medications may be discontinued. 
 
 
9.1. 
Hematologic Toxicity 
 
9.1.1 On day 1 of each new cycle, patients must meet the following criteria: 
• 
ANC ≥ 1.0 x 109 /L 
• 
Platelet count ≥ 50 x 109 /L 
 
9.1.2 If these conditions are not met on Day 1 of a new cycle: 
• 
The next cycle of treatment will not be initiated until the above conditions 
(section 9.3.1) are met. If ANC and platelet counts do not satisfy the 
requirements above after 2 weeks of withholding treatment, the subject will 
go off therapy. Transfusions and growth factors are permissible. 


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9.2 
Non-Hematologic Toxicities Requiring Dosing Modifications 
 
9.2.1 Any ≥Grade 3 non-hematologic toxicity require daratumumab to be held  
until resolved to Grade 1 or baseline prior to resuming therapy or initiating 
next cycle. Investigator will determine which drug will be held based on side 
effect profile and clinical judgment. If therapy has been held for more than 3 
weeks due to non-hematologic toxicity, the patient will be removed from 
protocol therapy. 
 
9.2.2 Protocol therapy will be withheld for patients who require treatment of 
Grade 3 infection. If therapy has been held for more than 3 weeks due to 
treating a grade 3 infection, the patient will be removed from protocol 
therapy. 
 
9.2.3 Electrolyte or metabolic abnormalities that are reversible with electrolyte 
replacement within 72 hours or < grade 3 infections that can be controlled 
by appropriate therapy are exempt from holding treatment or dose 
modifications. 
 
 
9.3 
Monitoring 
 
9.3.1 Routine labs (CBC, chemistry panel 14, LDH, magnesium, uric acid, phosphate) 
will be performed every 2 weeks for the first 2 cycles, then on day 1 for cycle 3-6, 
at end of therapy. Myeloma tests include serum protein electrophoresis, serum 
immunofixation, beta-2 microglobulin, quantitative immunoglobulins and serum 
free light chains assay will be performed at baseline, start of each cycle, at end of 
therapy. Routine labs, and myeloma labs can be performed 24 hrs in advance. 
 
9.3.2 Patients will have clinic visits with H&P or standard progress notes assessing for 
toxicity/side effects at baseline, day 1 of each cycle, end of therapy, 1-month after 
end of therapy. Treatment window for day 1 of start of each cycle is +/- 7 days. 
Treatment window for intra-cycle daratumumab doses is +/- 2 days. 
 
9.3.3 24-hr urine sample for protein electrophoresis (UPEP) and immunofixation will be 
performed at baseline 
 
9.3.4 At CR/sCR or end of therapy, routine labs (CBC, chemistry panel 14, LDH, 
magnesium, uric acid, phosphate), myeloma specific tests - serum protein 
electrophoresis, serum immunofixation, beta-2 microglobulin, quantitative 
immunoglobulins and serum free light chains assay, lymphocyte subsets, 24-hr 
urine sample for protein electrophoresis (UPEP) and immunofixation to assess for 
monoclonal protein in the urine (Bence-Jones proteinuria). A bone marrow aspirate 
will also be performed to assess the status of minimal residual disease by flow 
cytometry (Sample sent will be the first bone marrow “pull”).  Patient will have clinic 
visit (relevant clinical laboratories and H&P) 1 month after completing combination 
therapy to undergo assessment of toxicities/adverse events. 


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9.3.5 An Echocardiogram (2-D or strain echo) is optional at baseline (Please refer to 
Section 10.0). 
Outside echocardiograms are permissible 
 
9.3.6 Patients will have FDG-PET-CT at baseline, end of therapy or upon suspicion of 
progressive disease as clinically indicated. 
 
9.3.7 
PFS and OS data will be collected for patients. 
 
 
9.4 
After Protocol Therapy 
 
9.4.1 Upon completion of protocol therapy, patients will be encouraged to continue 
lenalidomide maintenance as standard of care treatment. 
 
 
 
CONCOMITANT 
MEDICATIONS/MEASURES 
BONE DISEASE 
1)  Bisphosphonate therapy: Approved bisphosphonate therapy (zoledronic acid or 
pamidronate) is allowed. Patients will be monitored for renal function and osteonecrosis of 
the jaw. Patients may require prior evaluation from dental specialist before instituting 
bisphosphonates. 
 
TRANSFUSIONS/GROWTH FACTORS 
1) Subjects may receive RBC or platelet transfusions if clinically indicated. 
2) Subjects may receive supportive care with erythropoietin or darbepoetin. 
3) Colony-stimulating factors may be used if neutropenia occurs. 
4) Growth factors and transfusions should not be administered prophylactically during cycle 1 
unless clinically indicated. 
 
ANTI-COAGULATION 
Oral Aspirin 81 mg or 325 mg or suitable alternative anti-coagulation for thrombotic prophylaxis as 
standard of care for lenalidomide. 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 


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Study 
Pre- 
Treatment 
Induction Treatment 
End of therapy j,k 
Follow-up 
Cycle 1-2 
Cycles 3-6 
1 month 
after end  
of 
therapyi,h,k 
Day 1k Day 8 
Day 15 
Day 22 
Day  k 
1 
Day 15 
CR/sCR 
reached 
Medical Record Review 
x 
x 
x 
H&P with blood pressure 
x 
x 
x 
x 
x 
EKG 
x 
Echo 
xm 
ECOG 
x 
x 
x 
Informed Consent 
x 
Viral Studiesb 
b 
x 
b 
x 
b 
x 
b 
x 
Routine Labsa 
n 
x 
n 
x 
x 
x 
x 
Lymphocyte subsets 
x 
x 
Myeloma testse,i 
e,I,n 
x 
n 
x 
e,i 
x 
e,l 
x 
Urine for UPEP and IFE i 
i,n 
X 
n 
x
i 
x
i 
x
Pregnancy Testc 
c 
x 
x 
c 
x
Research Blood/Urined 
x 
x 
x 
x 
x 
x 
x 
Bone Marrow/Aspirate 
x 
p 
X 
g,p 
X 
FDG PET-    j 
CT 
x 
j 
X 
Adverse Events/Toxicity 
x 
x 
x 
x 


