First-in- Human Imaging of Multiple Myeloma Using 89Zr-DFO-daratumumab, a CD38-targeting Monoclonal Antibody
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 1 of 33 
 
 
 
 
First-in-human imaging of multiple myeloma using 
89Zr-DFO-daratumumab, a CD38-targeting monoclonal antibody 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Gary Ulaner, MD, PhD 
Radiology 
Co-Principal 
Investigator(s)/Department: 
Ola Landgren, MD 
Jason Lewis, PhD 
Joseph O’Donoghue, PhD 
Medicine 
Radiology 
Medical Physics 
Investigator(s)/Department: 
Mithat Gonen, PhD 
Pat Zanzonico, PhD 
Adam Kesner, PhD 
Assen Kirov, PhD 
Neha Korde, MD 
Oscar Lahoud, MD 
Alexander Lesokhin, MD 
Nikoletta Lendvai, MD, PhD 
Hani Hassoun, MD 
Sham Mailankody, MBBS 
Jonathan Peled, MD, PhD 
Michael Scordo, MD 
Eric Smith, MD, PhD 
Malin Hultcrantz, MD, PhD 
David Chung, MD, PhD 
Heather Landau, MD 
Sergio Giralt, MD 
Gunjan Shah, MD 
Virginia Klimek, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Paul Hamlin, MD 
Philip Caron, MD, PhD 
Colette Owens, MD 
Biostatistics 
Medical Physics 
Medical Physics 
Medical Physics 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/  Myeloma 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Consenting 
Professional(s)/Department: 
Gary Ulaner, MD, PhD 
Ola Landgren, MD 
Neha Korde, MD 
Oscar Lahoud, MD 
Alexander Lesokhin, MD 
Nikoletta Lendvai, MD, PhD 
Hani Hassoun, MD 
Sham Mailankody,  MBBS 
Jonathan Peled, MD, PhD 
Radiology 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/Myeloma 
Medicine/MyelomaMedicine/Myeloma 
Medicine/Myeloma Medicine/Myeloma 
Medicine/Myeloma Medicine/Myeloma 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
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Page 2 of 33 
 
 
 
 
 
Michael Scordo, MD 
Eric Smith, MD, PhD 
Malin Hultcrantz, MD, PhD 
David Chung, MD, PhD 
Heather Landau, MD 
Sergio Giralt, MD 
Gunjan Shah, MD 
Virgina Klimek, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Paul Hamlin, MD 
Philip Caron, MD, PhD 
Colette Owens, MD 
Medicine/Myeloma 
Medicine/  Myeloma 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine/ABMT 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK  Sites 
Manhattan 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 5 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 11 
4.1 
Design................................................................................................................................. 11 
4.2 
Intervention .............................................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 15 
6.1 
Subject Inclusion Criteria ..................................................................................................... 15 
6.2 
Subject Exclusion Criteria ................................................................................................... 15 
7.0 
RECRUITMENT PLAN .................................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 17 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 17 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 18 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 19 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 22 
14.0 
BIOSTATISTICS ............................................................................................................... 22 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
24 
15.1 
Research Participant Registration ....................................................................................... 24 
15.2 
Randomization .................................................................................................................... 24 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 24 
16.1 
Quality Assurance............................................................................................................... 24 
16.2 
Data and Safety Monitoring .................................................................................................... 24 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 26 
17.1 
Privacy ................................................................................................................................ 26 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................ 26 
17.2.1  ........................................................................................................................................  28 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 28 
19.0 
REFERENCES ....................................................................................................................... 29 
20.0 
APPENDICES ................................................................................................................... 30 

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IRB Number: 18-267 A(3) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase I/II study with the goal to assess the feasibility of using the anti-CD38 
monoclonal antibody daratumumab, labeled with Zirconium-89 (89Zr ) through 
deferoxamine (DFO), known as 89Zr-DFO-daratumumab, for PET imaging of multiple 
myeloma. CD38 is an established therapeutic target in multiple myeloma that is expressed 
at high density by almost all myeloma cells. Daratumumab binds directly to CD38. 
Imaging with 89Zr-DFO-daratumumab may therefore provide a sensitive and specific way 
to detect and stage multiple myeloma. In addition, the degree of uptake of 89Zr-DFO- 
daratumumab may predict the effectiveness of daratumumab therapy. Finally, 
daratumumab labeled with a beta or alpha emitter may eventually be used to treat multiple 
myeloma. 
The study has two phases: a short phase 1 to confirm the safety of the imaging agent, 
identify the suitable antibody mass for imaging, and identify the most appropriate time for 
imaging; and a subsequent phase 2 to correlate tumor uptake on 89Zr-DFO-daratumumab 
PET serum M protein concentration, percentage plasma cells on bone marrow biopsy, and 
patient response to daratumumab/lenalidomide therapy.The total patient population is up 
to 30 (6-12 evaluable patients in phase 1 and 18-24 evaluable patients in phase 2). The 
study outline is as follows: 
Phase I (total of 6-12 evaluable patients). At least 6 and up to 12 evaluable patients will be 
needed to determine pharmacokinetics and radiation dosimetry for 89Zr-DFO- 
daratumumab. Only the number of patients needed to determine pharmacokinetics and 
radiation dosimetry will be enrolled in phase I. 
 
 
 
 
 
 
 
 
 
 
Three patients will be administered 2 mCi of 89Zr-daratumumab in a total 
of 50 mg of daratumumab antibody. 
Accrue patients with multiple myeloma and at least one malignant lesion on 
CT, MR, or FDG PET/CT within 60 days of protocol enrollment. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
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Phase II (total of 18-24 evaluable patients). After pharmacokinetics and radiation 
dosimetry are determined in phase I, additional patients will be enrolled in phase II. 
 
 
 
 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Phase I objectives 
 
• 
Determine the safety, pharmacokinetics, and radiation dosimetry of 89Zr-DFO- 
daratumumab PET/CT imaging of CD38 expression in multiple myeloma. 
 
 
• 
Determine the optimal parameters for imaging with 89Zr-DFO-daratumumab, including 
antibody mass and time post-administration imaging. 
Administer 89Zr-daratumumab at a dose and antibody amount, as 
optimized in phase I. Obtain PET/CT imaging at the time point optimized in 
phase I. 
Correlate 89Zr-daratumumab PET uptake with serum M protein 
concentration, percentage plasma cells on bone marrow biopsy, and 
patient response to daratumumab/lenalidomide therapy. 
Accrue patients with multiple myeloma and at least one malignant lesion on 
CT, MR, or FDG PET/CT within 60 days of protocol enrollment. 
Administered activity (1 to 5 mCi) of radioactivity and total amount of 
administered antibody (3 to 50 mg) will be adjusted in subsequent patients 
in order to maximize image quality. 
Patients in phase I will have up to 4 PET/CT scans, multiple blood draws, 
whole-body counts, and safety monitoring to determine pharmacokinetics, 
radiation dosimetry, and safety of 89Zr-DFO-daratumumab for PET/CT 
imaging. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
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Phase II objective 
 
 
• 
Obtain  data on the correlation between tumor uptake of 89Zr-DFO-daratumumab with 
patient serum M protein concentration, percentage of plasma cells on bone marrow 
biopsy, and patient response to daratumumab/lenalidomidetherapy 
 
Patients who are inevaluable will be replaced until 30 evaluable patients have been 
accrued to both Phase I and Phase II of this study. 
3.0     BACKGROUND AND RATIONALE 
 
Multiple myeloma 
 
Multiple myelomais a plasma cell neoplasm and the secondmost commonhematologic malignancy 
in adults (1). Large independent studies have shown that the genetic and molecular landscape 
underlying multiple myeloma pathogenesis is massively heterogeneous, including several recurrent 
mutations in KRAS, NRAS, TP53, and other genes (2-4). However, no single mutation is seen in 
all or most patients with multiple myeloma. Prospective studies have demonstrated that multiple 
myeloma is consistently preceded by a precursor state—monoclonal gammopathy of undetermined 
significance and smoldering myeloma (5, 6). Smoldering myelomais an earlier, asymptomatic stage 
of myeloma and is defined based on clinical and laboratory characteristics. It carries an increased 
risk of progression to multiple myeloma (7). Only limited information is available regarding the 
genetic profiles of smoldering myeloma and preliminary studies have suggested comparable 
mutational load and copy number profiles of myeloma cells in smoldering myeloma and multiple 
myeloma patients (8, 9). 
 