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a. Routine tests include CBC, reticulocyte count, Chem 14, magnesium, phosphate, uric acid, eGFR determination and LDH. Reticulocyte count will 
only be performed at baseline, day 1 of every cycle, and end of therapy. PT and PTT will only be performed at baseline. Peripheral blood 
lymphocyte subsets at baseline, C4D1, and end of therapy 
b. Viral studies include Hep B surface antigen, Hep B surface antibody, Hep B core antibody and Hep C antibody. If Hep C antibody positive, Hep C 
RNA PCR will be performed. 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. For subjects with serologic evidence of resolved HBV infection (i.e., positive Anti-HBs or positive Anti- 
HBc) at Screening, HBV DNA testing by PCR must be performed locally. Treatment phase: Q12W during treatment, at End of Treatment, and Q12W 
for up to 6 months after the last dose of study treatment. 
c. Pregnancy tests (urine or serum) for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months) 
d. To be stored at MSKCC HOTB biobank. 
e. Myeloma tests include serum protein electrophoresis, serum immunofixation, 24-hr urine electrophoresis, urine immunofixation, serum free light 
chains, quantitative immunoglobulins, beta-2 microglobulin and will be performed at baseline. 
f. 
Bone marrow aspiration and biopsy will be sent for histopathology, flow cytometry, FISH/cytogenetics. Lysate will also be sent for cell sorting into 
CD 138- and + fractions and whole bone marrow lysate for HOTB storage so molecular profiling with GEP and DNA-based sequencing at baseline 
can be performed as correlative work. 
g. Bone marrow aspirate and biopsy can be performed +/- 21 days of intended cycle day or achievement of CR/sCR. Bone marrow aspirate and 
biopsy will be sent to evaluate for histopathology, flow cytometry (bone marrow immunophenotyping of plasma cells), heavy/light chain 
immunoglobulin rearrangement. Aspirate lysate will also be sent for cell sorting into CD 138- and + fractions and whole bone marrow lysate for 
HOTB storage so molecular profiling with GEP and DNA-based sequencing at baseline can be performed as correlative work. For patients, 
reaching CR/sCR MRD negative timepoint earlier where MRD negative status is confirmed at earlier bone marrow evaluation, bone marrow 
aspiration and biopsy at end of study will be optional. Otherwise, all other bone marrow biopsies are mandatory. 
h. After study therapy ends, follow-up will be 1 month after study end date. Patients may be followed at more frequent time intervals, and thereafter if 
clinically indicated. Patients who have progressive disease while on therapy will be followed with restaging scans and laboratory tests as clinically 
indicated. At disease progression, marrow and FDG-PET/CT are optional but recommended. 
i. 
For patients with initial baseline 24-hr UPEP samples demonstrating ≥100 mg/24 hrs, patients will continue to have 24-hr UPEP samples day 1 of 
each cycle. Once 24-hr UPEP is <100 mg/24 hrs, patient can have random UPEP with IFE until achieving negativity.  If initial baseline 24-hr 
UPEP sample is IFE positive and/or <100 mg/24 hrs, patients can have random UPEP samples with IFE until achieving negativity. Once random 
UPEP and IFE is negative, no further urine samples are needed (unless patient’s disease is primarily measurable by 24 hr urines) 
j. 
FDG-PET scan will be performed on patients at baseline, end of therapy ( +/- 21 days) or upon suspicion of progressive disease as clinically 
indicated. 
k. Variations of +/- 7 days of scheduled visits are permitted. 
l. 
An echocardiogram (2-D or strain) will only be performed at baseline if the patient has had signs of significant cardiovascular disease. 
Outside  echocardiograms are permissible. 
m. If screening labs are performed within 5 days of C1D1 they can be used for treatment on day 1. 
n. Variations of +/-21 days of scheduled visits are permitted. 
o. Bone Marrow biopsy and aspirate will be required at time of serologic complete response. If patient is MRD negative on this bone 


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marrow one does not need to be completed at the end of treatment 


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Timepoints and potential analyses are listed below: 
Bone Marrow 
Sampling Time Points of Bone Marrow correlative studies 
 
a) Baseline 
b) End of therapy 
 
*Patients undergoing MRD evaluation or End of study evaluation, the first pulled sample will be sent 
for Multiparametric flow cytometry and NGS MRD evaluation. 
• 
Potential studies on the stored bone marrow samples may include but are not limited to the 
following: 
 
Bone Marrow Aspirate/Biopsy 
Pathology/Immunohistochemistry 
Immunohistochemical staining will be assessed using immunohistochemistry markers such as CD 
138, light chains, CD56 etc. Microenvironment interactions will also be assessed using various 
immunohistochemistry markers for osteoblasts, osteoclasts, stromal cells and proteasome 
components. 
 
Minimal Residual Disease 
Flow cytometry: Immunophenotyping of aberrant plasma cells by flow cytometry currently involves, 
but is not limited to, the use of the following reagents: CD138, CD19, CD45, CD38, and CD56. 
Characteristic changes in immunophenotypically abnormal plasma cells (CD38 bright and/or CD138 
positive) include but are not limited to decreased or absent CD19 and CD45, decreased CD38, 
increased CD56, decreased CD27, decreased CD81, increased CD117.  The first pulled bone 
marrow sample will be sent for multi-parametric flow cytometry as a priority.  Samples will undergo 
MRD testing per MSK institutional practice, see section 12.0 for further methodology practice. 
 
Molecular pathology: For MRD samples utilizing the NGS ClonoSEQ™ V2.0 (Adaptive 
Biotechnologies Seattle, WA) platform, immunoglobulin heavy and kappa chain variable, diversity, 
and joining gene segments from genomic DNA obtained from CD138+ bone marrow (BM) cell lysate 
or cell-free supernatant BM aspirate were amplified using universal primer sets as described 
elsewhere21. An MM clonotype was defined as an immunoglobulin rearrangement identified by NGS 
at a frequency of ≥5%. 
 
Mass spectrometry based proteomics for minimal residual disease assessment:  Serial urine and 
serum samples will be analyzed to detect clonotypic peptides representing patient’s monoclonal 
immunoglobulin heavy and light chains using high resolution mass-spectrometry-based proteomics. 
 
FISH and cytogenetics 
Interphase FISH/cytogenetics will be performed on patients enrolled in this protocol. 


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DNA-based target mutations 
Bone marrow aspirate samples will be analyzed for somatic mutations by exome-sequencing of 
targeted genes using MSKCC MyType assay. 
Cell Sorting and Bone marrow cell lysate 
Bone marrow aspirate storage samples will be sorted into CD 138 + and CD 138 – fractions and 
whole bone marrow cell lysate per HOTB SOP. 
Research Blood/Serum and Urine 
a) One 7-8 mL serum tube will be collected on Day 1, Day 8, Day 15, and Day 22 of Cycle 1 
and 2, Day 1 of every cycle during cycles 3-6, if and when CR/sCR is achieved, at the end of 
therapy, and at any time point if the patient has progression of disease. One 7-8 mL CPT 
tube will be collected on Day 1 of every cycle during cycles 1-6, if and when  CR/sCR is 
achieved, at the end of therapy, and at any time point if the patient has progression of 
disease. 
b) Urine (random samples of 10 mL) will be collected into a standard urine collection cup and 
sent for analysis and storage at each of the above time points. 
 
c) Peripheral blood and/or urine samples from patients will be analyzed for potential serum or 
urine biomarkers as well as drug concentrations, and describe the association with clinical 
outcomes if the results of the study indicate a clinical or translational rationale for analyzing 
the samples. The samples will be transferred to the HOTB and will be analyzed there per 
institutional SOP. 
 
 
Assessment/Evaluation Plan 
 
The protocol consent form asks participants for permission for re-contact to discuss research 
findings if an incidental research finding is made that may be critical to their health or preventive 
care, or that of their issue. If a participant agrees to be re-contacted, he/she will not be told the 
specific results of the research test, but will be informed that his/her samples were used in a project 
and a potential risk was discovered. If the participant is interested in further discussion of the 
research findings, he/she will be asked to contact MSKCC Clinical Genetics Service for counseling 
and specific genetic testing. 
 
In the event an investigator's research identifies a finding that he or she believes should be 
communicated to the subject (and/or family designee), the investigator can communicate that 
finding to the IRB Genomic Advisory Panel (GAP). The finding will be reviewed by the GAP to 
determine whether the incidental finding should be discussed with the participant. For MSK, in the 
event that the  GAP determi nes that the finding should be discussed with the participant, and the 
participant has consented to be re-contacted, then the treati ng/consenting physician shall be 
contacted by the panel and asked to refer the participant to the Clinical Genetics Service for 
further discussion of the research finding. 
 
After  appropriate counseling and consent, the Clinical Genetics Service will request permission to 
confirm  the result in a New York DOH-approved laboratory prior to communication of the specific 
result. If the patient is not available (e.g. deceased), then the surrogate designated on the consent 
will be contacted and the above will occur. 


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The below schema will be followed by MSKCC investigators who identify a potentially actionable 
incidental finding in the course of research conducted on samples collected under this protocol: 
 
 
 
 
 
 
IRB#: xx-yyy 
 
MEMORIAL SLOAN KETTERING CANCER CENTER 
IRB PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The IRB and Clinical Genetics Service, as per above flow chart, will be notified when a 
participant’s samples uncover a potentially reportable incidental finding(s). The following 
information must be provided to OCR-IRB representative and Clinical Genetics: 
 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, etc) 
• 
Incidental Finding 
• 
Project # (Waiver or Biospecimen Protocol #) that this analysis occurred under 
• 
Collection Protocol # 
Contact: ocrgapirb@mskcc.org 


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11.1 TOXICITIES/SIDE EFFECTS 
 
11.1 
Daratumumab 
 
 
Infusion Related Reactions 
 
Daratumumab is an antibody. An antibody is a large protein that is used by the immune system to 
identify and neutralize bacteria and viruses. A side effect to daratumumab that occurs during or 
shortly after an infusion is completed (when the medicine is given into a vein) is called an infusion- 
related reaction. Infusion–related reactions were reported in approximately half of all patients treated 
with daratumumab. It usually occurs with the first infusion and during or within the first few hours of 
the start of the infusion. Signs and symptoms of infusion-related reactions may include respiratory 
symptoms, such as stuffy nose, cough, throat irritation, as well as chills, vomiting and nausea. Less 
common symptoms are having trouble breathing (wheezing), runny nose, fever, chest discomfort, 
itching of the skin, and low blood pressure or high blood pressure. Most of the observed infusion- 
related reactions so far were mild or moderate, and ended by temporarily stopping the infusion and 
giving medicines to treat the side effect. Tell your doctor right away if you have above mentioned 
symptoms. 
 