Previously we reported results from two prospective studies including patients with high-risk 
smoldering myeloma and newly diagnosed multiple myeloma (10). In both cohorts, all patients were 
treated uniformly with 8 cycles of combination therapy including carfilzomib, lenalidomide, and 
dexamethasone (KRd) followed by two years of lenalidomide maintenance (KRd-R). We recently 
expanded our early results (10) by enrolling additional patients with high-risk smoldering myeloma 
and capturing a longer median follow-up of almost four years. Our promising early results of high 
overall response rate and minimal residual disease (MRD) negativity among high-risk smoldering 
myeloma patients treated with modern KRd-R combination therapy (10) prompted us to 
prospectively investigate the baseline genetic landscape and patterns of mutations in our cohort of 
patients. As a reference group, we included 40 patients with newly diagnosed multiple myeloma 
who received the same KRd-R therapy (10). In brief; the overall response rate was 100%. With 
median potential follow-up of 43.3 months, 10 (63%) remain in MRD negativity and the estimated 
4-year progression-free and overall survival is 71% and 100%, respectively (in press). Importantly, 
we report differences in mutational patterns in patients with high-risk smoldering myeloma and 
newly diagnosed multiple myeloma, reflected in a lower frequency of mutations in significant 
myeloma genes (6.6% vs. 45%) and NF-KB pathway genes (6.6% vs. 25%) (in press). Based on 
these data, important differences are evident  in the genetic  landscape of high-risk smoldering 

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myeloma and newly diagnosed multiple myeloma patients, suggestive of a more treatment- 
responsive biology in early disease. 
 
As mentioned above, we have pioneered the development of modern therapy in early disease, 
which has resulted in unprecedented high rates of MRD negativity (10). However, we still see MRD- 
positive disease in many patients (10). Also, many patients convert back from MRD-negative to 
MRD-positive status. A major clinical limitation with current MRD assays is the fact that they are 
based on blind bone marrow biopsies/aspirates (11). It is clinically well known that myeloma can 
grow in a patchy manner in the bone marrow, particularly at stages with lower-level disease burden. 
Therefore, current bone marrow biopsy/aspirate-MRD assays are inherently limited by potential 
sampling error (i.e., false MRD negativity) (11). Furthermore, current standard PET/CT assessment 
using FDG as a tracer is limited for the assessment of myeloma. It is based on glucose uptake and 
cell proliferation. Because myeloma cells typically have low cell proliferation,  FDG is only positive 
in about 70% of patients with established myeloma bone disease. In addition, there is a high rate 
of false positivity due to inflammatory and degenerative causes (12). Clearly, myeloma-specific PET 
tracers are currently lacking. 
 
 
Current monitoring of treated multiple myeloma patients is based on blood tests focusing on 
secreted abnormal immunoglobulins (monoclonal proteins and free light chains). Based on current 
guidelines, therapy is not initiated until the patient develops symptoms or the biomarkers are 
elevated (13). Similar to multiple myeloma patients, in patients with smoldering myeloma the current 
monitoring is based on blood tests focusing on secreted abnormal immunoglobulins. This remains 
the current standard although is it well established that all myeloma cells do not secrete proteins 
(14-16). 
 
 
 
Design of a targeted PET tracer for multiple myeloma 
 
To overcome the inherent dilemmas with blind bone marrow biopsies/aspirates and the limitations 
of blood-based protein markers, we have developed a targeted immuno-PET imaging agent to rule 
out MRD in multiple myeloma and its precursors. Specifically, we have developed a PET        
tracer based upon daratumumab for tracking CD38 expression. CD38 is expressed on the surface 
of virtually every multiple myeloma cell. Daratumumab (Darzalex®, Janssen Biotech) is a clinically 
approved antibody targeting CD38 for the treatment of multiple myeloma. In our laboratory, 
Daratumumab has been prepared for radiolabeling with 89Zr (t1/2  = 78.4 h) through conjugation  
with desferrioxamine (DFO). Western blot, flow cytometry, saturation binding assays, and 
internalization assays have been utilized to characterize CD38 expression and binding of 
daratumumab in an OPM2 myeloma cell line. A murine xenograft model of the OPM2 cell line has 
been generated for further in vivo studies. Longitudinal PET imaging is being performed following 
injection of 5-10 MBq 89Zr-DFO-daratumumab out to 120 h post-injection. Based on our  
successful preclinical results, this project is designed as a first-in-human trial of our CD38- 
targeted immuno-PET imaging agent. Primary objectives are to determine the safety, 
pharmacokinetics, and radiation dosimetry of 89Zr-DFO-daratumumab PET/CT imaging of CD38 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
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expression in multiple myeloma. In addition, we will determine the optimal timing and mass of 
antibody for imaging and acquire preliminary data on the sensitivity and specificity of 89Zr-DFO- 
daratumumab to visualize multiple myeloma lesions in patients. These are the first steps to 
develop a more sensitive and specific imaging test to assess MRD in multiple myeloma. 
89Zirconium (89Zr) was chosen as the radionuclide for immuno-PET due to favorable decay 
characteristics. It has a 78.4 h half life, allowing for multiple-day circulation times for antibodies, 
which are needed to increase target-to-background uptake. Standardized methods for the routine 
production and isolation of high-purity and high-specific-activity 89Zr using a small cyclotron are 
currently used at MSK and other institutions. Optimized cyclotron conditions reveal high average 
yields of 1.52 ± 0.11 mCi/muA*h at a proton beam energy of 15 MeV and current of 15 muA using 
a solid, commercially available 89 Y-foil target (0.1 mm, 100% natural abundance). The effective 
specific activity of 89Zr was found to be in the range of 5.28−13.43 mCi/microg (470−1195 
Ci/mmol) of zirconium. Radiolabeling studies using the trihydroxamate ligand desferrioxamine B 
(DFO) gave 100% radiochemical yields in <15 min at room temperature, and in vitro stability 
measurements confirmed that (89Zr) Zr-DFO is stable with respect to ligand dissociation in human 
serum for more than 7 days. 
 
 
Preclinical data on 89Zr-DFO-daratumumab  PET/CT 
 
Before animal studies were conducted, the expression of CD38 on OPM2 cells was determined 
by flow cytometry.  After conjugation of daratumumab to the DFO chelate, preservation of the 
immunoreactivity (>90%) of the antibody was determined by Lindmo assay in OPM2 cells. 
For the preliminary study, NSG mice were injected with a human multiple myeloma (MM) tumor cell 
line (OPM2) intravenously approximately four weeks before administration of the radiolabeled 
antibody. The intravenous injection of 1×106 OPM2s in NSG miceis a well-validated model to study 
MM bone disease (4). Myeloma cells accumulate in the bone marrow of the femurs and sternum 
primarily. We used OPM2 cells that were stably transduced with firefly luciferase to allow for in vivo 
imaging. 
Due to the NSG background of the mice used in this study, one group of mice received a coinjection 
with an excess of human IgG. It has been shown that the biodistribution of radiolabeled antibodies 
is affected by the lack of endogenous IgG in mouse strains bearing a SCID mutation (Sharma, SK, 
et al. Cancer Res; 78(7) April 2018). This manifests itself in reduced tumor uptake in these mice, 
along with higher nonspecific spleen and bone uptake. This uncharacteristic distribution can be 
blocked by coninjection of an isotype IgG. 
Mice were separated into three groups (Figure 1A) (n=5). Groups 1 and 2 were injected with OPM2 
cells; Group 3 consisted of healthy mice. Each mouse was injected with approximately 200μCi (70 
μg) of 89Zr-DFO-daratumumab via the tail vein. Group 1 was co-injected with cold IgG (400 μg) to 
block nontarget uptake in the spleen. PET/CT imaging was conducted at 24, 96, and 144 hours 
post-injection. Images are coronal maximum intensity projections. Biodistribution was performed at 

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120 hours post-injection for Group 2 and at 144 hours post-injection for Groups 1 and 3 (Figure 
1B). 
Approximately 24 hours prior to PET/CT imaging, mice were imaged by BLI so as to correlate the 
antibody distribution to the actual distribution of OPM2 cells. Free 89Zr which is not chelated to 
DFO in vivo is osteophilic and will become incorporated into bone due to its high affinity for 
phosphate. Because the OPM2 cells reside in the bone marrow in this model, it was necessary to 
extract the bone marrow from  the bone for a more accurate view of the biodistribution. Both 
hindlimbs from each mouse were collected and the bone marrow was extracted by centrifugation. 
With this technique, about 30 milligrams of bone marrow per mouse can be reproducibly obtained. 

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Figure 1: (A) Group 1 was co-injected with cold IgG (400 μg) to block nontarget uptake in the spleen. PET/CT imaging 
was conducted at 24, 96, and 144 hours post-injection. Images are coronal maximum intensity projections. (B) 
Biodistribution was performed at 120 hours post-injection for Group 2 and at 144 hours post-injection for Groups 1 and 
3. 
 
At 24 hours post-injection, Group 1 mice showed a significant amount of 89Zr-dartumamab in the 
blood circulation. Group 2 miceshow earlier uptake in the bones of the hind limbs and pelvic region, 
but also increased accumulation in the liver and spleen as compared to Group 1. At later time 
points, Group 1 mice show increasing accumulation in the hind limbs, pelvic region, and sternum. 
Group 2 mice also show higher accumulation in the hind limb region, but the sternum cannot be 
resolved due to significant uptake in the liver and spleen. The uptake in these bones is consistent 
targeted imaging of multiple myeloma in this cancer model and confirmed by the bioluminescence 
data. Importantly, the healthy control mice show significantly lower uptake in the bone as seen by 
imaging. (Data from the laboratory of Dr. Jason Lewis, unpublished data.) 
 
 
4.1 OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This protocol will perform first-in-human imaging of patients with 89Zr-DFO-daratumumab. 
Patients with known CD38-positive malignancy will be recruited. 
For phase I patients: 
 
• 
Biodistribution of 89Zr-DFO-daratumumab will be obtained from the serial PET/CT 
images. 
• 
Blood pharmacokinetics of 89Zr-DFO-daratumumab will be obtained from serial 
blood draws. 
• 
Radiation dosimetry will be determined from whole-body counts, blood counts, and 
PET/CT images. 
• 
Safety of the imaging dose of 89Zr-DFO-daratumumab will be documented through 
assessment of symptoms and physical examinations. 
• 
The optimal antibody mass of non-radiolabeled (cold) daratumumab to be added to 
radiolabeled 89Zr-DFO-daratumumab will be determined by administration of 
varying amounts of “cold” (i.e., non-radioactive) daratumumab. 
• 
The optimal timing of 89Zr-DFO-daratumumab PET/CT imaging will be determined 
by sequential scanning of patients over 1-8 days post-administration. 
 
 
For phase II patients we will correlate tumor uptake of 89Zr-DFO-daratumumab with: 
 
• 
Serum M protein concentration; 
• 
Percentage of plasma cells on bone marrow biopsy; and 
• 
Patient response to daratumumab/lenalidomidetherapy. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
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Serum M protein concentration and bone marrow biopsy will be required for all phase 
II patients. As all myeloma patients will have clinically standard serum M protein 
concentration and bone marrow biopsy results, this should not impede patient 
recruitment. 
 
 
4.3 
Intervention 
 
89Zr-DFO-daratumumab PET/CT and PET/CT interpretation: 89Zr-DFO-daratumumab 
PET/CT studies will be performed as hybrid PET/CT examinations for attenuation 
correction, lesion localization, and availability of additional findings on CT images. The 
patient will be positioned on a GE PET/CT scanner. The CT component will be obtained 
utilizing a low mA (80 mA) to minimize radiation exposure. 3D imaging will be obtained 
from skull apex to feet (approximately 10 bed positions). 89Zr-DFO-daratumumab PET/CT 
images will be reconstructed using iterative reconstruction and displayed in a multiplanar 
format. All routinely applied corrections will be implemented and the reconstructed images 
parameterized in terms of standard uptake values (SUVs). 
89Zr-DFO-daratumumab PET/CT scans will be interpreted by a nuclear medicine physician 
experienced in the use of routine and novel research PET radiotracers. Physiologic 89Zr- 
DFO-daratumumab uptake will be determined from the images. Physiologic 89Zr-DFO- 
daratumumab may be expected in the blood pool, liver, spleen, and kidneys, similar to 
other radiolabeled antibodies. Radiotracer uptake in areas that are not physiologic will be 
graded both qualitatively and semiquantitatively. For qualitative scoring, we will use a  
scale of one to five where 1 = definitely normal, 2 = probably normal, 3 = equivocal, 4 = 
probably abnormal, and 5 = definitely abnormal. Semiquantitative analysis of tracer uptake 
will be performed for all lesions receiving a score of 4 or 5, as well as for apparently  
normal background blood pool. Three-dimensional regions of interest (ROIs) will be placed 
over grade 4 and 5 lesions and the mediastinal blood pool and tracer uptake will be 
quantified using maximum SUV = decay-corrected maximum ROI activity (μCi/ml) / 
(injected dose (μCi) / body weight (g)). 89Zr-DFO-daratumumab PET/CT images are for 
research purposes only, and will not be used to influence patient care. This approach was 
recently utilized for first-in-human work with 89Zr-DFO-pertuzumab, MSK IRB 17-059. 
For patients in phase I, the following will be performed to determine 89Zr-DFO- 
daratumumab tissue distribution, pharmacokinetics, and radiation dosimetry: 
1. 89Zr-DFO-daratumumab kinetic measurements: Blood and serum samples will be 
weighed and counted in a scintillation well counter calibrated for 89Zr. Immediately before 
or after each PET/CT imaging session, whole-body activities will be measured using a 
scintillation detector probe, with whole-body net count rates converted to the percent of 
the administered activity by normalization to the first whole-body net count rate (i.e., the 
count rate measured shortly after administration of the 89Zr-DFO-daratumumab). 