If you have a breathing problem now or had breathing problems in the past (like chronic obstructive 
pulmonary disease (COPD) or asthma), you should tell your study doctor. Also, if you start to have 
breathing problems while you are on the study you should tell your study doctor right away. You may 
be asked to see a doctor who takes care of patients with airway diseases, and additional medicines 
for airway problems may be given to you. Your doctor will explain how these additional medicines 
should be taken. Get emergency medical help if you have any of following: hives, wheezing, difficulty 
breathing, swelling of your face, lips, tongue, or throat or pain in chest. 
 
Severe reactions have occurred, including narrowing and obstruction of the respiratory airway 
(bronchospasm), low oxygen, shortness of breath, high blood pressure, swelling in the throat and 
fluid accumulation in the lungs (pulmonary edema). Your study doctor and their staff will be ready to 
treat such a reaction in case it happens. In the future, you should tell any doctor you visit that you 
received daratumumab (an antibody) in this research study and if you had an allergic reaction 
including anaphylaxis, the worst case of allergic reaction. 
 
The sponsor will continue to monitor infusion-related reactions and make changes to the way 
daratumumab is administered and/or recommend additional medications as necessary. 
 
In this study, the following will be done to reduce the chance of a daratumumab infusion related 
reaction: 
• 
You will get medications, including steroids, acetaminophen and antihistamine, before the 
infusion. 
• 
If you have a reaction, the infusion will be paused and the symptoms treated as needed. 
Dependent on the reaction, the infusion may continue at a slower rate. If you have a life- 
threatening reaction, you will need to stop further treatment with daratumumab and your 
doctor will discuss alternative treatments with you. 


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• 
If you are considered higher risk for breathing problems (for example COPD, asthma), you 
may also get medications, including inhaled steroids, after the infusion. 
• 
You may stay overnight in hospital after the infusion so medical staff can check you. 
 
 
Possible Side Effects of Daratumumab 
 
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. 
 
Among the 283 patients who received daratumumab in combination with lenalidomide and 
dexamethasone in the POLLUX trial12, please see Table 7 and Table 8 (DRd (N=283) %) for the 
most frequently reported AEs (reported in >10% of subjects) and the most frequently reported 
Grade 3 or higher AEs. All other Grade 3 and higher AEs were reported in <5% of subjects. 
 
 
 
 


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Indirect Antiglobulin Testing 
 
Daratumumab treatment will affect one of these tests known as an indirect antiglobulin test (IAT; 
also known as an indirect Coombs test). Therefore, an IAT will be done before receiving 
daratumumab. 
 
Birth control and pregnancy during the study 
 
The effects of daratumumab on fertility, the human embryo, the fetus, or the breast-fed infant are 
unknown. Both male and female patients must use effective methods of birth control during the 
course of the study and for 3 months after stopping daratumumab. Women must not donate eggs 
during the study and for 3 months after your last dose of study drug. Men must not donate sperm 
during the study and for 3 months after your last dose of study drug. 
 
 
 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Disease Parameters 
 
 
Minimal Residual Disease 
For patients undergoing MRD or end of study assessment, the first pulled bone marrow sample will 
be sent for multi-parametric flow cytometry as a priority.  Flow cytometry based assay to rule out 
MRD in bone marrow aspirates and for MRD negative status using an assay with a sensitivity of at 
least 1 in 10 ^ -5 cells. Patients with <CR/sCR are considered MRD positive. We will use the 
MSKCC flow cytometry MRD method which is based on 10-colors in a single tube.16. The test 
demonstrates highly similar results when compared to the current Euroflow approach. This test is 
validated and already in clinical use at MSK.  Immunophenotyping of aberrant plasma cells by flow 
cytometry currently involves, but is not limited to, the use of the following reagents: CD138, CD19, 
CD45, CD38, and CD56. Characteristic  changes in immunophenotypically abnormal plasma cells 
(CD38 bright and/or CD138 positive) 
include but are not limited to decreased or absent CD19 and CD45, decreased CD38, increased 
CD56, decreased CD27, decreased CD81, increased CD117. 
 
Traditional Response Criteria from International Myeloma Working Group Criteria for Multiple 
Myeloma22 
Evaluation of Response Criteria 
a) Stringent Complete Response (sCR) 
o Complete Response as defined below plus: Normal FLC ratio and absence of clonal 
cells in bone marrow by immunohistochemistry or immunofluorescence (presence/ 
absence of clonal cells is based on the kappa/ lambda ratio. 
b) Complete Response (CR) 