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2. Timing of 89Zr-DFO-daratumumab PET/CT: Radiolabeled antibodies normally require 
several days to clear blood pool, accumulate in targets, and yield reliable tumor images 
(17). 89Zr-DFO-daratumumab will be administered on day 0. PET/CT images will be 
obtained on post-administration days 1, 2-4, 5-6, and/or 7-8 following administration of 
89Zr-DFO-daratumumab to determine the optimal time point for imaging. (At least three 
PET/CT images at different time points are required to calculate dosimetry—i.e., the 
radiation dose received throughout the body—for the novel radiotracer. We will obtain 
three or four sets of images at the time points described above.) 
 
 
For patients in phase II, a single PET/CT scan will be performed using the dose of 89Zr- 
DFO-daratumumab, antibody mass of daratumumab, and timing determined from phase I 
patients. No blood samples for dosimetry or whole-body counts will be performed. The 
research PET/CT will be performed to correlate 89Zr-DFO-daratumumab PET uptake with 
serum M protein concentration (measured prior to 89Zr-DFO-daratumumab PET/CT), 
percentage plasma cells on bone marrow biopsy (measured prior to 89Zr-DFO- 
daratumumab PET/CT), and patient response to daratumumab/lenalidomide therapy. 
The radiologist evaluated the 89Zr-DFO-daratumumab PET/CT will be blinded to patient 
serum M protein concentration and percentage of plasma cells on bone marrow biopsy. 
As patient response to daratumumab/lenalidomide therapy will be subsequently 
determined, that information will not be avialable at the time of 89Zr-DFO-daratumumab 
PET/CT.  Combined daratumumab/lenalidomide therapy is a standard-of-care 
combination for treatment of myeloma, with response rates of up to 90%.  Single agent 
daratumumab therapy has lower response rates, and thus the combination therapy is the 
current appropriate standard of care.  Please see section 14.0 for statistical details. 
 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
89Zr-DFO-daratumumab: 89Zr-DFO-daratumumab is an investigational new drug (not FDA 
approved) produced on demand by the Cyclotron-Radiochemistry Core at MSK (under the 
direction of Dr. Jason Lewis), under GMP conditions adequate for clinical trials. 89Zr-DFO- 
daratumumab is composed of the native CD38 targeting drug daratumumab labeled with the 
positron-emitting radionuclide zirconium 89 (89Zr) through the linker DFO. Daratumumab is an 
FDA-approved monoclonal antibody. 89Zr is a metallo-radionuclide with a half-life of 78 hours,   
long enough to allow favorable biodistribution of radiolabeled antibodies. The final product will be 
radiolabeled and tested for sterility, endotoxin, identity, purity, and potency as described in the 
chemistry, manufacturing, and controls section of the IND application. 89Zr-DFO-daratumumab will 
be administered intravenously over a 30-60 minute period. 
 
 
No patient will receive 89Zr-DFO-daratumumab until the FDA approves the IND. 

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Administered activity of 89Zr-DFO-daratumumab: For phase 1 patients, the administered activity of 
 
89Zr-DFO-daratumumab will be between 1 and 5 mCi in 3 mg radiolabeled (“hot”) antibody. 
Successful imaging of other 89Zr-labeled antibodies will be performed with 1-5 mCi (17, 18). 
Changes in administered activity alter counts of radioactivity detected by the PET/CT camera and 
may affect image quality. The administered activity of 89Zr-DFO-daratumumab will start at 2 mCi, 
as this is an administered activity which has resulted in successful imaging in past radio-antibody 
imaging trials, including the principle investigator’s trial of 89Zr-DFO-pertuzumab (IRB 17-059). If 
2 mCi does not provide sufficient radioactive counts for successful imaging, then we will increase 
the administered dose to 5 mCi.   If 2 mCi provides more radioactive counts than is needed for 
successful imaging, then we will attempt imaging with 1 mCi, to see if successful imaging can be 
obtained with a lower exposure to radiation dose.  This approach was recently utilized for first-in- 
human work with 89Zr-DFO-pertuzumab, MSK IRB 17-059. 
For phase 2 patients, the optimal dose of 89Zr-DFO-daratumumab determined in phase I will be 
utilized. 
Antibody mass of 89Zr-DFO-daratumumab: Radiolabeled PET antibodies have been shown to 
demonstrate superior imaging when administered together with cold antibody to block non- 
specific binding (17). For phase I patients, to determine the optimal antibody mass for imaging, 0, 
17, or 47 mg of unlabelled (“cold”) antibody will be added to the radiolabeled antibody to produce 
total administered antibody masses of 3, 20, and 50 mg. Antibody masses between 20 and 50 mg 
per dose have provided the best image contrast in several prior studies with radiolabeled 
antibodies at MSK (18-20). Changes in total amount of administered antibody alter distribution of 
specific and non-specific binding of antibody and may affect image quality. The first three patients 
will be imaged with a total antibody mass of 50 mg based on MSK’s prior experience with Zr- 
labeled antibodies, as higher antibody mass usually results in better imaging due to cold antibody 
occupying non-specific in vivo binding sites. Antibody mass will be reduced to 20 mg in the next 
three patients to evaluate the effect on image quality. The choice of total antibody mass for each 
group of three  patients will depend on the quality of images already obtained from prior patients. 
Thus, in this trial the first three patients will receive an antibody mass of 50 mg, and the fourth 
through sixth patients will receive an antibody mass of 20 mg. If an improvement in image quality 
is observed at 20 mg, or if image quality at 50 mg and 20 mg is comparable, then any subsequent 
patients will receive an antibody mass of 3 mg. If image quality worsens at 20 mg, then the 
antibody mass will be increased back to 50 mg for the remaining patients. The means of 
determining whether one antibody mass is superior to another is described in section 14.0, 
Biostatistics. 
In summary, the antibody mass received by patients will be: 
 
• 
Patients 1, 2 and 3: 50 mg 
• 
Patients 4, 5, 6: 20 mg 
• 
Any subsequent patients: 50 mg, 20 mg, or 3 mg, depending on imaging results of the 
prior 6 patients. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 15 of 33 
 
 
 
 
For any further patients, antibody mass will be determined based on imaging results from prior 
patients. This approach was recently utilized for first-in-human work with 89Zr-DFO-pertuzumab, 
MSK IRB 17-059. 
For phase 2 patients, the optimal daratumumab antibody mass determined in phase I will be 
utilized. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Age 21 years or greater 
• 
Histologically/Immunohistochemistry confirmed CD38-positive multiple myeloma 
• 
At least one tumor lesion on CT, MRI, or FDG PET/CT within 60 days of protocol 
enrollment 
• 
ECOG performance status 0 to 2 
• 
For Phase II patients only: plan for initiation of standard-of-care 
daratumumab/lenalidomide  therapy. 
 
 
6.3 
Subject Exclusion Criteria 
• 
Life expectancy < 3 months 
• 
Pregnancy or lactation 
• 
Patients who cannot undergo PET/CT scanning because of weight limits. PET/CT 
scanners may not be able to function with patients over 450 pounds. 
• 
History of anaphylactic reaction to humanized or human antibodies or a Grade 3 or 4 
administration reaction during a daratumumab administration. 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients who meet the above inclusion and exclusion criteria will be invited to participate in the 
study by their primary oncologist. We will invite men and women of all races/ethnicities on an 
equal basis. 
 
Consenting professionals will meet with the patients and obtain informed consent in either the 
oncologist’s clinic or the Molecular Imaging and Therapy Service clinic. As patients in Phase I will 
require multiple visits, a small honorarium ($400) will be provided to patients that complete the 
trial, in order to compensate them for their time and expenses. No payments will be offered to 
patients in phase II. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 16 of 33 
 
 
 
 
If the investigator is a member of the treatment team, s/he will screen their patients’ medical 
records for suitable research study participants and discuss the study and their potential for 
enrolling in the research study. Potential subjects contacted by their treating physician will be 
referred to the investigator/ research staff of the study. 
 
The principal investigator may also screen the medical records of patients with whom they do not 
have a treatment relationship for the limited purpose of identifying patients who would be eligible 
to enroll in the study and to record appropriate contact information in order to approach 
these patients regarding the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/ research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/ research staff may also review portions of their medical 
records at MSKCC in order to further assess eligibility. They will use the information provided by 
the patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment. If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation 
and medical records review, except for any information that must be maintained for screening log 
purposes. 
 
In most cases, the initial contact with the prospective subject will be conducted by either the 
treatment team, investigator or the research staff working in consultation with the treatment team. 
The recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal protected health information (PHI) will be maintained as part of a 
screening log. For these reasons, we seek a (partial) limited waiver of authorization for the 
purposes of (1) reviewing medical records to identify potential research subjects and obtain 
information relevant to the enrollment process; (2) conversing with patients regarding possible 
enrollment; (3) handling of PHI contained within those records and provided by the potential 
subjects; and (4) maintaining information in a screening log of patients approached (if applicable). 
 
We anticipate an accrual rate of 1-2 patients per month. We may accrue multiple patients at the 
same time however, in phase I, tracer administration for the next patient will wait until the prior 
patient has completed all anticipated scans. 
 
 
 
8.1 
PRETREATMENT EVALUATION 
 
Prior to enrollment in the protocol, the following will be available: 
 
• 
History and physical exam 
• 
Histology demonstrating CD38-positive multiple myeloma. 
• 
Clinically standard imaging scans (CT, MR, FDG PET/CT) demonstrating at least one 
focus of suspected malignancy within 60 days of protocol enrollment 
• 
Negative blood pregnancy test for women of childbearing potential 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 17 of 33 
 
 
 
 
 
 
 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
For women of childbearing age, pregnancy will be excluded before 89Zr-DFO-daratumumab 
administration. This will be accomplished by the use of a serum pregnancy test within two weeks 
of 89Zr-DFO-daratumumab administration or a urine pregnancy test on the day of 89Zr-DFO- 
daratumumab administration. 
89Zr-DFO-daratumumab administration: 89Zr-DFO-daratumumab will be administered 
intravenously on day 0. 
 
 
Prior to 89Zr-DFO-daratumumab administration, the patient will be premedicated with 
Acetaminophen 650 mg orally, Diphenhydramine 25mg intravenously, and Dexamethasone 20 
mg intravenously. 
Physical exam and vital signs will be obtained prior to the 89Zr-DFO-daratumumab administration, 
as well as 30-60 minutes post-administration to document the absence of any acute toxicity from 
the low imaging dose of 89Zr-DFO-daratumumab. 
 
 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
For Phase I patients: Patients in phase I will have up to 4 PET/CT scans, multiple blood draws, 
whole-body counts, and safety monitoring to determine pharmacokinetics, radiation dosimetry, 
and safety of 89Zr-DFO-daratumumab for PET/CT imaging. 
89Zr-DFO-daratumumab PET/CT: Patients will undergo up to 4 serial 89Zr-DFO-daratumumab 
PET/CT scans. PET/CT images will be obtained on days 1, 2-4, 5-6, and/or 7-8 following 
administration of 89Zr-DFO-daratumumab. All CT scans will be acquired as low-dose CT scans to 
minimize radiation exposure. PET/CT images will be obtained from skull apex to feet 
(approximately 10 bed positions) and reconstructed using our standard iterative reconstruction 
algorithm. 
Radiation dosimetry of 89Zr-DFO-daratumumab: The measured time-dependent blood, whole- 
body, and PET-derived organ activities will be fit to exponential functions and the corresponding 
89Zr residence times calculated by integration of the respective exponential functions, accounting 
for the physical decay of the 89Zr. The resulting residence times will then be entered into the 
OLINDA radiation dosimetry program and mean organ-absorbed doses (in rad and rad/mCi) and 
the effective dose (in rem and rem/mCi) calculated. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 18 of 33 
 
 
 
 
W hole-body count measurements: Patients will undergo whole-body count rate measurements 
using a sodium iodide (NaI) probe placed approximately 3 meters from the patient. Pre- and post- 
first-void measurements will be performed within 6 hours of administration of 89Zr-DFO- 
daratumumab, as well as each time the patient returns for PET/CT scanning. 
Blood samples for determination of pharmacokinetics of 89Zr-DFO-daratumumab: Approximately 
3-5 ml of blood will be drawn at each of the following time points. Drawn blood will be collected in 
lavender-top tubes (to prevent coagulation). 
• 
Day 0: Pre-dose 
• 
Day 0: Within 30 minutes of completion of dose administration 
• 
Day 0: 30-60 minutes of completion of dose administration 
• 
Day 0: 60-120 minutes of completion of dose administration 
• 
On each return visit for PET/CT imaging 
 
After all samples have been collected, weighed blood and serum aliquots will be counted in a 
scintillation well counter calibrated for 89Zr and counts will be corrected for time of decay. 
For Phase II patients: 89Zr-DFO-daratumumab will be administered at a dose and antibody 
amount as optimized in phase 1. PET/CT imaging will be obtained at the time point optimized in 
phase I. 89Zr-DFO-daratumumab PET ue will be correlated with serum M protein, percent plasma 
cells on bone marrow biopsy, and patient response to daratumumab therapy as described in 
section 4.2. 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
89Zr-DFO-daratumumab: 89Zr-DFO-daratumumab is a diagnostic (not therapeutic) agent, and the 
doses of 89Zr-DFO-daratumumab used for PET/CT are very low compared to approved 
therapeutic daratumumab doses, and are expected to have a very low incidence of adverse 
events. Prior results from patients who received 89Zr-DFO-trastuzumab as part of protocol #14- 
156 demonstrated no grade 3 or 4 toxicities, with one patient reporting chills the night of antibody 
administration, which is a recognized side effect of antibody administration. Nevertheless, 
patients will be monitored closely for evidence of adverse events, including vital signs before and 
after tracer administration. Phase I patients will be scheduled for a brief visit to the nuclear 
medicine clinic the day after tracer administration to confirm that there have been no side effects 
requiring treatment. If a severe adverse effect (Common Terminology Criteria for Adverse Events 
grade 3 or 4) attributable to 89Zr-DFO-daratumumab occurs in any patient, then further use of 89Zr- 
DFO-daratumumab will be suspended and the protocol will be reviewed with the MSK Data Safety 
Monitoring  Committee. 
Less Likely: Infusion or allergic reactions, which may include fevers, chills, tiredness, rashes, 
hives, tachycardia, or shortness of breath. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 19 of 33 
 
 
 
 
Radiation risk: The effective dose from 2 mCi of 89Zr-DFO-daratumumab is estimated to be 
between 1.74 and 1.90 centiGray (see Appendix 1). A low milliampere CT scan, performed as  
part of the hybrid 89Zr-DFO-daratumumab PET/CT, contributes an additional effective dose of 0.9 
rem. The effective dose from an experimental 89Zr-DFO-daratumumab PET and up to 4 CT 
examinations is in the range of 7.1 to 7.4 centiGray, which is comparable to the dose from other 
89Zr-labeled radiolabeled antibodies received by oncology patients in MSK clinical trials. A table of 
projected radiation doses to normal tissues based on extrapolation  from animal biodistribution, 
including contribution from CT scans, is shown in Appendix 1.  No specific patient instructions are 
required for the low level of radioactivity encountered from the doses of 89Zr administered in this 
protocol (21). 
Pregnancy risk: Even low diagnostic levels of radiation, such as those that will be received in this 
protocol from the investigational 89Zr-DFO-daratumumab PET/CT studies, have been associated 
with a risk of inducing childhood cancer. A negative pregnancy test will be required before a 
patient is accrued to this protocol. Patients on this protocol will be advised not to become 
pregnant for at least one month following administration of 89Zr-DFO-daratumumab. 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
There is no therapy arm or measurement of response to the imaging agent. This is a diagnostic 
imaging study; therefore, no criteria for therapeutic response are included. The doses of 89Zr- 
DFO-daratumumab used for imaging are very low compared to therapeutic daratumumab doses, 
and we do not expect a significant therapeutic effect from the diagnostic (not therapeutic) dose of 
this agent. This protocol will be a first-in-human CD38-targeted imaging study with 89Zr-DFO- 
daratumumab PET/CT. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 20 of 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow chart for phase 1 patients 
 