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o Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <= 5% plasma cells in bone marrow 
c) Very Good Partial Response (VGPR) 
o 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 <100mg per 
24h. If the serum and urine M-protein are unmeasurable, a ≥ 90% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the M- 
protein criteria. 
d) Partial Response (PR) 
o ≥ 50% reduction in M protein and reduction in 24-h urinary M-protein by ≥ 90% or to < 
200 mg per 24h. If the serum and urine M-protein are unmeasurable, a ≥ 90% 
difference between involved and uninvolved FLC levels is required in place of the M- 
protein criteria 
e) Stable Disease (SD) 
o Not meeting criteria for CR, VGPR, PR or progressive disease. 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. 
f) Progressive disease (PD) 
o Requires any one or more of the following: 
▪ 
Increase of ≥ 25% of nadir in: 
▪ 
Serum M-component and/or (absolute increase must be ≥ 0.5 g/dl. The 
serum M-component increases of ≥ 1gm/dl are sufficient to define relapse if 
starting M-component is ≥ 5 gm/dl. 
▪ 
Urine M-component and/or (the absolute increase must be ≥ 200 mg/24h 
▪ 
Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be >10mg/dl. 
▪ 
Bone marrow plasma cell percentage: the absolute % must be ≥ 10% 
▪ 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in size of existing bone lesions or soft tissue 
plasmacytomas 
▪ 
Development of that can be attributed solely to the plasma cell proliferative 
disorder 
g) Relapse from CR 
o Any one or more of the following: 
▪ 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis.  (Appearance of monoclonal or oligoclonal bands that are 
different from original isotype may not be defined as “relapse from CR”. 
Often times, such bands may indicate fluctuations in immunological 
parameters that are not reflective of MM disease.  In these situations, 
immunofixation and electrophoresis will be interpreted by the clinician before 
being labeled as “relapse”23,24. 
▪ 
Development of ≥ 5% plasma cells in the bone marrow 
▪ 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic 


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bone lesion, hypercalcemia 
Progression-Free Survival 
PFS is defined as time of start of treatment to time of progression or death, whichever occurs first. 
Patients alive and progression-free at the end of study will be censored at that time. 
 
Overall Survival 
Overall survival is defined as the time of start of treatment to death from any cause. Patients alive at 
the end of study will be censored at that time. 
 
Toxicity Criteria 
 
The following adverse event management guidelines are intended to ensure the safety of 
each patient while on the study. The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
Off-therapy Criteria 
Patients with medically concerning grade 3 or 4 adverse events related to drug therapy may be 
taken off therapy at the discretion of the principal investigator. 
 
• 
Hematologic toxicity has not completely resolved or resolved to < grade 1 or baseline after 2 
weeks of withholding treatment 
• 
Therapy has been held for more than 3 weeks due to grade 3 or higher non-hematologic 
toxicity 
• 
Patient completes the protocol treatment 
• 
Progression of disease 
• 
Patient chooses to go off therapy 
• 
The principal investigator may remove patient from protocol therapy if deemed necessary 
due to medical conditions, compliance, etc. 
• 
Patient becomes pregnant. 
Off-Study Criteria 
• 
Patient requests to be withdrawn from study 
• 
Death 
• 
Physician’s determination that withdrawal is in the patient’s best interest. 
 
• 
Patient who have gone on to other treatments aside from revlimid 


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maintenance (5-15 mg daily 21-28/ 28-day cycle) 
 
 
 
 
14.1 
BIOSTATISTICS 
 
Study Design/Primary Endpoints 
 
This is a single arm phase II study designed to evaluate the efficacy of short course therapy with 
daratumumab, in multiple myeloma patients achieving a VGPR or better with MRD positive state 
while on lenalidomide maintenance for at least 6 months at the time of enrollment. The primary 
objective of this study is to determine the rate of conversion to MRD negativity by the completion of 
6 cycles of treatment. 
 
Rationale 
 
The primary objective of this trial is to determine whether treatment with daratumumab is associated 
with a substantial fraction of patients with MRD positive multiple myeloma converting to a MRD 
negative state as assessed by multicolor flow cytometry. Previously studies have reported that 
approximately 10% of patients will achieve deeper responses including MRD negativity after 
maintenance therapy with lenalidomide alone18. The current study will be considered positive if the 
rate of MRD negativity is 30% or higher with daratumumab. 
 
Power Calculations 
 
This study will implement a Simon’s two-stage minimax design to distinguish between an 
unpromising rate of 10% and a promising rate of 30%. The study is designed to have a type I error 
and a type II error of 0.10. The maximum sample size is 25 patients. 
 
Primary analysis 
 
In the first stage of the study, a total of 16 patients will accrue. If 2 or more patients achieve MRD 
negativity, additional 9 patients will accrue. If at the end of the study, 5 patients or more out the total 
25 patients achieve MRD negativity, the short course daratumumab will be considered promising for 
future investigation. 
Accrual will be held after the 16th patient if 2 or more patients have not yet achieved MRD negativity. 
We anticipate that one to two patients will accrue each month. 
 
Analysis population for primary endpoint 
 
All patients who receive at least one dose of daratumumab will be considered evaluable for the 
primary endpoint. Patients who do not have the end of therapy bone marrow for any reason and 
have not achieved MRD negativity at any point while on study will be considered a treatment failure. 
 
 
Secondary endpoints: 
 
1. To estimate the rate of sustained MRD negativity. Among patients achieving MRD negativity, 
sustained negativity is defined as remaining MRD negative at the 1-year post treatment 


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completion bone marrow biopsy. The proportion along with the 95% confidence interval will 
be estimated. 
 
2. Kaplan-Meier methodology will be used to estimate the duration of MRD negativity. This 
endpoint is defined as the time from MRD negativity achievement to MRD positivity, 
progression of disease, or death. The median along with the corresponding 95% 
confidence interval will be  estimated. 
 
3. To explore the concordance of different MRD methodologies. MRD status by multiparametric 
flow cytometry will be compared to next-generation sequencing and to mass spectrometry 
based proteomics methodologies. The kappa statistic will be reported. 
 
4. Kaplan-Meier methodology will be used to estimate progression-free survival and overall 
survival. Estimates of survival along with 95% confidence intervals will be provided for select 
time points. 
 