Screening 
On study 
Within 60 
days 
Day 
0 
Day 
1 
Day 
2-4 
Day 
5-6 
Day 
7-8 
Informed consent 
X 
Medical history 
X 
Physical exam 
X 
Prior radiographic studies (CT, 
MR, FDG PET/CT) reviewed 
X 
Histology/Immunohistochemistry 
proof of CD38-positive myeloma 
X 
Vital signs 
X 
89Zr-DFO-daratumumab 
administration 
X 
Adverse events monitored 
X 
X 
X 
X 
X 
Whole-body counts 
X 
X 
X 
X 
X 
Blood samples for 
pharmacokinetics 
X 
X 
X 
X 
X 
PET/CT scan 
X 
X 
X 
X 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 21 of 33 
 
 
 
 
 
 
 
 
 
 
 
Flow chart for phase 2 patients 
 
Screening 
On study 
Within 60 days 
Day 
0 
Day 
TBD1 
Up to 2 years 
Informed consent 
X 
Medical history 
X 
Physical exam 
X 
Prior radiographic studies (CT, MR, 
FDG PET/CT) reviewed 
X 
Histology/Immunohistochemistryproof 
of CD38-positive myeloma 
X 
Pregnancy test for women with active 
menstrual cycles 
x 
Vital signs 
X 
89Zr-DFO-daratumumab injection 
X 
Adverse events monitored 
X 
X 
PET/CT scan 
X 
Standard-of-care daratumumab therapy 
and monitoring of disease response 
X 
 
1   The day of the PET/CT scan will be determined bythe results from the phase I patients. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 22 of 33 
 
 
 
 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
• 
Patients may withdraw from the protocol voluntarily at any time. 
• 
Development of unacceptable toxicity. 
• 
The patient is found to be ineligible for the protocol as designated in the section on Criteria 
for Patient/Subject Eligibility (i.e., a change in diagnosis). 
 
 
14.0 
BIOSTATISTICS 
 
This is a pilot first-in-human trial of 89Zr-DFO-daratumumab in patients with multiple myeloma. 
 
In phase I, we will determine the tissue distribution, pharmacokinetics, radiation dosimetry, and 
safety of 89Zr-DFO-daratumumab for PET/CT imaging. 
The organ/tissue uptake and dosimetry following IV injection of 89Zr-DFO-daratumumab will be 
determined. Standardized uptake value (SUV) in various organs will be estimated from VOI 
analysis of clinical images and converted to activity-time curves. The areas under the activity-time 
curves will be derived by integration, converted to residence times, and used as input to the 
OLINDA/EXM dosimetry program to obtain absorbed dose estimates for normal tissues. 
Additionally,  SUVmean, max and peak for lesions will be summarized with descriptive statistics. 
 
Pharmacokinetic analysis will be performed using a compartmental analysis (SAAM or GraphPad 
V5); standard parameters such as AUC, clearance, volume of distribution of central compartment, 
and Co will be reported. Descriptive statistics will be tabulated. 
There are three scan parameteers that will be optimized in phase I:   administered radioactivity, 
antibody mass, and time of scan.  The primarily method of determining these variables will be 
quantitative, based of the proportion of lesions identified of the research 89Zr-DFO-daratumumab 
scans. The number of lesions in the patient will be determined from the lesions seen on CT, MR, 
and FDG PET/CT studies perfromed within the last 60 days.  Then the number of 89Zr-DFO- 
daratumumab avid lesions will be counted on the 89Zr-DFO-daratumumab PET/CT.  The greatest 
proportion of lesion lesions detected on 89Zr-DFO-daratumumab PET will be the primary method 
of determining optimal scan parameters.  Since it is possible that the same proportion of lesions 
may be identified using different scan parameters and that contrast may vary between the  
different imaging days, a consensus visual assessment of a group of experienced Molecular 
Imaging and Therapy investigator who will grade the studies separately (GU, CR, and JO), will be 
used to make the final decision.  This qualitative assesement will be a secondary method, after 
using the primary quantitative comparison of number of lesions visualized.  It is possible that  
these three scan parameters will interact to effect optimal scan parameters.  By sequential 
modification of administered activity and antibody mass and obtaining imaging at multiple time 
points for each combination of activity and antibody mass, we will obtain adequate comparisons 
with which to make quantitative and qualitative comparisons.  This approach has been 
successfully used in prior radio-antibody imaging trials, including the principle investigator’s trial of 
89Zr-DFO-pertuzumab (IRB 17-059). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 23 of 33 
 
 
 
 
89Zr-DFO-daratumumab is a diagnostic (not therapeutic) agent, and the doses of 89Zr-DFO- 
daratumumab used for PET/CT are very low compared to approved therapeutic daratumumab 
doses. We expected to have a very low incidence of adverse events. Prior results from patients 
who received 89Zr-DFO-trastuzumab as part of protocol #14-156 demonstrated no grade 3 or 4 
toxicities, with one patient reporting chills the night of antibody administration, which is a 
recognized side effect of antibody administration. Nevertheless, phase I patients will be monitored 
closely for evidence of adverse events, including vital signs before and after tracer administration 
and a brief visit to the Nuclear Medicine Clinic the day after tracer administration to confirm that 
there are no side effects requiring treatment. This diagnostic agent is not expected to result in 
significant adverse effects, but the number and propotion of patients with any adverse effect from 
tracer administration will be deermined. 
In the phase II portion, we will correlate tumor uptake of 89Zr-DFO-daratumumab with serum M 
protein concentration, percentage plasma cells on bone marrow biopsy and patient response to 
daratumumab/lenalidomidetherapy. The total planned sample size for both phases is 30 
evaluable patients; hence Phase II component will enroll 18-24 evaluable patients, depending on 
how many patients were needed for the Phase I.  The total sample size was chosen given 
budgetary concerns. 
Phase II patients will be monitored for adverse effects, including vital signs before and after 
tracer administration.  This disagnostic agent is not expected to result in significant adverse 
effects, but the number and propotion of patients with any adverse effect from tracer 
administration will be deermined. 
Serum M protein concentration: Serum M protein concentration (including heavy-chains and 
serum free light-chains) is a standard of care laboratory measurement and reported as a 
continuous metric. High serum M protein concentration represents high tumor burden in the 
blood. We will explore the correlation between 89Zr-DFO-daratumumab PET SUVmax and serum 
M protein concentration using scatterplots and Spearman’s rank correlation. 
Percentage plasma cells on bone marrow biopsy: Percentage plasma cells on bone marrow 
biopsy is a standard of care pathology measurement and reported as a continuous metric. High 
percentage plasma cells on bone marrow biopsy represents a high tumor burden. We will explore 
the correlation between 89Zr-DFO-daratumumab PET SUVmax and percentage plasma cells on 
bone marrow biopsy by scatterplots and Spearman’s rank correlation. 
Patient response to daratumumab/lenalidomidetherapy: We will evaluate response by one 
dichotomous and one continuous method. Dichotomous evaluation will categorize patients as 
complete/partial response vs. stable disease/progressive disease, as defined by International 
Myeloma Working Group consensus criteria for response (IMWG). Continuous evaluation will 
assess best anti-tumor response as a percentage of change from baseline by IMWG, and will be 
graphed as a waterfall plot. We will explore the correlation between  89Zr-DFO-daratumumab PET 
SUVmax and anti-tumor efficacy of daratumumab using a Wilcoxon test and an ROC curve in the 
case of IMWG response and scatterplots with Spearman rank correlation in the case of percent 
change from baseline. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 24 of 33 
 
 
 
 
 
 
 
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 
 
N/A 
 
16.1 
DATA MANAGEMENT ISSUES 
 
16.2 
Quality Assurance 
 
Accrual rates and 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. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. 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” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSK were 
established and are monitored by the Clinical Research Administration. The MSK Data and Safety 
Monitoring Plans can be found on the MSK Intranet 
at:https://one.mskcc.org/sites/pub/clinresearch/Pages/protocol-review-committees/data-and-   safety-
monitoring-committee.aspx 
 
. 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees: Data and Safety Monitoring Committee 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 25 of 33 
 
 
 
 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 26 of 33 
 
 
 
 
 
 
 
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 IRB guidelines. 
Confidentiality: All patient records will be kept as confidential as is possible under the law. No 
individual identifiers will be used in any reports or publication resulting from this study, but the data 
will be used in the interest of the ongoing research. 
 
Benefits: There is no guarantee of any benefits. 
 
Incentives: $400 will be provided to patients/subjects for participation in Phase I of the study. No 
incentive will be provided to patients in phase II. 
Costs: The research 89Zr-DFO-daratumumab radiotracer and 89Zr-DFO-daratumumab PET/CT 
scan(s) will be performed without charge. Patients in phase II requiring a bone marrow biopsy will be 
performed without charge. The patient will be responsible for the costs of standard medical care. 
Alternatives: The patient can choose not to be on this study and follow the treatment outlined by his 
or her treating physician. 
Treatment and Compensation: If the patient is injured as a result of participating in this study, 
emergency care, hospitalization, and outpatient care will be made available by the hospital and 
billed to the patient and his insurance company as part of his medical expenses. If the patient 
desires additional information about the consent process, research patient’s rights, or research- 
related injury, he/she may call the Patient Representative’s office at (212) 639-8254 
 
 
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) 
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 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 27 of 33 
 
 
 
 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
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 or subject 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 treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required 
for 30-days after the participant’s last investigational treatment or intervention. Any events 
that occur after the 30-day period and that are at least possibly related to protocol treatment 
must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org. All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 28 of 33 
 
 
 
 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject 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 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
17.2.1 
 
Any additional SAE reporting information required by the sponsor or drug supplier should be 
included in this section. 
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. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 29 of 33 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. 
2. 
Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple 
myeloma: implications for targeted therapy. Cancer Cell. 2014;25(1):91-101. 
3. 
Bolli N, Avet-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and 
mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997. 
4. 
Lawson MA, Paton-Hough JM, Evans HR, et al. NOD/SCID-GAMMA  mice are an ideal strain 
to assess the efficacy of therapeutic agents used in the treatment of myeloma bone disease. PloS 
one.  2015;10(3):e0119546. 
5. 
Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined 
significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 
2009;113(22):5412-7. 
6. 
Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy 
precedes multiple myeloma in most patients. Blood. 2009;113(22):5418-22. 
7. 
Ghobrial IM, Landgren O. How I treat smoldering multiple myeloma. Blood. 
2014;124(23):3380-8. 
8. 
Walker BA, Boyle EM, Wardell CP, et al. Mutational Spectrum, Copy Number Changes, and 
Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol. 
2015;33(33):3911-20. 
9. 
Zhao S, Choi M, Heuck C, et al. Serial exome analysis of disease progression in 
premalignant gammopathies. Leukemia. 2014;28(7):1548-52. 
10. 
Korde N, Roschewski M, Zingone A, et al. Treatment With Carfilzomib-Lenalidomide- 
Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed 
Multiple  Myeloma. JAMA  Oncol. 2015;1(6):746-54. 
11. 
Mailankody S, Korde N, Lesokhin AM, et al. Minimal residual disease in multiple myeloma: 
bringing the bench to the bedside. Nat Rev Clin Oncol. 2015;12(5):286-95. 
12. 
Hillengass J, Landgren O. Challenges and opportunities of novel imaging techniques in 
monoclonal plasma cell disorders: imaging "early myeloma". Leuk Lymphoma. 2013;54(7):1355-63. 
13. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-48. 
14. 
Chawla SS, Kumar SK, Dispenzieri A, et al. Clinical Course and Prognosis of Non-Secretory 
Multiple Myeloma. Eur J Haematol. 2015. 
15. 
Dimopoulos MA, Kastritis E, Terpos E. Non-secretory myeloma: one, two, or more entities? 
Oncology (Williston Park). 2013;27(9):930-2. 
16. 
Lopes da Silva R, Monteiro A, Veiga J. Non-secretory multiple myeloma relapsing as 
extramedullary liver plasmacytomas. J Gastrointestin Liver Dis. 2011;20(1):81-3. 
17. 
Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab and 
PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clinical 
pharmacology and therapeutics. 2010;87(5):586-92. 
18. 
Ulaner GA, Hyman DM, Ross DS, et al. Detection of HER2-Positive Metastases in Patients 
with HER2-Negative Primary Breast Cancer Using 89Zr-Trastuzumab PET/CT. J Nucl Med. 
2016;57(10):1523-8. 
19. 
Divgi CR, Uzzo RG, Gatsonis C, et al. Positron emission tomography/computed tomography 
identification of clear cell renal cell carcinoma: results from the REDECT trial. J Clin Oncol. 
2013;31(2):187-94. 
20. 
O'Donoghue JA, Smith-Jones PM, Humm JL, et al. 124I-huA33 antibody uptake is driven by 
A33 antigen concentration in tissues from colorectal cancer patients imaged by immuno-PET. J Nucl 
Med.  2011;52(12):1878-85. 
21. 
Williamson MJ, Dauer LT. Activity thresholds for patient instruction and release for positron 
emission tomography radionuclides. Health  Phys. 2014;106(3):341-52. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
Page 30 of 33 
 
 
 
 
 
 
 
 
 
20.0 
APPENDICES 
 
 
 
Appendix 1:  89Zr-DFO-daratumumab Radiation Dosimetry 
 
A primary objective of this study is to quantify the biodistribution and pharmacokinetics of 89Zr-DFO- 
daratumumab in human patients and thereby generate absorbed radiation dose estimates. 
Absorbed dose projections for humans, based on animal biodistribution data from the lab of Dr 
Jason Lewis, are provided below. 