 
Exploratory Studies: 
 
1. The gene panel MyType (or alternative equivalent platform) will explore whether any mutations 
appear to be associated with the achievement of MRD negativity. This analysis is for hypothesis- 
generation, and all results will be cautiously interpreted. Fisher’s exact test may be used to assess 
any potential association. The variant allele frequency (VAF) will be summarized for each 
mutation. VAFs will be adjusted for the cancer cell fraction. All results will be adjusted for multiple 
comparisons. 
 
2. MyType (or alternative equivalent platform) will also be evaluated using samples at the  time of 
progression of disease and will be compared to the pre-treatment baseline samples to explore 
whether pathways leading to emergence of resistance to the drug regimen can be identified. 
Similar to the previous objective, this aim is for hypothesis generation, and all results will be 
cautiously interpreted. Changes in the VAF from baseline will be summarized for patients with an 
ongoing response and for patients who have progression of disease. A paired t-test may be used 
to further describe this association. VAFs will be adjusted for the cancer cell fraction. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures.  During the registration process registering individuals will be required to  
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. 
 
Study staff are responsible for ensuring that all institutional requirements necessary to  enroll a 
participant to the study have been completed.  See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
15.3 
Randomization 


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This study will not include randomization. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
All patients will be enrolled on protocol at Memorial Sloan-Kettering Cancer Center. We 
expect to be able to enroll the necessary 25 patients into this study in 2 years. 
 
The study coordinator (Clinical Research Associate, CRA) will be responsible for confirming 
eligibility and assisting the MD with the registration process. All study data will be collected 
by an assigned data manager (Clinical Research Coordinator, CRC) who will enter this 
information into the Clinical Research Database (CRDB). This database will be utilized for 
data collection and storage and for reporting protocol specific events such as accrual 
demographics, toxicities and adverse events to the IRB, and the sponsor. 
 
The CRC will collect toxicity and concomitant medication information and patient interviews. 
Adverse events, including all toxic effects of treatment will be tabulated individually according 
to severity or toxicity grade. The data manager will also monitor laboratory testing throughout 
the study. Laboratory data will be tabulated and summarized by descriptive statistics, as well 
as on the basis of MSKCC specified normal ranges. 
16.2 
Quality Assurance 
 
Monthly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates, extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
 
Random sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM Plan, 
where applicable. 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. The plans address the new policies set forth by 
the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety    
Monitoring of Clinical Trials.” 
 
There are several different mechanisms by which clinical studies are monitored for data, safety 
and quality. At a departmental/PI level there exists procedures for quality control by the 
research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA and 
two institutional committees that are responsible for monitoring the activities of our clinical 


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trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I 
and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Deputy Physician-in-Chief, Clinical Research. 
 
The degree of monitoring required will be determined based on level of risk and documented. 
 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. The 
DSMB/C have oversight over the following trials: 
• 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
• 
External studies where MSK is the data coordinating center 
• 
Low risk studies identified as requiring DSMB/C review 
 
The DSMC will initiate review following the enrollment of the first participant/or by the end of 
the year one if no accruals and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will initiate 
review once the protocol is open to accrual. 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to MSKCC and collaborating centers IRB guidelines. 
Patients will be eligible for this trial regardless of gender or racial/ethnic background.  All 
patients must follow the guidelines for pregnancy testing birth control and counseling related 
to the risk of fetal exposure to lenalidomide and bortezomib. 
 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB and 
the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the declaration, 
as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Subjects and Part 56 Institutional Review Boards. 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
The consent also indicates that samples and genetic information collected may be shared 
with other qualified researchers. Such information will not include identifying information such 
as name. It is also stated in the consent and Research Authorization that research data (e.g. 
genomic sequence) may be placed into databases monitored by the National Institutes of 


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Health, and may be made accessible to investigators approved by the U.S. government. 
 
Consent for re-contact 
 
Patients are asked in a series of check boxes at the end of the consent if 1) if they consent to 
be contacted to discuss research findings which may derive from their sample; and 2) if not 
available (e.g. deceased), if they wish to have their designated representative on the consent 
to be contacted. 
 
Use of identifiable information for genetic studies 
 
It will be explained to participants that future research may also be done to identify changes 
in genes that predict risk for cancer or other diseases; if such germline genetic research is 
performed, then to be in compliance with New York State law (see section 3.5), it will not be 
possible to provide results of research tests not performed in a New York State Department 
of Health approved clinical laboratory. It is stated in the consent that participants will be told 
that they will not receive any specific results from potential research tests. The consent will 
tell participants that if they wish to have genetic testing done for personal reasons than they 
should make an appointment with the MSKCC Clinical Genetics Service. 
 
If in the course of this research a research finding is obtained that may be critical to the 
preventive care of the participant or their family, as determined by procedures overseen by 
the IRB, those participants, if they consent to checklist questions 1, 2, will be referred to the 
Clinical Genetics Service for a consultation. At that time, genetic counseling can be offered in 
accordance with New York State requirements, and appropriate clinical testing offered in an 
approved laboratory. Please see flow chart and requirements for reporting under section 
10.0. 
 
Patients will be informed that future research may also identify changes in genes that predict 
risks for cancer or other diseases. Procedures for informing patients or their designees, 
confirmation by a New York State approved laboratory, and follow-up assessments and 
counseling are already detailed in Section 10.0 above. 
 
For tumor (somatic) genetic studies, germline studies of genetic variants of unknown 
significance (e.g. for example, in pharmacogenetics studies), gene discovery studies, and 
cellular, immunologic, or other studies using banked correlative tissues, the name and 
personal identifiers may be removed from the sample, but a coded link will be maintained. 
 
Research analysis of tumor genomes may inadvertently reveal, or require some knowledge 
of the germline genome. Such research studies could be performed on samples not 
identifiable to the researcher but with identifying links maintained by the TPS, HOTB or 
similar, and approved via IRB mechanisms. See section 10.0 for instructions on how to 
report incidental findings on research samples. 
 
Future use of samples 
 
Researchers at MSKCC may either keep indefinitely or dispose of any specimen(s) collected 


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under this protocol including DNA that the samples contain. Specimens will be stored with 
identifiers in secure banks at MSKCC.  Samples could be lost or ruined because of 
mechanical failure, and MSKCC cannot guarantee that samples will be stored indefinitely. 
The samples will be stored for as long as deemed useful for research purposes. 
 
Risks of research participation 
 
Risks are those of the procedure to obtain the specimen and are considered minimal. 
Another risk is release of information from health or research records in a way that violates 
privacy rights.  MSKCC protects records so that name, address, phone number, and any 
other information that identifies the participant will be kept private and confidential, along with 
all personal health information. 
Benefits of research participation 
 
It is unlikely that the research using biospecimens will be of any medical benefit to 
participants.  Neither the patient nor the treating physician will necessarily be told of the 
results of any research tests on the samples, except an incidental finding that may be critical 
to the preventive care of the subject or his/her issue.  Research using biospecimens 
collected in this study could lead to medical and scientific products that could improve 
prevention, diagnosis, and treatment of disease; but those benefits are unlikely to accrue to 
the participants. 
 
Occasionally, however, there are tests conducted in research labs, the results of which might 
contribute toward treatment decisions. These studies would not yet have been reduced to 
clinical practice, but patients may be informed of such results and how they may affect 
diagnosis and treatment. 
 
 
 
 
Costs/compensation 
 
There is no cost to enroll or participate in this research. Biospecimens obtained under this 
research protocol may be used to make secondary products, and such products may be 
patented or licensed with commercial value.  Participants are not financially compensated for 
use of their human biological specimens or secondary products, tests, and discoveries that 
derive from their biospecimens. 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 


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• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient of participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/ 
intervention. SAE reporting is required for 30-days after the participant’s last investigational 
treatment/intervention. Any event that occur after the 30-day period that is unexpected and at 
least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test of procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar days 
of the event. 
 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the adverse event was expected 
• 
Detailed text that includes the following 
o An explanation of how the adverse event was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
17.2.1 
 
 
AE/SAE Reporting by Investigator-sponsor to Janssen 
 
As the sponsor of the Study, PRINCIPAL INVESTIGATOR shall be solely responsible for 
complying, within the required timelines, any safety reporting obligation to competent Health 
Authorities, IRB/ECs and any participating (co or sub) investigators, as defined in applicable 
laws and regulations.  For the purposes of this section, safety data includes adverse events, 
product quality complaints (PQCs), and special situations including pregnancies. 
 
The PRINCIPAL INVESTIGATOR will provide safety information to Janssen Scientific Affairs, 
LLC on adverse events, special situations including pregnancies and product quality 
complaints as defined within this section. 
 
This Study has been designated as an interventional study. As such, all adverse events for 
daratumumab regardless of causality and special situations excluding those from subjects 
not exposed to a J&JMedicinal Product and product quality complaints with or without an 
adverse event as described in this Exhibit will be reported from the time a subject has 


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signed and dated an Informed Consent Form (ICF) until completion of the subject’s last 
study-related procedure (which may include contact for follow-up safety). Serious adverse 
events will be reported for 30 days after the last dose of study drug. 
 
Adverse Event (AE) Definition: 
 
An adverse event is any untoward medical occurrence in a clinical study subject administered 
a medicinal (investigational or non-investigational) product. An adverse event do 
es not necessarily have a causal relationship with the treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational or non- 
investigational) product, whether or not related to that medicinal (investigational or non- 
investigational) product. (Definition per International Conference on Harmonisation [ICH]) 
 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
Adverse Event of Special Interest Definition: 
 
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. 


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Individual Case Safety Report (ICSR) Definition: 
 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address) 
• 
an identifiable reporter (investigational site) 
• 
a J&J medicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected J&J medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• 
J&J protocol ID 
 
Product Quality Complaint (PQC) 
A product quality compliant 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 
 
Serious Adverse Event (SAE) 
 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 


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• 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious. 
 
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 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. 
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 


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Special Reporting Situations 
 
Safety events of interest for a J&J 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 J&J medicinal product 
• 
Exposure to a J&J medicinal product from breastfeeding 
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a J&J medicinal product 
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
• 
Medication error involving a J&J 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 J&J medicinal product 
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a J&J 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. 
 
Pregnancy 
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC by the 
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. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
 
Maintenance of Safety Information 
 
All safety data should be maintained in a clinical database in a retrievable format. The 
PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious and non- 
serious, in report format. However, in certain circumstances more frequent provision of 
safety data may be necessary, e.g. to fulfill a regulatory request, and as such the data 
shall be made available within a reasonable timeframe at Janssen Scientific Affairs, LLC 


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request. 
 
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
J&J Medicinal Products to Janssen Scientific Affairs, LLC 
 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to a J&Jmedicinal product are  to be documented  by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators 
must record in the CRF their opinion concerning the relationship of the adverse event to a 
J&Jmedicinal product. 
 
All (serious and non-serious) adverse events reported for a J&J medicinal product 
should be followed up in accordance with clinical practice. 
 