Page 31 of 33 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
89Zr-DFO-daratumumab: Absorbed Radiation Dose estimates for 70-kg Standard Man 
Includes X-ray CT (for anatomic fusion and attenuation correction) 
Fields in blue must have values entered 
# of Injections/CT scans 
 
 
Activity of 89Zr-DFO-daratumumab 
2 
mCi 
1 
low dose CT scan (80mA) 
0.9 
cGy 
4 
ultra-low dose CT scan (10mA) 
0.11 
cGy 
0 
Absorbed Dose 
89Zr-DFO-daratumumab 1 
total 89Zr-DFO-daratumumab + CT 
Target Organ 
Adrenals 
cGy/mCi 
1.78 
cGy per inj 
3.6 
cGy 
7.2 
Brain 
1.11 
2.2 
5.8 
Breasts 
0.91 
1.8 
5.4 
Gallbladder Wall 
1.45 
2.9 
6.5 
LLI Wall 
1.39 
2.8 
6.4 
Small Intestine 
1.46 
2.9 
6.5 
Stomach Wall 
1.35 
2.7 
6.3 
ULI Wall 
1.38 
2.8 
6.4 
Heart Wall 
3.27 
6.5 
10.1 
Kidneys 
2.21 
4.4 
8.0 
Liver 
2.16 
4.3 
7.9 
Lungs 
2.86 
5.7 
9.3 
Muscle 
1.30 
2.6 
6.2 
Ovaries 
1.28 
2.6 
6.2 
Pancreas 
1.56 
3.1 
6.7 
Red Marrow 
3.28 
6.6 
10.2 
Osteogenic Cells 
6.59 
13.2 
16.8 
Skin 
0.82 
1.6 
5.2 
Spleen 
2.16 
4.3 
7.9 
Testes 
0.87 
1.7 
5.3 
Thymus 
1.39 
2.8 
6.4 
Thyroid 
1.15 
2.3 
5.9 
Urinary Bladder Wall 2 
1.08 
2.2 
5.8 
Uterus 
1.18 
2.4 
6.0 
Total Body 
1.52 
3.0 
6.6 
Effective Dose (rem/mCi; rem) 
1.74 
3.5 
7.1 
 
1 Based on biodistribution of Zr-89-DFO-daratumumab in nude mice 
(data from Nicholas Sobol, Lewis Lab) 
OLINDA/EXM-based absorbed dose estimates by J O'Donoghue 
2 (assumed 3-hr voiding interval) 
 
The following table indicates human dose projections in cases where a large multiple myeloma load 
is present in bone and bone marrow. This is based on data derived from a mouse model of multiple 
myeloma in comparison with normal healthy mice. 

Page 32 of 33 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
89Zr-DFO-daratumumab: Absorbed Radiation Dose estimates for 70-kg Standard Man 
Includes X-ray CT (for anatomic fusion and attenuation correction) 
Fields in blue must have values entered 
# of Injections/CT scans 
 
 
Activity of 89Zr-DFO-daratumumab 
2 
mCi 
1 
low dose CT scan (80mA) 
0.9 
cGy 
4 
ultra-low dose CT scan (10mA) 
0.11 
cGy 
0 
Absorbed Dose 
89Zr-DFO-daratumumab 1 
total 89Zr-DFO-daratumumab + CT 
Target Organ 
Adrenals 
cGy/mCi 
1.90 
cGy per inj 
3.8 
cGy 
7.4 
Brain 
1.14 
2.3 
5.9 
Breasts 
0.79 
1.6 
5.2 
Gallbladder Wall 
1.30 
2.6 
6.2 
LLI Wall 
1.34 
2.7 
6.3 
Small Intestine 
1.31 
2.6 
6.2 
Stomach Wall 
1.20 
2.4 
6.0 
ULI Wall 
1.24 
2.5 
6.1 
Heart Wall 
3.31 
6.6 
10.2 
Kidneys 
2.29 
4.6 
8.2 
Liver 
2.20 
4.4 
8.0 
Lungs 
2.94 
5.9 
9.5 
Muscle 
1.34 
2.7 
6.3 
Ovaries 
1.19 
2.4 
6.0 
Pancreas 
1.47 
2.9 
6.5 
Red Marrow 
4.85 
9.7 
13.3 
Osteogenic Cells 
9.40 
18.8 
22.4 
Skin 
0.80 
1.6 
5.2 
Spleen 
2.16 
4.3 
7.9 
Testes 
0.69 
1.4 
5.0 
Thymus 
1.28 
2.6 
6.2 
Thyroid 
1.09 
2.2 
5.8 
Urinary Bladder Wall 2 
0.81 
1.6 
5.2 
Uterus 
0.98 
2.0 
5.6 
Total Body 
1.65 
3.3 
6.9 
Effective Dose (rem/mCi; rem) 
1.90 
3.8 
7.4 
 
1 Based on biodistribution of Zr-89-DFO-daratumumab in normal and MM mice 
(data from Nicholas Sobol, Lewis Lab) 
OLINDA/EXM-based absorbed dose estimates by J O'Donoghue 
2 (assumed 3-hr voiding interval) 

Page 33 of 33 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-267 A(3) 
Approval date: 20-Jan-2020 
 
 
 
 
Absorbed Dose Projections for Phase 2 
 
In phase 2, a single PET/CT scan will be acquired following administration of 1-5 mCi of 89Zr-DFO- 
daratumumab at the mass dose and time deemed optimal from phase 1 Absorbed dose projections 
for low and high disease burdens for the minimum and maximum activities envisaged are provided 
below: 
 
89Zr-DFO-daratumumab Phase 2: 
Absorbed Radiation Dose estimates for 70-kg Standard Man including X-ray CT 
 
min 
max 
Activity of 89Zr-DFO-daratumumab (mCi) 
1 
5 
low dose CT scan (80mA) 
 0.9 
cGy 
ultra-low dose CT scan (10mA) 
0.11 
cGy 
 
 
 
 
Target Organ 
Adrenals 
Brain 
Breasts 
Gallbladder Wall 
LLI Wall 
Small Intestine 
Stomach Wall 
ULI Wall  
Heart Wall 
Kidneys 
Liver 
Lungs 
Muscle 
Ovaries 
Pancreas 
Red Marrow 
Osteogenic Cells 
Skin  
Spleen 
Testes 
Thymus 
Thyroid 
Urinary Bladder Wall 2 
Uterus 
Total Body 
Effective Dose (rem/mCi; rem) 
# of Injections/CT scans 
1 
1 
0 
 
1 Based on biodistribution of Zr-89-DFO-daratumumab in nude mice (Nicholas Sobol, Lewis Lab) 
OLINDA/EXM-based absorbed dose estimates by J O'Donoghue 
2 (assumed 3-hr voiding interval) 
Absorbed dose for 89Zr-DFO-daratumumab + CT (cGy) 
Low disease burden 
High disease burden 
min 
max 
min 
max 
2.7 
9.8 
2.8 
10.4 
2.0 
6.5 
2.0 
6.6 
1.8 
5.5 
1.7 
4.8 
2.3 
8.1 
2.2 
7.4 
2.3 
7.8 
2.2 
7.6 
2.4 
8.2 
2.2 
7.4 
2.3 
7.7 
2.1 
6.9 
2.3 
7.8 
2.1 
7.1 
4.2 
17.3 
4.2 
17.5 
3.1 
11.9 
3.2 
12.3 
3.1 
11.7 
3.1 
11.9 
3.8 
15.2 
3.8 
15.6 
2.2 
7.4 
2.2 
7.6 
2.2 
7.3 
2.1 
6.9 
2.5 
8.7 
2.4 
8.2 
4.2 
17.3 
5.7 
25.1 
7.5 
33.8 
10.3 
47.9 
1.7 
5.0 
1.7 
4.9 
3.1 
11.7 
3.1 
11.7 
1.8 
5.2 
1.6 
4.4 
2.3 
7.8 
2.2 
7.3 
2.1 
6.7 
2.0 
6.4 
2.0 
6.3 
1.7 
4.9 
2.1 
6.8 
1.9 
5.8 
2.4 
8.5 
2.5 
9.1 
2.6 
9.6 
2.8 
10.4