SAEs 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 PRINCIPAL INVESTIGATOR will transmit all SAEs and special situations following 
exposure to a Janssen product under study in a form provided by Janssen Scientific 
Affairs, LLC in accordance with Section 10,Transmission Methods, in English by the next 
business day after becoming knowledgeable of the event   
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR 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 PRINCIPAL 
INVESTIGATOR, by the next business day after becoming knowledgeable of the event   
within 24 hours becoming aware, to Janssen Scientific Affairs, LLC using the Janssen 
Scientific Affairs, LLC Serious Adverse Event Report 
 
All available clinical information relevant to the evaluation of a related SAE, serious ADR 
or special situation is required. 
 
• 
The PRINCIPAL INVESTIGATOR 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 


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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 10 from this Exhibit by the next business 
day after such a report or correspondence being sent to the applicable health 
authorities.   
Non-Seriou s 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. 
 
PQC Reporting 
 
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 or any 
reports 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 J&J medicinal product under study must be reported to 
Janssen Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR by the next business 
day after becoming knowledgeable of the event The Janssen contact will provide additional 
information/form to be completed. 
 
If the defect for a J&J medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR 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. 
 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-J&JMedicinal Products 
 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the 
appropriate regulatory/competent authority or the manufacturer of that medicinal product 
(in the absence of appropriate local legislation) as soon as possible. 
 
Transmission Methods 
 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
• 
Electronically via Janssen SECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs, LLC. 


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18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics 2017. CA Journal. 67(1):7-30. 
2. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma. Lancet Oncology. 2014; 15(12):e538- 
548. 
3. 
Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Bjorkholm M. Patterns of survival in 
multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 
2003. J Clin Oncol. May 20 2007;25(15):1993-1999. 
4. 
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the 
impact of novel therapies. Blood. 2008;111(5):2516-2520. 
5. 
Konopleva M, Estrov Z, Zhao S, et al. Ligation of cell surface CD38 protein with agnostic 
monoclonal antibody induces a cell growth signal in myeloid leukemia cells. J Immunol 1998; 
161:4702-08. 
6. 
Deaglio S, Vaisitti T, Billington R, et al. CD38/CD19: a lipid raft-dependent signaling complex 
in human B cells. Blood 2007; 109:5390-5398. 
7. 
Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 
cases of multiple myeloma. Am J Clin Pathol2004;121:482-488 
8. 
Santonocito AM, Consoli U, Bagnato S, et al. Flow cytometric detection of aneuploid 
CD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and 


Memorial Sloan Kettering Cancer Center 
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PBSC harvest in multiple myeloma patients. Leuk Res 2004;28:469-477 
9. 
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 
hematologic al 
tumors. J Immunol 2011;186:1840-1848. 
10. 
Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to 
the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple 
myeloma. MAbs 2015;7:311-321. 
11. 
Lokhorst HM, Plesner T, Laubach J, et al. Targeting CD38 with daratumumab monotherapy 
in multiple myeloma. NEJM 2015; 373:1207-1219. 
12. 
Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for 
multiple myeloma. NEJM 2016; 375: 1319-1331. 
13. 
Mailankody S, Korde N, Lesokhin AM, et al. Minimal residual disease in multiple myeloma: 
bringing the bench to the bedside. Nat Rev Clin Onc 2015; 12:286-295. 
14. 
Landgren O, Devlin S, Boulad S, Mailankody S. Role of MRD status in relation to clinical 
outcomes in newly diagnosed multiple myeloma patients: a meta-analysis. BMT 2016; 
51(12):1565-1568. 
15. 
Munshi NC, Avet-Loiseau, Rawstron A, et al. Association of minimal residual disease with 
superior survival outcomes in patients with multiple myeloma: A meta-analysis. JAMA Onc 
2017; 3(1):28-35. 
16. 
Flanders A, Stetler-Stevenson M, Landgren O. Minimal residual disease testing in multiple 
myeloma by flow cytometry: major heterogeneity. Blood. Aug 8 2013;122(6):1088-1089. 
17. 
Roshal M, Flores-Montero JA, Gao Q, et al. MRD detection in multiple myeloma: comparison 
between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods. Blood 
Advances 2017; 1:728-732. 
18. 
Oliva S, Gambella M, Gilestro M, et al. Minimal residual disease after transplantation or 
lenalidomide-based consolidation in myeloma patients: a prospective analysis. Oncotarget 
2017; 8(4):5924-35. 


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20.0 
APPENDICES 
 
Appendix A 
 
 
To characterize bone marrow aspirate specimens for somatic base mutations and copy number 
alterations in key cancer-associated genes, we will perform a custom, targeted deep-sequencing 
assay on matched tumor and normal pairs. The assay, termed MYTYPE involves massively parallel 
sequencing, coupled with solution-phase exon capture. Exon capture will be performed on 
barcoded pools of sequence libraries by hybridization (Nimblegen SeqCap Target Enrichment) using 
custom oligonucleotides to capture all exons and select introns of 585 cancer genes, including all 
genes significantly mutated in hematologic malignancies. Barcoded pools will subsequently be 
sequenced on an Illumina HiSeq 2500 to 500-1000x coverage per sample in order to maximize 
sensitivity for detecting low-abundance alterations. Through many iterations of the design of the 
capture probe set, we have maximized the coverage uniformity across all exons in our panel, thus 
reducing the number of poorly-covered exons. As a result, for a sample sequenced by MYTYPE  to 
1000x coverage, >98% of target exons are covered at >500x. The platform includes all genes that 
are druggable by approved therapies or are targets of experimental therapies being investigated in 
clinical trials at MSKCC. Custom probes have been designed to capture translocations involving 
recurrently rearranged genes.